Frailty and the Geriatric Assessment

Evaluating the Older Patient with Cancer:

Understanding Frailty and the Geriatric Assessment
Sumanta Kumar Pal, MD1; Vani Katheria, BSc2; Arti Hurria, MD3

Abstract
The majority of cancer incidence and mortality occurs in individuals aged older than 65 years, and the number of
older adults with cancer is projected to signicantly increase secondary to the aging of the US population. As such,
understanding the changes accompanying age in the context of the cancer patient is of critical importance. Agerelated changes can impact tolerance of anticancer therapy and can shift the overall risk-benet ratio of such
treatment. A challenge in implementing evidence-based approaches in older adults is the underrepresentation of
this group in oncology clinical trials. In addition, although older adults are particularly vulnerable to the side effects
of cancer therapy, few oncology studies to date have incorporated a measure of health status other than the
Eastern Cooperative Oncology Group or Karnofsky performance scales. Novel metrics such as frailty indices or the
geriatric assessment recognize heterogeneity among older adults, and may allow for risk-adapted approaches to
therapy. It is increasingly recognized that several laboratory markers may predict morbidity and mortality in older
adults; these biologic variables may further aid in stratifying this group of patients based on risk. This review
describes key studies from the geriatric literature that provide principles for assessing health status in the older
patient, and ways that these principles can be applied to oncology care in an older population are proposed. CA
Cancer J Clin 2010;60:120132. 2010 American Cancer Society, Inc.

Introduction
Estimates from the US Census Bureau predict a rapid rise in the number of individuals aged older than 65 years.1
Furthermore, the number of individuals over the age of 65 years and 85 years is projected to double to nearly 62
million and 10 million, respectively, by the year 2030 and centenarians are anticipated to be the fastest-growing
group within this demographic.2 Of particular concern in this population is the association between cancer and
aging. It is estimated that 1,479,350 new cases of cancer were diagnosed in 2009, and 562,340 deaths occurred.3
Of these, it is projected that approximately 60% of cancer incidence and 70% of cancer-related mortality will occur
in individuals aged older than 65 years, with even more pronounced gures reported for specic diseases.4-6
Several unique concerns arise in the older adult with cancer. With increasing age, physiologic reserve decreases;
however, the pace of this decline varies with each individual.7 Similarly, variations in functional status, cognition,
and comorbidity accompany increased age, and may affect life expectancy, risk of subsequent functional decline,
hospitalization, and other morbidity.8-11 These age-related changes can inuence tolerance to cancer therapy, as
well as the overall risk-benet ratio of cancer treatment. The rate of these changes also varies between individuals.
Although older adults have been identied as being vulnerable to side effects from cancer therapy, few oncology
studies to date have specically incorporated baseline metrics for measuring health conditions other than
functional status (Eastern Cooperative Oncology Group [ECOG] or Karnofsky performance status [PS]) to
1
Assistant Professor, Division of Genitourinary Malignancies, Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive
Cancer Center, Duarte, CA; 2Cancer Control and Population Sciences Program, City of Hope Comprehensive Cancer Center, Duarte, CA; 3Associate Professor,
Department of Medical Oncology and Experimental Therapeutics, Cancer Control and Population Sciences Program, and Director, Cancer and Aging Research
Program, City of Hope Comprehensive Cancer Center, Duarte, CA.

Corresponding author: Arti Hurria, MD, Department of Medical Oncology and Experimental Therapeutics, Cancer Control and Population Sciences Program, and Director,
Cancer and Aging Research Program, City of Hope Comprehensive Cancer Center, Duarte, CA 91010; ahurria@coh.org
DISCLOSURES: The authors reported no conicts of interest.
2010 American Cancer Society, Inc. doi:10.3322/caac.20059.
Available online at http://cajournal.org and http://cacancerjournal.org

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CA CANCER J CLIN 2010;60:120132

identify individuals most at risk.

Furthermore, older adults have
been under-represented in oncology clinical trials, and only a few
studies published to date have focused on individuals who are considered physically unable to receive standard cancer therapy.12,13
Because the oncology literature
provides little data regarding the
subject, general principles from
the geriatric literature can be used
to guide the oncologist in identifying those patients who are frail
and at high risk for functional decline, hospitalization, institutionalization, and mortality.
In this review, we describe key FIGURE 1. Cycle of Frailty. VO2max indicates maximum oxygen consumption. Adapted with permission from
LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med
studies from the geriatric litera- Fried
Sci. 2001;56:M146M157.15
ture, and propose an application
of these studies to care in an
physical activity. Measurable parameters for each of
older oncology population. We also discuss potential
these variables were developed, and are described in
biologic markers of aging, which provide an insight
Table 1. With data from 5317 patients assessed, apinto clinical manifestations.
proximately 7% of the study population was considered
frail (meeting greater than 3 frailty criteria), and 47%
Understanding Frailty
were considered to be prefrail (meeting 12 frailty criUntil recently, a consistent denition of frailty remained
teria). There was an association noted between frailty
elusive. However, emerging data are providing a uniand 5 adverse outcomes: 1) hospitalization, 2) falls, 3)
form denition of frailty within the geriatric population.
worsening activity of daily living (ADL) disability, 4)
A position statement from the American Medical Asworsening mobility disability, and 5) death (P .0001
sociation dened the term frailty as characterizing
for all) (Fig. 2). Patients currently undergoing treatment
the group of patients that presents the most complex
for cancer were excluded from enrollment. Nevertheand challenging problems to the physician and all
less, the number of patients with cancer (not receiving
health care professionals, because these are the indiactive treatment) did not differ signicantly between
viduals who have a higher susceptibility to adverse outthe frail, prefrail, and nonfrail groups (14%, 15%, and
comes, such as institutionalization or mortality.14-16
16%, respectively; P .42). As such, the effects of a
cancer diagnosis on frailty are difcult to assess in this
study. However, distinct demographic characteristics
Clinical Manifestations of Frailty
associated with the frail population were identied,
including older age, female gender, and African AmerPhenotype Derived from the Cardiovascular
ican race.17
Health Study
Data from the Cardiovascular Health Study (CHS)
have been used to construct a widely cited denition of
frailty.15 Based on a proposed cycle of frailty (Fig. 1),
the investigators posited that 5 variables estimated a
phenotype of frailty: 1) shrinking (weight loss), 2)
weakness, 3) poor endurance, 4) slowness, and 5) low

Womens Health and Aging Studies

The Womens Health and Aging Studies (WHAS) I
and II were used to further validate the results of the
CHS.18 In the WHAS studies, previously established
criteria were used to stratify women into 1 of 3 tertiles
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TABLE 1. Frailty Criteria Proposed in the Cardiovascular Health Study15

FRAILTY CRITERIA

CHARACTERISTIC

Shrinking

Weight loss (unintentional) of 10 lbs in prior y OR

Weight loss at follow-up of 5% of body weight in prior y (by direct measurement of weight).

Weakness

Grip strength in the lowest 20% at baseline, adjusted for gender and BMI.

Poor endurance
and energy

Poor endurance and energy as indicated by self-report of exhaustion.

Self-reported exhaustion, identied by 2 questions from the CES-D scale, is associated with
stage of exercise reached in graded exercise testing as an indicator of VO2 max and is predictive
of cardiovascular disease.

Slowness

Slowest 20% of the population was dened at baseline based on time to walk 15 ft, adjusting
for gender and standing height.

Low physical level

of activity

Weighted score of Kcal expended per wk was calculated at baseline, based on each
participants report.
Lowest quintile of physical activity was identied for each gender.

BMI, body mass index; CESD, Center for Epidemiologic Studies Depression Scale; VO2 max, maximum oxygen consumption; Kcal, kilocalories.

of disability.19 WHAS I enrolled women aged 65 years

and older who were in the most disabled tertile among
the community-dwelling population (N1002). In
contrast, WHAS II enrolled women ages 70 to 79 years
who were in the 2 least disabled tertiles (N436). With
a slight modication of the 5 criteria derived from the
CHS (Table 2), there was agreement to within 7% in
the frequency of frailty in the 2 studies. Furthermore,
the criteria predicted mortality in the WHAS experience. The Three-City Study conducted in France,
however, yielded different results.20 Using the same
criteria, a similar proportion of frail individuals (7%)
was identied in a population of 6078 communitydwelling older men and women. Although frailty was
found to be associated strongly with the need for assistance with ADLs and instrumental ADLs (IADLs)
(Table 3), it failed to predict adverse outcomes such as
hospitalization or mortality.

FIGURE 2.

Incidence of Adverse Outcomes Associated With Frailty. The

3-year outcomes denoted here were adapted from Table 6 in Fried LP, Tangen
CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol
A Biol Sci Med Sci. 2001;56:M146M157.15

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In an effort to simplify the CHS model, the Study

of Osteoporotic Fractures (SOF) index was examined. The SOF index includes just 3 components
(weight loss, inability to rise from a chair, and poor
energy). In separate analyses of 3130 older males and
6701 older females, the SOF index demonstrated
predictive capabilities for morbidity and mortality
similar to a slightly modied CHS frailty index.21,22
Retornaz et al assessed the 5 CHS frailty markers
(Table 1) in addition to mood and cognition in 50
chemotherapy recipients aged 70 years and older.23
Although this analysis did not provide data regarding
clinical outcome based on these measures, it did
appear that the use of this wide panel of frailty
makers identied a distinct group of patients compared with the assessment of ADL and IADL dependency alone. In fact, 42% of patients included in
the study had no ADL or IADL disability, but
nonetheless had more than 1 frailty marker.
Bylow et al described a theoretical framework for
the development of frailty in the setting of androgen
deprivation therapy (ADT) for prostate cancer.24 Existing data support an association between ADT and
each of the 5 CHS frailty markers. For example,
unintentional lean weight loss (as a consequence of
sarcopenia) frequently occurs in older adults receiving
ADT.25 Sarcopenia consequently leads to increases in
weakness and decreases in mobility, 2 separate components of the CHS frailty model. Finally, ADT has
been associated with both fatigue and lowered physical activity, which are the remaining components of
the model.26 Prospective studies are needed to validate this theoretical framework.

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TABLE 2. Frailty Dened by the Womens Health and Aging Study and the Cardiovascular Health Study18
FRAILTY
CRITERIA

CHS

WHAS

Weight loss

Lost 10 lbs unintentionally in last y

10% weight loss compared with weight at age 60 y

OR
BMI at examination 18.5 kg/m2

Exhaustion

Self-report of either:
Feeling everything I did was an effort in the last wk
Could not get going in the last wk

Self-report of any:
Low usual energy level (3; range, 0-10)a
Felt unusually tired in the last mo
Felt unusually weak in the past mo

Low energy
expenditure

MLTA questionnaire (short version)

Evaluating all 18 items
270 Kcals per wk on activity scale

MLTA questionnaire (short version)

Evaluating 6 of 18 items:
- Walking
- Strenuous household chores
- Strenuous outdoor chores
- Dancing
- Bowling
- Exercise
90 Kcals per wk on activity scale

Slowness

Walking 15 ft (4.57 m):

Time 7 s for height 159 cm
Time 6 s for height 159 cm

Walking 4 m:
Walking speed (m/s) same as the CHS criteria

Weakness

Grip strength (in kg) in dominant hand, measured by

a Jamar handheld dynamometer:
17 for BMI 23 kg/m2
17.3 for BMI of 23.1-26 kg/m2
18 for BMI of 26.1-29 kg/m2
21 for BMI 29 kg/m2

Grip strength:
Same as CHS criteria

Overall frailty
status

Robust: met none of the criteria

Intermediate: met 1 or 2 criteria
Frail: met 3 criteria

CHS indicates Cardiovascular Health Study; WHAS, Womens Health and Aging Study; BMI, body mass index; MLTA, Minnesota Leisure Time Activity; Kcals,
kilocalories.
a

Rated on a scale of 0-10, in which 0 indicates no energy and 10 indicates the most energy that you have ever had.

Canadian Study of Health and Aging

Data from the Canadian Study of Health and Aging
(CSHA) were used to validate a separate set of frailty
criteria derived from the Geriatric Status scale. This
tool utilizes both functional and cognitive criteria in
the denition of frailty (Table 4).16 The CSHA
included 9008 adults aged 65 years and older, with a
baseline assessment and 5-year follow-up for adverse
outcomes. In this model, the prevalence of frailty was
TABLE 3. ADLs and Instrumental ADLs125
ADLS

IADLS

Bathing
Dressing
Toileting
Transferring
Continence
Feeding

Ability to use telephone

Shopping
Food preparation
Housekeeping
Laundry
Mode of transportation
Ability to take own medications
Ability to handle nances

ADLs indicates activities of daily living; IADLs, instrumental ADLs.

lower than that identied by the CHS; specically,

frailty was identied in 0.7%, 2%, and 4%, respectively, of patients ages 65 to 74 years, 75 to 84 years,

TABLE 4. Frailty Markers Proposed in Canadian Study of

Health and Aging16
MARKERS

CHARACTERISTICS

Able to walk without assistance

Able to perform ADLs without assistance

Bladder incontinence only

2 (Mild frailty)

1 or more of the following (2 if

incontinent):
Needs assistance with mobility or ADLs
Cognitive impairment without dementia
Bowel or bladder incontinence

3 (Moderate/severe frailty)

2 or more of the following (3 if

incontinent):
Totally dependent for transfers
Totally dependent for 1 or more ADLs
Bowel or bladder incontinence
Diagnosis of dementia

ADLs indicates activities of daily living.

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and 85 years and older. Similar to the previous studies, frailty served to predict mortality, and was associated with poor self-ratings of health, more comorbid illness, and increased social isolation. Data
pertaining to specic comorbidities, including cancer
diagnosis, were not reported in this analysis.

Balducci Frailty Criteria

Although the above frailty models provide important
prognostic information for the geriatric population at
large, to the best of our knowledge, data applicable to
oncology patients are lacking. Frailty criteria for older
adults with cancer have been proposed, combining
elements of existing denitions. For example, the
Balducci criteria are derived in part from observations
reported in a study by Winograd et al assessing
predictors of mortality and institutionalization
among male patients aged 65 years and older at the
Palo Alto Veterans Affairs Medical Center.27 Winograd et al identied functional impairment, comorbidity, and the presence of geriatric syndromes as
predictors. The Balducci frailty criteria (Table 5)
supplement these predictors with a criterion of age
older than 85 years, given the purported high incidence of functional and cognitive changes in this
demographic.28
Mohile et al evaluated the Balducci frailty criteria
using data from the 2003 Medicare Beneciary Survey.29 With analysis restricted to 12,480 communitydwelling individuals aged 65 years and older, a total
of 2349 patients (19%) were identied with a cancer
diagnosis (excluding skin cancer). Dementia or
memory loss, inability to perform ADLs, and geriTABLE 5. Balducci Criteria for Frailty125
FRAILTY CRITERIA

CHARACTERISTICS

Age

85 y

ADLs

Dependence for 1 or more

Comorbidity

3 or more

Geriatric syndromes

One or more of the following:

Delirium
Dementia
Depression
Osteoporosis
Incontinence
Falls
Neglect and abuse
Failure to thrive

ADLs indicates activities of daily living.

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atric syndromes were assessed by self-report. Subjects

satisfying the Balducci criteria for frailty were ultimately found to be more common in the cancer
group versus the noncancer group (80% vs 73%;
P .001). Eight cancer subtypes were also examined
in this multivariate analysis: lung, colon, breast, cervical/uterine, prostate, bladder, ovarian, or other.
Ultimately, a diagnosis of colon cancer (odds ratio
[OR], 1.40; 95% condence interval [95% CI], 1.021.93 [P .04]), breast cancer (OR, 1.32; 95% CI,
1.01-1.72 [P .04]), prostate cancer (OR, 1.45;
95% CI, 1.16-1.80 [P .001]), and bladder cancer
(OR, 2.04; 95% CI, 1.21-3.43 [P .007]) were
found to be signicantly associated with frailty. Furthermore, it was found that a cancer diagnosis (compared with no cancer diagnosis) was associated with
poorer self-rated health (OR, 1.46; 95% CI, 1.291.65 [P .001]).

Using a Geriatric Assessment to

Predict Morbidity and Mortality
Although composite criteria for frailty have been
devised to characterize older adults, the comprehensive geriatric assessment contains domains with independent predictive capabilities, including an evaluation of functional status, comorbid medical
conditions, cognitive function, psychological state,
social support, nutritional status, and geriatric syndromes. Each of these domains predicts the risk of
morbidity and mortality in older adults. The domains
of the geriatric assessment are described below.

Functional Status
Functional status is a strong predictor of morbidity
and mortality in the geriatric population.30 Although
functional status can be measured in many different
ways, a commonly used tool for evaluating functional
status is the ability to complete ADLs and IADLs.
ADLs are those basic self-care skills required to maintain independence in the home, such as the ability to
bathe, dress, toilet, transfer, maintain continence, and
feed oneself.31 IADLs are those skills required to maintain independence in the community, such as the ability
to use the telephone, shop, prepare meals, do housekeeping or laundry, take transportation, take medications, and handle nances.32 Available guidelines recommend assessment of the ability to complete ADLs
and IADLs on an annual basis in patients aged older

CA CANCER J CLIN 2010;60:120132

than 70 years.33,34 These guidelines may be particularly

relevant among older adults with cancer because large
epidemiologic studies have reported that a substantial
proportion of older patients with cancer need assistance
with the performance of ADLs and IADLs.35 Although 70% to 80% of older adults with cancer present
with an ECOG PS of 0 to 1, greater than half require
assistance with IADLs.36
The need for ADL and IADL assistance is reported to be predictive of mortality in the geriatric
population.9,37 More recently, need for assistance
with IADLs has been shown to have the same predictive capability among older adults with cancer.38
This relation has also been explored in a diseasespecic setting. In a comparison of single-agent or
combination chemotherapy in older adults with non
small cell lung cancer, the need for assistance with
IADLs was found to be correlated with poorer survival on multivariate analysis (P .04).39 The need
for functional assistance may be dependent on stage
of disease. An observational study including 1398
cancer patients suggested that the need for assistance
with ADLs was more common in hospitalized patients with metastatic cancer compared with patients
with nonmetastatic cancer (31% vs 22%, respectively;
P .0001).40 It appears that among cancer survivors,
a greater need for functional assistance persists compared with age-matched controls.41
In addition to mortality, assessment of functional
impairment in older adults with cancer may correlate
with other unique clinical outcomes. For example, the
need for assistance with IADLs appeared to predict
postoperative complications in a series of older adults
undergoing cancer-related surgery (P .043).42 Similarly, in a series of patients with ovarian cancer receiving
standard cytotoxic chemotherapy, the need for functional assistance (dened as living at home with assistance or living in an institution with medical assistance)
was found to be predictive of severe treatment-related
toxicity (P .048).43 Observational data have indicated
that pain severity in older adults with cancer is correlated directly with ADL and IADL disability.44 Functional impairment has also been linked more recently to
psychological status in older adults with cancer. The
need for assistance with IADLs has been reported to be
correlated signicantly with the incidence of psychological distress in a population of older adults with cancer
(P .0001).45

Comorbidity
The extent of comorbidity increases with age, and
increasing comorbidity may substantially affect morbidity and mortality in older adults with cancer.46,47
This was illustrated in an observational study of
17,712 patients with a new primary diagnosis of
cancer, in which survival was found to be inversely
related to age and comorbid medical conditions had
an impact on survival independent of cancer stage.46
Similar ndings have been noted in disease-specic
studies. For example, in a retrospective cohort study
of 29,733 patients aged 67 years and older with
nonmetastatic colorectal cancer, comorbid conditions
were found to be signicantly associated with mortality (P .001).48 A similar impact of comorbidity
on survival was demonstrated in a study of 936
women with early stage breast cancer. Patients with 3
or more of 7 selected comorbid medical conditions
were 20 times more likely to die from causes other
than breast cancer, and patients with severe comorbidity were uniformly found to have higher mortality
rates compared with patients who had no comorbid
conditions.49
Comorbidity may also have a substantial impact on
tolerance of anticancer therapy. A prospective assessment comparing vinorelbine alone or in combination
with gemcitabine in patients aged older than 70 years
identied an association between a Charlson Comorbidity Index (CCI) score of 2 or higher and treatment
discontinuation.50 Similarly, an assessment of 162
patients aged older than 60 years who were treated
with dose-dense chemotherapy for stage I to III
breast cancer suggested that a CCI score of 1 or
higher was associated with an increased risk of grade
3 and 4 toxicities. It is interesting to note that 22% of
patients in this study discontinued therapy prior to
the planned 8 cycles of treatment.51 Certain comorbidities may also have a specic impact on treatment
tolerance. For example, hypertension may lead to an
increased rate of both trastuzumab-related and anthracycline-related cardiomyopathy.52,53
Comorbidity also has practical implications for
cancer screening. Guidelines from the US Preventive
Services Task Force (USPSTF) and the American
Cancer Society (ACS) advocate consideration of comorbid illness and associated prognosis when implementing screening for colorectal and breast cancer.54
For example, ACS guidelines indicate that screening
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for colorectal cancer may be discontinued in those

patients with severe comorbidity that would preclude
treatment.55 Similarly, USPSTF guidelines for breast
cancer suggest that screening may be unnecessary in
women with comorbid conditions that limit life expectancy.56 An inherent challenge in implementing
these guidelines is the determination of an accurate
prognosis.

Psychological State
A link between depression and aging has been established in several epidemiologic studies. It is estimated
that 12% to 20% of community-dwelling persons
aged 65 years and older experience signicant depressive symptoms.57-59 Similarly, the link between depression and cancer has long been acknowledged.60
Depressive symptoms are particularly prominent
among older, terminally ill, cancer patients. In one
report, increasing age was paralleled by an increasing
likelihood for thoughts of hurting oneself or feeling
better off dead.61,62 The incidence of suicide has, in
fact, been noted to be higher among older adults with
cancer compared with older adults diagnosed with
another medical illness.63 The use of psychosocial
interventions may be effective in this population, and
the majority of randomized controlled trial (RCT)
data assessing psychosocial interventions support this
strategy.64 These services may be underutilized in an
older population. A study of 326 patients with metastatic gastrointestinal or lung cancer demonstrated
that 100% of patients aged younger than 40 years
with depressive symptoms were referred for psychosocial oncology care.65 In contrast, only 22% of patients aged 70 years and older with depressive symptoms were similarly referred. With regard to
pharmacotherapy, a review of RCTs for depression
interventions identied the use of selective serotonin
reuptake inhibitors (SSRIs) for 6 weeks and longer as
an effective strategy in depressed patients with cancer.64 However, the potential for interaction between
anticancer agents (eg, tamoxifen) and SSRIs is an
important consideration.66

A Surveillance, Epidemiology, and End Results

(SEER)Medicare database review assessed women
aged 65 years and older with a diagnosis of breast
cancer.69 Those who were unmarried had a higher
likelihood than married women of being diagnosed
with stage II to IV breast cancer versus stage I disease. Furthermore, unmarried women with stage I or
II breast cancer were less likely to receive chemotherapy. To the best of our knowledge, limited data exist
to guide interventions for older adults with cancer
who lack social support. In one study, unmarried
patients or those living alone were more frequently
referred for psychosocial oncology care; however, as
previously noted, other studies indicate that these
services are underutilized among older adults with
depressive symptoms.65

Cognitive Function
Declines in cognitive function are associated with
both increasing age and an increased risk for all-cause
mortality.70,71 In the setting of oncology, cognitive
impairment may be associated with a delay in the
diagnosis of cancer. For example, a SEER-Medicare
review examining 17,507 individuals aged 67 years
and older with invasive colon cancer found that a
diagnosis of colon cancer after death (ie, by autopsy
or death certicate) was more than twice as likely to
occur in patients with dementia.72 A diagnosis of
cognitive impairment may also alter clinical decisionmaking in geriatric oncology. A review of the New
Mexico Tumor Registry identied a correlation between decreased mental status (assessed via a screening test of cognitive function) and nonreceipt of
denitive surgery in 669 cancer patients aged 65 years
and older.73 The risk of cognitive impairment with
anticancer therapy appears to have a strong bearing
on patient decision-making as well. In a survey of
patients aged 60 years and older with cancer, congestive heart failure, or chronic obstructive pulmonary disease and a limited life expectancy, the majority of patients (89%) said they would refuse lifeprolonging therapy if it resulted in severe cognitive
impairment.74

Social Support
In older adults, studies have identied an association
between social isolation and mortality.19,67,68 Available social support may also play a role in the diagnosis and treatment of the older adult with cancer.
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Polypharmacy
Older adults may be particularly susceptible to polypharmacy, given the increased number of comorbidities in this population.75 Polypharmacy raises the

CA CANCER J CLIN 2010;60:120132

likelihood of adverse drug reactions (ADRs) in older

cancer patients, and has been associated with increased mortality.76,77 Certain drug classes are implicated in a higher frequency of ADRs, including
anticoagulants (specically warfarin) and benzodiazepines.78 Notably, both medications are frequently
used in the treatment of oncology patients (warfarin
for cancer-related thrombosis, and benzodiazepines
for the management of anxiety or chemotherapyrelated emetogenesis).62,63 Pharmacist-based medication review programs may reduce polypharmacy and
the associated frequency of ADRs, although follow-up is needed to determine whether such programs have a substantial impact on clinical outcome
in older adults with cancer.79

Nutrition
Several studies in community-dwelling older adults
have identied an association between a low body
mass index (BMI) and an increased risk of mortality
(relative to a normal BMI), underscoring the importance of adequate nutrition.80,81 Adequate nutrition is
particularly important in patients with cancer. In an
analysis of 3047 patients enrolled in ECOG protocols across multiple malignancies, weight loss was
associated with lower response rates to chemotherapy
and decreased survival.82 The observation of poorer
clinical outcome in patients with cancer and concomitant weight loss has also been made in diseasespecic studies of patients with small cell lung cancer
and gastrointestinal malignancies.83,84
The nutritional evaluation of older patients should be
expanded in the setting of cancer to include treatmentrelated considerations. For example, treatment-induced
nausea, vomiting, or mucositis can impede oral intake.
Furthermore, cancer-related fatigue can hinder the patients ability to shop for food and cook, thereby compromising nutritional status. Various screening tools
assess nutritional status in the older adult, beyond BMI
alone. These tools are listed in Table 6.85

Geriatric Syndromes
Geriatric syndromes (Table 5) are of particular relevance in the cancer patient, and appear to increase
with age.86,87 In the study of Medicare beneciaries
by Mohile et al, a signicant association was found
between a diagnosis of cancer and a geriatric syndrome (OR, 1.27; 95% CI, 1.151.41).29 These syn-

TABLE 6. Screening Tools to Assess Nutritional Status

TOOL

COMPONENTS

Malnutrition Universal
Screening Tool

BMI
Weight loss within the past 3-6 mo
No nutritional intake in 5 d
Acute illness

Short Nutritional Assessment

Questionnaire

Involuntary weight loss

Loss of appetite
Use of tube feeding or supplemental
drinks

Mini Nutritional Assessment

Reduction in food intake

Weight loss
BMI
Mobility
Acute psychological distress or acute
disease
Neuropsychological problems: dementia
or depression

Nutritional risk score

Undernutrition (BMI, % weight loss,

change in food intake)
Severity of disease

BMI indicates body mass index.

dromes have, in turn, been linked to multiple adverse

clinical outcomes.88 Interventions have been devised
to combat the progression of geriatric syndromes,
and data from a randomized study indicate that these
interventions result in improved functional abilities
and mental well-being in vulnerable older adults.89

Geriatric Assessment in Oncology

Practice
The geriatric assessment has emerged as a useful
oncology tool. It adds information to more generalized measures of functional status usually employed
in oncology, such as the Karnofsky or ECOG PS.
Repetto et al juxtaposed assessment by ECOG PS
and by geriatric assessment in a cohort of 363 patients admitted with a diagnosis of a solid or hematologic malignancy.90 Elements of the geriatric assessment used in this study included demographic
characteristics, physical function, disability, depression, and cognitive status. Components of the geriatric assessment and ECOG PS were found to be
strongly associated. For example, the presence of
ADL or IADL dependence conferred a 5-fold higher
risk of poor PS (ECOG PS of 2 or higher). However,
no association between comorbidity and PS was observed in this study. Presumably, these data suggest
that although some domains of the geriatric assessment (ie, disability assessment) may serve as a surroVOLUME 60 NUMBER 2 MARCH/APRIL 2010

127

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gate for PS, other components (such as comorbidity)

may offer supplementary information that could augment its prognostic value.
A similar tool has been applied in a disease-specic
setting. The geriatric assessment was used to characterize a series of 84 patients (age 65 years and older) who
were treated for diffuse, large B-cell lymphoma at a
single institution.91 The majority of patients (74%) received either the combination of cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP) or a
CHOP-like regimen. A total of 42 patients were characterized by the geriatric assessment as t. Response
rates (93% vs 49%; P .0001) and median survival (not
reached vs 8 months; P .0001) were found to be
superior in the patients characterized as t compared
with those characterized as unt. Approximately half of
the patients deemed unt were treated with palliative
therapy, whereas the remainder was treated with curative intent. There did not appear to be a survival difference in either strategy, raising the possibility that
patients characterized as unt or frail may derive similar
benet from palliative approaches. Thus, use of a geriatric assessment may aid in therapeutic decision-making, although additional studies are needed.
The geriatric assessment may further aid in predicting treatment toxicity. A prospective analysis
conducted at several French institutions over a 12year interval (1988-2000) included 83 patients aged
70 years and older with advanced ovarian carcinoma
who were treated with carboplatin and paclitaxel.43 A
geriatric assessment was performed prior to the initiation of therapy. Ultimately, several elements of the
geriatric assessment predicted the occurrence of severe toxicity with chemotherapy, including depression (P .003) and intake of 6 or more nonchemotherapy medications per day (P .043).
The geriatric assessment has also been correlated
with outcomes from surgical resection of solid tumors.
Using the Pre-operative Assessment of Cancer in the
Elderly (PACE) tool, which combines traditional elements of the geriatric assessment with surgery-specic
metrics, a cohort of 460 patients aged older than 70
years who underwent cancer-related surgery were evaluated preoperatively.92 On univariate analysis, ADL or
IADL dependence and poor ECOG PS (higher than
2) were found to be associated with a longer hospital
stay. On multivariate analysis, components of the
PACE tool were found to correlate with postoperative
complications, including increased fatigue score (ac128

CA: A Cancer Journal for Clinicians

cording to the Brief Fatigue Inventory), ECOG PS

(greater than 2), and IADL dependence.
As a logical extension of the prognostic and predictive capabilities of the geriatric assessment, the
tool has been applied prospectively to guide the treatment of older adults with cancer. In a study of 245
patients with cancer who were aged 65 years and
older, a self-administered questionnaire including all
domains of the geriatric assessment was used to guide
referrals to a multidisciplinary team consisting of
social workers, psychiatrists, nutritional services,
ophthalmologists, otolaryngologists, and rehabilitation specialists.93 In addition, referrals were made to
community resources (ie, visiting nurses or home
health aides) on the basis of the questionnaire, and
communication was initiated with the patients primary care provider to assist in managing comorbid
medical conditions that could be exacerbated by the
cancer. The self-administered format of the geriatric
assessment appeared to be feasible, with patients
completing the questionnaire within an average of 15
minutes. The Cancer and Leukemia Group B
(CALGB) is leading an effort to evaluate the feasibility of incorporating a primarily self-administered
geriatric assessment94 into its ongoing protocols
(CALGB 360401).95 Efforts such as these may ultimately aid in prospectively validating the stratication of treatment by geriatric assessment result.

Biological Markers of Frailty

Emerging laboratory research has identied molecular
markers that may be associated with frailty. With increasing age, levels of the proinammatory cytokine
interleukin-6 (IL-6) and C-reactive protein (CRP)
demonstrate concomitant increases.96-98 Both appear to
play a role in the development of the frailty criteria
established in the CHS, including weight loss. Hubbard et al assessed frailty characteristics and cytokine
levels in 3 groups of patients: 1) 40 patients housed in
an inpatient geriatric ward (median age, 85 years), 2) 40
patients attending a day hospital (median age, 83 years),
and 3) 30 healthy controls (median age, 23 years).99
Increases in IL-6 and CRP were paralleled by a decrease in BMI and increasing frailty. In separate studies,
increases in IL-6 and CRP have been associated with
other domains of the frailty assessment, including poor
walking speed and grip strength.100 In addition, Ddimer and other coagulation markers may play a prog-

CA CANCER J CLIN 2010;60:120132

nostic role in this population. An assessment of IL-6

and D-dimer in 1723 older adults indicated that higher
circulating levels of these markers were correlated with
an increased risk of mortality.101 Furthermore,
D-dimer, factor VIII, and CRP levels in 4735 patients
enrolled in the CHS were found to be associated with
clinical frailty.102
Levels of insulin-like growth factor 1 (IGF-1) decline with advancing age, and there is some indication
that this molecular mediator may also play a key role in
the pathogenesis of frailty.103,104 In the WHAS I study,
low IGF-1 and high IL-6 levels were associated with a
marked increase in walking limitation. Furthermore, in
the subset of patients with low IGF-1 and high IL-6
levels, an increase in mortality was observed; at 5 years
of follow-up, approximately 46% of these patients had
died compared with 23% of patients with high IGF-1
and low IL-6 levels.105 Levels of CXC chemokine ligand 10 (CXCL10) have also been associated with the
development of frailty.106 CXCL10 is a proinammatory chemokine associated with several autoimmune
diseases, such as multiple sclerosis and autoimmune
thyroiditis.
The molecular markers noted to predict frailty may
also play a prognostic role in the setting of cancer.
For example, elevated CRP has been associated with
poorer survival in patients with localized renal cell
carcinoma, and high D-dimer has been shown to
predict poorer survival and disease progression in
patients with metastatic colorectal cancer.107,108 In
addition, IL-6 may be associated with a poorer prognosis in patients with breast cancer, perhaps by upregulating levels of angiogenic mediators such as
vascular endothelial growth factor.109 Elevated IL-6
has also been linked to worsened clinical outcome in
patients with advanced nonsmall cell lung cancer,
and may be useful in differentiating hormone-refractory prostate cancer from hormone-sensitive disease
or benign prostatic conditions.110,111 Ultimately,
these molecular markers may guide therapy for the
older adult with cancer. Several of these markers
(IL-6, IGF-1, and CXCL10) serve as targets for
anticancer agents currently in development.73,112,113

Frailty as a Dynamic Process: The

Potential for Intervention
Regardless of the schema used to classify frailty, the
imperative is to nd ways to identify transitions be-

tween clinical states (ie, from normal to prefrail, or from

prefrail to frail) because these intermediaries offer opportunities for intervention. Data from the CHS did
identify a greater risk for the development of frailty in
those patients characterized as prefrail.15 For example,
patients classied as prefrail at baseline (demonstrating
1 or 2 frailty characteristics) were found to have more
than double the risk of becoming frail at 3 to 4 years of
follow-up (OR, 2.63; 95% CI, 1.94-3.56 [P .001]).
A prospective exploration of this phenomenon was reported by Gill et al, in which 754 community-dwelling
individuals aged 70 years and older were assessed for
frailty at 18-month intervals for a total of 54 months.114
Using the CHS frailty markers, it was noted that
greater than half of the patients (58%) experienced a
transition in frailty status during the evaluation period.
Transitions between nonfrail and prefrail states were
consistent throughout the study period; in contrast, the
probability of going from the frail to the prefrail state
decreased over time; only 2 patients had their status
change from frail to nonfrail. With extended follow-up,
the probability of death in the frail group increased over
time. The likelihood of death in this group of patients
compared with the nonfrail or prefrail groups was 3 to
5 times higher, depending on the study period. This
suggests that frailty represents a dynamic process, underscoring the potential for developing strategies to
impede its progression.
Efforts are currently ongoing in the search for ways
to reduce the progression of functional decline. A randomized trial in frail adults comparing those receiving
intensive, home-based physical and occupational therapy with those undergoing a less rigorous educational
program indicated that the level of disability (dened by
ADL dependence) declined more rapidly in the patients in the latter group.115 Intervention studies have
aimed to mitigate functional decline in oncology patients through various targeted approaches. One such
study identied 641 overweight patients aged 65 years
and older with breast, colorectal, or prostate cancer.116
These patients were randomly assigned to receive either
a 12-month, home-based program of telephone counseling with mailed materials promoting sound physical
activity and dietary practices or the same intervention
after a 12-month period (representing the delayed
arm). In comparison with the delayed intervention,
immediate use of the intervention led to a lesser decline
in physical function, as classied by the Short-Form 36
metric.117,118
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Frailty and the Geriatric Assessment

Emerging data have suggested that pharmacologic

interventions might decrease the risk of frailty. An
analysis of nonfrail participants (ages 65-79 years) enrolled in the Womens Health Initiative Observational
Study demonstrated a signicant association between
the use of low-dose statins for a prolonged period and a
decrease in the risk of frailty, as dened by CHS criteria
(P .02).119 The authors postulate that reductions in
inammatory mediators (ie, IL-6 and CRP) associated
with statin therapy could lead to declines in frailty
characteristics. These data are particularly provocative
in the face of studies that have reported an association
between breast cancer and statin use.120-124

Conclusions
Several denitions of frailty have been described to date,
including those derived from the CHS, the CSHA, and
empiric criteria as dened by Balducci et al.15,16,28 The
challenge for the oncologist is to incorporate elements
from these denitions into a framework optimized for
the older adult with cancer. The geriatric assessment

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