Management of Cancer in the Older Person: A Practical Approach

Lodovico Balducci and Martine Extermann

The Oncologist 2000, 5:224-237.

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 Management of Cancer in the Older Person:
A Practical Approach
LODOVICO BALDUCCI, MARTINE EXTERMANN
Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
Key Words. Cancer · Elderly · Older person · Geriatric assessment · Pharmacokinetics
A BSTRACT
The management of cancer in the older aged person
is an increasingly common problem. The questions aris-
ing from this problem are: Is the patient going to die
with cancer or of cancer? Is the patient able to tolerate
the stress of antineoplastic therapy? Is the treatment
producing more benefits than harm?
This article explores a practical, albeit evolving,
approach to these questions including a multidimen-
sional assessment of the older person and simple phar-
macologic interventions that may ameliorate the
toxicity of antineoplastic agents. Age may be construed
as a progressive loss of stress tolerance, due to decline in
functional reserve of multiple organ systems, high
prevalence of comorbid conditions, limited socioeco-
nomic support, reduced cognition, and higher preva-
lence of depression. Aging is highly individualized:
chronologic age may not reflect the functional reserve
and life expectancy of an individual. A comprehensive
geriatric assessment (CGA) best accounts for the diver-
sities in the geriatric population. The advantages of the
CGA include:
A. Recognition of potentially treatable conditions
such as depression or malnutrition, that may
lessen the tolerance of cancer treatment and be
reversed with proper intervention;
B. Assessment of individual functional reserve;
C. Gross estimate of individual life expectancy; and
INTRODUCTION
In the US, 50% of all malignancies occur in persons
aged 65-95 [1-3]. With the increase in the older population,
it is expected that 60% of all cancers will be detected in
elderly patients in the next two decades [2]. The issues of
Correspondence: Lodovico Balducci, M.D., Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, Florida 33612, USA. Telephone 813-979-3822; Fax: 813-972-8468; e-mail: Balducci@moffitt.usf.edu
Website: http://www.moffitt.nsf.edu Received March 31, 2000; accepted for publication May 17, 2000. ©AlphaMed Press
1083-7159/2000/$5.00/0
The Oncologist 2000;5:224-237 www.TheOncologist.com
D. Adoption of a common language to classify older
cancer patients.
The CGA allows the practitioner to recognize at
least three stages of aging:
A. People who are functionally independent and with-
out comorbidity, who are candidates for any form
of standard cancer treatment, with the possible
exception of bone marrow transplant.
B. People who are frail (dependence in one or more
activities of daily living, three or more comorbid
conditions, one or more geriatric syndromes),
who are a candidate only for palliative treatment;
and
C. People in between, who may benefit from some spe-
cial pharmacological approach, such as reduction
in the initial dose of chemotherapy with subsequent
does escalations.
The pharmacological changes of age include
decreased renal excretion of drugs and increased sus-
ceptibility to myelosuppression, mucositis, cardiotoxic-
ity and neurotoxicity. Based on these findings, the
proposal was made that all persons aged 70 and older,
treated with cytotoxic chemotherapy of dose intensity
comparable to CHOP, receive prophylactic growth fac-
tor treatment, and that the hemoglobin of these
patients be maintained ≥12 gm/dl. The Oncologist
2000;5:224-237
geriatric oncology include: Is the patient going to die with
cancer or of cancer? Is the person going to suffer the com-
plications of cancer during his/her lifetime? Is the patient
able to tolerate the treatment safely? Will the treatment pro-
vide more benefits than harm? We explore these issues
 Balducci, Extermann 225

using cytotoxic chemotherapy as a model because cytotoxic relevant for treatment with anthracyclines, taxanes, and
chemotherapy has a wider array of side effects than other epipodophyllotoxins that are heavily bound to red blood cells
forms of cancer treatment. [5, 10-13]. The correction of anemia with erythropoietin may
This review consists of two parts: A) pharmacologic be particularly beneficial to older individuals, as anemia is
consequences of age, and B) individualized management of the only component of Vd that can be manipulated.
the older cancer patient. Aging is highly individualized in A decline in glomerular filtration rate (GFR) is one of
terms of life expectancy, functional reserve, social support, the most predictable changes associated with age [4, 5].
and personal preference [3]. To be effective, treatment plans This decline may lead to enhanced drug toxicity through
need to account for this diversity. two mechanisms:
A. Reduced excretion of active drugs, such as
CANCER CHEMOTHERAPY AND AGE
methotrexate, bleomycin, or carboplatin, or
Aging is associated with a progressive decline in the
functional reserve of multiple organ systems [3, 4]. This B. Reduced excretion of active metabolites whose parent
may influence pharmacokinetics (PK) and pharmaco- compounds are not excreted through the kidneys.
dynamics of antineoplastic drugs and reduce the tolerance Examples of these metabolites include idarubicinol
of normal tissues for treatment complications [4, 5]. from idarubicin, or daunorubicinol from daunorubicin
[5, 14-16].
PK of Aging
The effects of GFR decline on the management of older
Whereas the majority of PK parameters (Fig. 1) may
persons with cancer were highlighted by the study of Gelman
change with aging, the most consequential changes involve
and Taylor [17]. In a retrospective analysis these authors
volume of distribution (Vd) and renal excretion of drugs [4, 5].
demonstrated that the toxicity of a combination of cyclophos-
The Vd is a function of body composition, serum albumin,
phamide, methotrexate and fluorouracil (CMF) was mini-
and red blood cell concentration. With aging, the Vd of water-
soluble drugs decreases as a result of decline in total body mized, without reduction of the antineoplastic activity, when
water; drop in albumin and hemoglobin concentration may the doses of methotrexate and cyclophosphamide were
further restrict the Vd of these agents and enhance their toxic- adjusted to the GFR in women aged 65 and over.
ity. The incidence and prevalence of anemia increases with As one acknowledges the effects of renal function on
age, especially after 65 [6-9]. Anemia may be particularly cancer chemotherapy, one must also realize that the PK of
drugs are variable and the area under the concentration time
curve may not be fully predictable from the GFR. For
example, Borkowski et al. [18] studied the renal and plasma
PARENTERAL
ABSORPTION
ADMINISTRATION clearance of dichloromethotrexate in patients aged 70 and
older and in younger subjects. Whereas the renal clearance
of the drug declined with age, the plasma clearance did not,
P which is surprising because dichloromethotrexate is com-
H
A pletely excreted through the kidneys. This observation sug-
R
M gests alternative forms of drug disposition when the GFR
VOLUME OF A
DISTRIBUTION C declines. Thus, we cannot support a recommendation that
O
(Vd) K the dosage of antineoplastic agents be adjusted to the renal
I
HEPATIC N
E
function in all older individuals.
METABOLISM
T Age may influence the hepatic metabolism of drugs, but
I. C. I
EXCRETION C
METABOLISM
S
the consequences of this change on cancer chemotherapy are
Renal
Biliary largely unknown [5], partly because the study of this para-
THERAPEUTIC
EFFECT meter is complex. The hepatic metabolism of drugs is a func-
TOXICITY tion of the hepatic blood flow [19] of the rate of drug
extraction by the hepatocytes, and of the hepatocyte mass, in
addition to the intracellular concentration and activity of
drug-metabolizing enzymes [20]. Two types of drug-metab-
PHARMACODYNAMICS
olizing reactions occur within the liver [20]. Type I reactions
are oxydo-reductive reactions, that may generate both active
Figure 1. PK and pharmacodynamic parameters. and inactive metabolites of drugs, and involve the P450
226
cytochrome system. These reactions are influenced by other
medications, such as barbiturates or cimetidine, that may
augment or diminish the concentration and activity of the
P450 enzymes. Type II reactions are conjugative reactions,
that give origin to water-soluble compounds excreted
through the bile or urine. Some of the age-related changes in
liver function include:
• Decline in hepatic blood flow and hepatic mass [4].
• Decline in the intracellular activity of P450 cyto-
chrome enzymes. This decline is particularly pro-
nounced in the so-called “frail patients” (see below)
[21, 22]. Compounds that require intrahepatic activa-
tion, such as oxophosphorines (cyclophosphamide
and ifosfamide), should be avoided in frail patients.
• The risk of hepatic drug interactions may increase in
older individuals as polypharmacy becomes more
common with age [23].
Recently it was shown that the metabolites from type
II reactions may maintain some of the activity of the par-
ent compounds. For example, the 6 glucuronide of mor-
phine maintains opioid activity, and the half-life of this
metabolite, which is excreted through the kidneys, may
become more prolonged in older individuals, which
explains in part the increased sensitivity of the older person
to opioids [24-26].
Pharmacodynamics
Pharmacodynamic changes may influence both the
toxicity and antineoplastic activity of cytotoxic agents [5].
Rudd et al. reported cisplatin-induced DNA adducts
were cleared from circulating monocytes in 24 h in individ-
uals aged 50 and younger, and in more than 90 h in indi-
viduals aged 70 and older [27]. Delay in DNA repair may
cause enhanced toxicity in older individuals. Another
mechanism of increased toxicity may involve a delay in
intracellular drug catabolism. For example, the concentra-
tion of dehydropyrimidine dehydrogenase that catabolizes
fluorinated pyrimidines, may be reduced in the elderly [28].
Pharmacodynamic changes may cause resistance to cyto-
toxic chemotherapy in older individuals. At least three mecha-
nisms of multidrug resistance have been suggested
in the aged. The prevalence of myeloblasts expressing the
p-glycoprotein increases in patients with acute myelogenous
leukemia aged 60 and older [29]. The p-glyoprotein is encoded
by the multidrug resistance (MDR-1) gene, and is responsible
for extruding natural anticancer agents (antibiotics, plant
derivatives) from the tumor cells.
Tumors occurring in older individuals may be more likely
to manifest resistance to apoptosis because these neoplasms
Management of Cancer in the Older Person: A Practical Approach
may develop from senescent cells that are unable to undergo
apoptosis [30]. Resistance to apoptosis is another mechanism
of multidrug resistance because all cytotoxic agents kill neo-
plastic cells through apoptosis. Tumors occurring in older
individuals may manifest poorer oxygenation, due to com-
promised angiogenesis [31]. Hypoxia may be responsible for
resistance to alkylating agents and radiation therapy.
Susceptibility of Normal Tissues to the Toxicity
of Antineoplastic Drugs
The susceptibility of older tissues to the complications
of cytotoxic agents may be enhanced by at least three
mechanisms:
• Decreased stem cell reserve that may compromise the
recovery of tissue losses (Fig. 2). This mechanism
may be responsible for the complications concerning
rapidly renewing tissues, including the hemopoietic
tissue and mucosas [28, 32].
• Decreased ability to catabolize cytotoxic drugs and repair
the cellular damage of these drugs. This mechanism
may be operative in the majority of older tissues and
has already been described in circulating monocytes
and intestinal mucosas [27, 28].
• Critical reduction in functional tissue, so that the loss
of additional tissue may lead to organ failure. This
5 5 5
10
10
10
90 20 0
5 25
5
NORMAL REDUCED
PHSC REDUCED
PHSC
RESERVE
RESERVE PHSC
HOMEOSTASIS
RESERVE STRESS
HOMEOSTASIS
Figure 2. Stem cell reserve and toxicity of chemotherapy. Each figure consists of
four compartments: a circle representing the total stem cell population that is
arbitrarily established at 100; a square with dotted margin, representing the num-
ber of stem cells lost to commitment and differentiation; a small square repre-
senting the proliferative pool of the stem cells, and a large square representing the
stem cells that re-enter the general pool after replication. In condition of home-
ostasis for every five stem cells lost to commitment and differentiation, five stem
cells enter the proliferative pool and regenerate the initial pool of stem cells. This
occurs both when the stem cell reserve is intact and when it is moderately
depleted. In conditions of stress, however, the demand for commitment and dif-
ferentiation may overcome the ability of a reduced stem cell reserve to replicate
itself, and marrow failure may ensue.
 Balducci, Extermann 227

mechanism may be responsible younger patients. In a number of phase II studies involving

Table 1. Complications
of cytotoxic chemotherapy for the increase in the incidence different tumors, Giovannazzi-Bannon et al. showed the risk
more common in older of cardiomyopathy [33] and and severity of myelodepression did not increase with the
individuals neurotoxicity [5, 34, 35]. age of the patients [39]. These studies clearly demonstrate
Myelodepression that age itself is not necessarily a risk factor for myelotoxi-
Table 1 lists the complications of
Neutropenia city. However, all of these studies have the limitations typi-
Thrombocytopenia cytotoxic chemotherapy that become
cal of retrospective analysis:
Anemia? more common in older individuals.
Some controversy exists over • Older persons were underrepresented. Persons over
Mucositis
Oropharyngo-esophagitis whether the risk of myelotoxicity 70 made up only 10%-15% of the total patient popu-
Enterocolitis increases with the age of the patient. At lation, while 40% of all malignancies occur in this
Cardiodepression least five retrospective studies com- age group.
Peripheral neuropathy pared the incidence and severity of • The oldest old (i.e., patients aged 80 and older) were
Central neurotoxicity myelodepression in younger and older virtually absent.
Cognitive decline patients, and failed to demonstrate • Patients were highly selected in terms of performance
Delirium increased incidence, severity, or dura- status and comorbidity, as they all had been treated
Cerebellar dysfunction tion of myelodepression [17, 36-39]. according to cooperative groups or major cancer cen-
The study of Gelman and Taylor [17], ter protocols.
previously described, showed that the toxicity of CMF was
• The dose intensities of most chemotherapy regimens
not increased in patients over 65 receiving CMF for metasta-
were lower than those of current regimens.
tic breast cancer, when the doses of cyclophosphamide and
methotrexate were adjusted to the patient’s GFR. Christman A quite different picture emerges from the exam of a
et al. [36] compared women aged under 55, 55-70 and over number of clinical trials of large-cell lymphoma, that were
70, with metastatic breast cancer, treated according to the directed specifically to older patients (Table 2) [40-47].
protocols of the Piedmont Oncology Group. Ibrahim et al. With the exception of the study of Armitage [47], all stud-
[37] also compared women aged 70 and older and younger ies were prospective and involved treatment regimens with
women, treated according to the M.D. Anderson protocols a dose intensity comparable to CHOP. In three cases [41,
during a 15-year period. Beggs and Carbone [38] reviewed 43, 44], randomized controlled studies compared the bene-
the cases of patients treated according to 10 solid tumor pro- fits of CHOP (or CTVP, the French version of CHOP) with
tocols within the Eastern Cooperative Oncology Group a treatment regimen of lower toxicity, and demonstrated
(http://ecog.dfci.harvard.edu), and compared the risk and that CHOP produced the best outcome in terms of response
severity of myelotoxicity in patients aged 70 and older and rate and overall survival.

Table 2. Incidence of neutropenia, neutropenic fever, and treatment-related death among older individuals with non-Hodgkin’s lymphoma receiving
CHOP and CHOP-like chemotherapy
Author(s) Patient n Regimen Age Neutropenia Neutropenic Treatment-related Growth
Fever Deaths Factor
Zinzani [40] 350 VNCOP-B 60+ 17% 8% – G-CSF
60+ 44% 32% 1.3% –
Sonneveld [41] 148 CHOP 60+ NR NR 14% –
CNOP 60+ NR NR 13% –
Gomez [42] 26 CHOP 60+ 24% 8% 0 GM-CSF
70+ 73% 42% 20% GM-CSF
Tirelli [43] 119 VMP 70 + 50% 21% 7% –
CHOP 70+ 48% 21% 5% –
Bastion [44] 444 CVP 70+ 9% 7% 12% –
CTVP 70+ 29% 13% 15% –
Bertini [45] 98 P-VEBEC 65+ 22% 4% 0 G-CSF
65+ 46% 9% 2% –
O’Reilly [46] 63 POCE 65+ 50% 20% 8% –
Armitage [47] 20 CHOP 70+ NR NR 30% –
228
The exam of Table 2 clearly shows that CHOP, or regi-
mens of similar dose-intensity, were associated with a risk of
grade III-IV neutropenia in older individuals higher than 50%,
and with a risk of treatment-related death varying between
5%-30%. Gomez et al. [43] showed that myelodepression was
particularly common among patients aged over 70.
The risk of grade III-IV thrombocytopenia was around
20% in the majority of studies. Two randomized and con-
trolled studies [40, 45], demonstrated that G-CSF reduced the
risk of severe neutropenia and neutropenic infections in older
individuals by more than 50%. Zinzani et al. [40] reported
life-threatening neutropenia in 18 of 77 (23%) patients who
had received G-CSF and 40/72 (55.5%) patients treated with-
out G-CSF (p = 0.00005). The rate of severe infection was
4/77 (5%) and 21/72 (21%), respectively (p = 0.004). Similar
results were reported by Bertini et al. [45] among 100 patients
aged over 65 treated with etoposide, epirubicin, cyclophos-
phamide, vincristine and prednisone.
A number of studies of patients with AML aged 60
and older also showed that the risk of life-threatening
myelodepression was increased during induction and con-
solidation treatment [48, 49]. In the case of AML, the dis-
ease itself may cause a depletion of the reserve of normal
hemopoietic stem cells [29]. The benefits of growth fac-
tors in the older patients with AML are controversial. The
Eastern Cooperative Oncology Group reported decreased
risk of neutropenic infections and infectious death and
more prolonged survival for patients aged 65 and older
treated with GM-CSF after induction treatment [48]. A
number of studies summarized by Schiffer [49] showed
that use of growth factors during consolidation treatment
decreased the duration of hospital admissions.
Examination of these data indicates:
• The risk of neutropenic complications and death from
neutropenic infections is increased for older individu-
als receiving moderately toxic chemotherapy.
• This risk is more pronounced after age 70.
• Hemopoietic growth factors are effective in prevent-
ing life-threatening neutropenia and neutropenic
infections.
Until recently, scarce attention has been paid to the risk
of anemia in patients receiving cytotoxic chemotherapy. In
older individuals anemia may have a number of serious
consequences, including:
• Enhanced toxicity of cytotoxic chemotherapy [5-9].
• Increased risk of fatigue that in older individuals may
lead to functional dependence [50, 51].
• Increased risk of complications from medications or
infections [52].
Management of Cancer in the Older Person: A Practical Approach
These findings support correction of anemia in older
individuals undergoing cytotoxic chemotherapy.
The risk of mucositis increases with age. This issue was
reviewed by Stein [28] who showed that mucositis may lead
to lethal fluid depletion in individuals aged 66 and older.
Decreased concentration of mucosal stem cells, increased
destruction of rapidly proliferating mucosal cells, and
decreased intracellular catabolism of fluoropyrimidine may
contribute to the risk of mucositis in the elderly. Of interest,
the risk and severity of mucositis was increased for women
aged 65 and over, even in the study of Gelmann and Taylor
[17] despite dose adjustment. This finding indicates that
the mucosas of older individuals are more vulnerable by
cytotoxic chemotherapy.
The risk of anthracycline cardiomyopathy increases with
the age of the patient [33], but this risk is largely limited to
elevated total doses of the drugs (equivalent to doses of dox-
orubicin ≥450 mg/m2 of body surface area). In the absence of
other risk factors, it does not appear reasonable to use special
measures to prevent cardiotoxicity in patients receiving
lower doses of the medications. Continuous slow infusion of
anthracyclines may lead to enhanced risk of mucositis [53],
whereas dexrazoxane may enhance myelosuppression and
attenuate the antineoplastic activity of doxorubicin [54].
Adjuvant chemotherapy was found to compromise the
cognitive function of young women with breast cancer [55];
therefore, the possibility that chemotherapy may precipitate
dementia in older individuals is a reasonable concern.
Cerebellar toxicity is typical of high doses of cytara-
bine. In addition to age, a decline in GFR is a risk factor
for this complication [35]. Cerebellar toxicity appears to be
due to the accumulation of arauridine in the cerebellum
[56]. Arauridine is a product of the catabolism of cytara-
bin, and is excreted from the kidneys. When the GFR is
reduced, arauridine accumulates in the plasma and tissues.
Surprisingly, the nephrotoxicity of cytotoxic chemotherapy
does not appear enhanced in the aged [3].
Prevention and Amelioration of Chemotherapy-Related
Toxicity in Older Individuals
A better understanding of PK and pharmacodynamics
of antineoplastic agents, and the development of a number
of antidotes to drug toxicity, may make the treatment of
older individuals safer and more effective. Table 3 summa-
rizes a number of recommendations that were recently pre-
sented to the National Cancer Center Network (NCCN)
(http://www.nccn.org) [57]. As one can see, the only guide-
lines that are specific for older patients involve the admin-
istration of hemopoietic growth factors and erythropoietin,
and the adjustment of the doses of chemotherapy to the
GFR of patients at particular risk for toxicity. Given the
Balducci, Extermann 229

Table 3. Provisions that may reduce complications of cytotoxic chemotherapy in older cancer patients
A. Antidotes
Antidote Indication
G-CSF; GM-CSF Patients aged 70 and older receiving moderately toxic chemotherapy (CHOP, CA)
Erythropoietin Patients aged 70 and older to maintain hemoglobin levels ≥12 gm/dl
IL-11 Patients with solid tumors who have needed platelet transfusions
Amifostine To prevent nephrotoxicity from high doses of cisplatin
To prevent salivary toxicity in patients with head and neck cancer receiving radiation therapy
Desrazoxane Patients for whom a dose of doxorubicin ≥300 mg/m2 is expected

B. PK changes
PK intervention
Dose adjustment to GFR
Continuous infusion or low
daily doses of anthracyclines
Low weekly doses of taxanes
Indication
Drugs for which the parent compound or an active metabolite is excreted through the kidneys when:
• The patient has experienced a grade IV toxicity during the previous administration of the drug
• The patient is considered at high risk for complications according to the geriatric evaluation
• The patient presents an abnormal serum creatinine
No specific indications
As an alternative to full doses every three weeks in breast cancer

significant risk of neutropenic infections and death, it was

Table 4. Suggested dose adjustment for common antineoplastic
felt that the use of G-CSF or GM-CSF should be recom- agents to the GFR
mended in all patients over 70 receiving chemotherapy with
Creatinine clearance ≤60 ≤45 ≤30
a dose intensity comparable to CHOP. ml/min
A hemoglobin level of 12 mg/dl is recommended
Bleomycin 0.7 0.6 NR
because the control of fatigue appears optimal at that level
Carboplatin Calvert’s formula
[40, 41], since anemia may enhance the risk of chemother-
Carmustine 0.8 0.75 NR
apy-related toxicity [5-9], and anemia has other serious
implications in the older person [32]. Cisplatinum 0.75 0.50 NR
The dose adjustment to a patient’s individual GFR Cytarabine (high doses) 0.6 0.5 NR
(Table 4) is recommended for patients deemed at Dacarbazine 0.8 0.75 0.70
increased risk of complication based on a comprehensive Fludarabine 0.8 0.75 0.65
geriatric assessment (CGA). This assessment is important Hydroxyurea 0.8 0.75 0.7
to account for the diversity of the geriatric population that Ifosfamide 0.8 0.75 0.7
underlies individual benefits and risk of cancer treatment. Melphalan 0.85 0.75 0.7
In the next section we illustrate how a CGA may guide the Methotrexate 0.65 0.5 NR
management of older individuals with cancer.
NR = Not recommended.
ASSESSMENT OF THE OLDER CANCER PATIENTS AND
DECISION-MAKING IMPLICATIONS
A. Recognition of those patients who may benefit most
In the previous discussion aging was defined as a progres-
sive loss in the functional reserve of multiple organ systems from standard treatment, and those for whom the
and consequent reduction in the tolerance of stress, including therapeutic risks overwhelm the potential benefits.
cytotoxic chemotherapy. Also, aging is associated with B. Institution of medical, psychological and social
reduced life expectancy. Seemingly, the benefits of antineo- interventions that may improve the tolerance of
plastic treatment are reduced, and the risks enhanced in the chemotherapy by individual patients.
older person. The management of the older person with can-
cer, aimed to maximize the benefits and minimize the risk Chronologic age and laboratory tests are of limited assis-
of treatment in individual situations, is based on two types of tance in these decisions. As a general rule, two age land-
clinical decisions: marks may be established: age 70 and age 85. The adoption
230 Management of Cancer in the Older Person: A Practical Approach

of age 70 as the lower limit of clinical senescence is suggested

Table 5. Elements of a comprehensive geriatric assessment
by the fact that the prevalence of age-related changes is rep-
resented by an almost flat line up to age 70, but increases Parameter assessed Elements of the assessment
sharply between age 70 and 75 [58]. Approximately 90% of Function Performance status
the persons with clinical signs of aging are over 70. After age ADL
IADL
85, the prevalence of clinical frailty (see following discus-
sion) increases sharply [59-63]. Persons aged 85 and older are Comorbidity Number of comorbid conditions
referred to as “oldest old” in geriatric circles; a more rapid Severity of comorbid conditions
decline in visual and hearing function makes these patients (comorbidity index)
more susceptible to environmental injury and more prone to Socioeconomic conditions Living conditions
Presence and adequacy of a caregiver
functional dependence [60]. These landmarks are useful to
identify groups of persons that need special attention, because Cognition Folstein’s minimental status
Other tests
they may be old or frail, but chronologic age is otherwise
Emotional conditions Geriatric depression scale (GDS)
inadequate to reflect individual functional reserve and life
expectancy. This information is not provided by any labora- Pharmacy Number of medications
Appropriateness of medications
tory test at present. Though GFR declines with aging [4, 64], Risk of drug interactions
this decline is quite variable from individual to individual, and
Nutrition Mini-nutritional assessment (MNA)
may be influenced by a host of comorbid conditions. The cir-
Geriatric syndromes Dementia
culating levels of interleukin 6 (IL-6) may be increased in the
Delirium
presence of dementia, osteoporosis, or other geriatric syn- Depression
dromes [65], but this elevation appears confined to a group of Falls
frail patients, whose functional reserve is practically Neglect and abuse
exhausted [59]. Recently, German investigators reported that Spontaneous bone fractures
aging may be reflected by the ratio of cystein/thiolic groups
in the circulation [66]. This index is also influenced by chemotherapy. Many comorbid conditions may be
malnutrition and needs clinical validation. reversed or ameliorated, and chemotherapy may be
Currently, the best estimates of individual functional safer under these circumstances.
reserve and life expectancy may be provided by a CGA,
accounting for the multidimensional nature of aging • Assessment of socioeconomic conditions that may
(Table 5) [67]. prevent compliance with chemotherapy or enhance the
Aging involves changes in the functional, emotional, risk of complications. This includes the inadequacy
socio-economic and cognitive domains [68-70]. In addition, of transportation and home caregiving, as well as the
age is associated with increased incidence of chronic diseases inability to achieve timely help in case of serious
(comorbidity) [71-74] and a number of syndromes typical of complications.
the older persons, the so-called “geriatric syndromes” [43, 75- • Assessment of functional dependence that may affect
78], that imply shortened survival and enhanced vulnerability the tolerance of complications from cytotoxic agents.
to even minimal stress.
In randomized and controlled studies, the CGA was • Recognition of frailty, a condition in which most
found extremely helpful in the management of a number of functional reserve is exhausted, and the aim of treat-
geriatric problems, including prevention of institutionaliza- ment is palliation.
tion and maintenance of independence [79], prevention of • Assessment of emotional and cognitive conditions, such
delirium for hospitalized patients [77], falls [76], and hos- as depression and memory disorders, that may interfere
pital readmission [79-81]. In addition, the CGA was found with comprehension and acceptance of treatment plans.
to detect new and unsuspected problems in 76% of elderly
persons living at home [80-82]. When the CGA was • Some gross estimate of life expectancy, based on
repeated yearly, the incidence of new problems was functional status, comorbidity, cognition, presence or
approximately 30%. absence of geriatric syndromes. In general, this esti-
mate is critical before instituting treatments whose
In the management of the older person with cancer, the
benefits may be seen only years later, such as adju-
value of the CGA includes:
vant treatment for breast cancer or colorectal cancer,
• Assessment of comorbidity that may render older primary treatment of prostate cancer, or the use of
individuals more susceptible to the complications of chemotherapy in myelodysplasia.
Balducci, Extermann 231

Table 6. Proposed screening tests

Realm Screening Confirmatory test
Mental status Serial three: tell patient: “I am going to name three objects (pencil, Folstein minimental status. If score
truck, book, and I am going to ask you to repeat them now and a <24 institute work-up for dementia.
few minutes from now.”
Emotional status/depression Ask patient: “Do you feel often depressed or sad?” GDS. If positive (score >10), work up
for depression.
ADL Can you dress yourself? Formal Katz ADL scale
Do you need help to go to the bathroom?
Do you wet yourself?
Can you eat without help?
Can you move from one place to another without help?
Do you need help for taking a bath or a shower?
IADL Do you drive? Are you able to use public transportation? Formal IADL scale
Do you prepare your own meals?
Do you go shopping?
Do you do your own checking?
Can you call somebody on the telephone?
Do you remember to take your medications?
Home environment Do you have trouble with stairs inside and outside the house?
Do you trip often on rugs?
Social support Who would be able to help you in case of emergency? If no caregiver, try to arrange for a caregiver.
If the caregiver is a spouse, a sibling or a
friend of the same age of the patient,
assess independence of the caregiver.
Comorbidity Evaluate the presence of following conditions from ROS: congestive Confirm the presence of the condition and
heart failure, coronary artery disease, valvular heart disease, chronic grade the seriousness.
lung disease (obstructive or restrictive), cerebrovascular disease,
peripheral neuropathy, chronic renal insufficiency, hypertension,
diabetes, coexisting malignancies, collagen vascular diseases,
incapacitating arthritis.
Nutrition Weigh patient, measure height, inquire about weight loss. Mininutritional assessment (MNA)
Polypharmacy Review number and type of medications. If more than three medications look for
duplications, interactions, and compliance.

• Application of a common language to the evaluation
of the older patient. This common language is essen-
tial to compare the outcome of treatment in different
practice and for quality assurance.
Although the CGA has not been standardized, the con-
sensus is that it should include the elements summarized in
Table 6.
The assessment of function needs to include Activities
of Daily Living (ADL) and Instrumental Activities of Daily
Living (IADLs) in addition to performance status. ADLs
include transferring, grooming, continence, using the toilet,
dressing, and feeding. IADLs include use of transportation,
money management, shopping, taking medications, and
being able to provide one’s own meals. This assessment is
important for the following reasons:
• Functional dependence is associated with shortened
survival [80, 83, 84]. Average life expectancy for a
person dependent in one or more ADLs is shorter than
three years [83].
• Dependence in some IADLs, such as shopping, use of
transportation and telephone, and money manage-
ment predicts clinical dementia in the following two
years [85] and is associated with reduced tolerance of
cytotoxic chemotherapy [86].
• Dependence in one or more ADLs is a sign of
frailty, a condition in which functional reserve is
severely reduced and tolerance of even small stress
is compromised [59].
• ADL and IADLs bear a poor correlation with perfor-
mance status [87].
The assessment of comorbidity is important for the
following reasons:
• Comorbidity is associated with decreased life
expectancy [73] and is an independent prognostic
factor for cancer outcome [88].
• Comorbidity may compromise the tolerance of cancer
chemotherapy [1, 88].
232
• The prevalence of comorbidity increases with age [72].
Ideally, comorbidity should be assessed as a comorbid-
ity index, a number expressing the risk of death and thera-
peutic complications [70, 71]. Several comorbidity indices
are used in geriatrics. Of these, the Charlson’s scale [89],
and the Cumulative Illness Rating Scale-Geriatrics (CIRS-
G) [90], are the most popular. Ongoing studies assess the
value of the CIRS-G and the Charlson’s scale in older can-
cer patients. Currently, the assessment of comorbidity
includes the number of conditions that may compromise
survival [73], including coronary artery diseases, conges-
tive heart failure, chronic obstructive pulmonary diseases,
renal insufficiency, cerebrovascular diseases, neurovascu-
lar complications of diabetes mellitus, arthritis that restricts
mobility, and anemia [71-73].
Cognition becomes progressively more compromised
with age; after age 85 approximately 50% of the population
presents some degree of dementia [61]. A number of tests
are available for the rating of dementia, and of these, the
Folstein Minimental status is used most commonly because
of its simplicity [78]. Dementia has been associated with
decreased survival [91, 92]. Also, dementia may be wors-
ened by cytotoxic chemotherapy [55] and associated with
decreased tolerance of antineoplastic treatment [86].
Screening for depression is also important because
depression may reduce the motivation to receive treatment
[93]. The geriatric depression scale is a simple 15-item
instrument that may be self-administered and proved very
accurate for screening purposes [93]. Depression has been
associated with decreased survival in older individuals [94,
95], and depression may be reversible by pharmacologic
treatment. Severe depression, associated with weight loss
and failure to thrive, is considered a geriatric syndrome [59].
The assessment of nutrition by the mini-nutritional
assessment [96] allows recognition of patients who are mal-
nourished and at risk of developing malnutrition. Some
degree of protein/calorie malnutrition is present in approxi-
mately 20% of persons aged 70 and older [97]. In the pres-
ence of cancer, the prevalence and risk of malnutrition are
higher [98]. Malnutrition in the aged has multiple causes,
including decreased threshold for bitter taste, increased
threshold for sweet taste, decreased gastric secretion,
depression, forgetfulness, limited mobility, decreased ability
to feed oneself from arthritis, and poverty [96]. Thus, older
individuals are more vulnerable to nutritional complications
of cancer and cancer treatment. Malnutrition is associated
with a number of complications, including enhanced toxic-
ity of cytotoxic chemotherapy [97]. With timely interven-
tion malnutrition may be prevented or reversed in older
cancer patients [98].
Management of Cancer in the Older Person: A Practical Approach
Polypharmacy is a common problem in the elderly and
may be associated with a number of complications including
cognitive deterioration, delirium, emotional instability, and
drug interactions [23]. Elimination of unnecessary drugs may
reduce the risk of both complications and treatment expenses.
Adequate social support is essential for several aspects
of treatment including transportation, timely management
of fever, bleeding and other emergencies during chemother-
apy, and emotional and physical assistance to the patient
during treatment. Pivotal to the social management of the
patient is an effective home caregiver [99] whose functions
include:
• To coordinate the patient’s treatment;
• To recognize treatment complications in a timely
manner;
• To arrange for transportation to the clinic and hospi-
tal on short notice;
• To bridge possible communication gaps among
patient, family, and practitioner, and
• To facilitate the communication among family mem-
bers, promoting the solution of conflicts and incom-
prehension.
The outcome of the treatment of the older cancer patient
may be predicated upon the identification and selection of
the family caregiver. Common problems related to the care-
giver include the fact that caregiving is sometimes provided
by an elderly spouse with health problems of his/her own, or
by a married daughter who must take care of her own fam-
ily at the same time, and caregiver burn-out. The practitioner
needs to be sensitive to these problems and provide proper
counseling to maintain an effective caregiver.
Whereas the general benefits of a CGA are easily rec-
ognized, it is not clear whether the CGA may fulfill the main
need of geriatric oncology—an accurate estimate of risks
and benefits of treatment. This estimate is desirable from
both a practical and a research standpoint. From a practical
standpoint it would provide valuable guidelines for the treat-
ment of older individuals; from a research standpoint, it
would allow stratification of older patients undergoing clin-
ical trials according to the risk of treatment complications.
According to the CGA it is possible to recognize at least
three groups of older cancer patients, with different life
expectancies and risks of therapeutic complications (Fig. 3).
[62, 63]. Group 1 patients are functionally independent and
without serious comorbidity; group 2 patients may be
dependent in one or more IADLs and/or may present one or
two comorbid conditions; group 3 patients represent the frail
patients. As expected the prevalence of group 1 patients
 Balducci, Extermann
80
Percentage of
people 60 1
belonging to
different
geriatric 40 2 EXPECTANCY
groups
3
20 3
0 1
70 75 80 85 90
AGE
Figure 3. Prevalence of different groups of older individuals according to
the age of the population. This is a theoretical estimate, not based on actual
population studies.
declines and that of group 3 patients increases with age,
whereas the prevalence of group 2 patients increases until
age 85 and declines thereafter. Of these groups, the frail
patients are the best defined [59, 62, 63].
Frailty involves limited life expectancy and near-to-
exhausted functional reserve [59]. In the management of frail
patients, symptom palliation and quality-of-life preservation
are paramount. Whereas the frail patients may still benefit
from chemotherapy with drugs with low complication rates
such as gemcitabine, navelbine, or weekly taxanes [100],
they are not candidates for more toxic treatment. General
agreement exists on the definition of frailty [59, 100], that
includes dependence in one or more ADLs, three or more
comorbid conditions, and one or more geriatric syndromes.
An area of controversy is whether there are chronologic
boundaries of frailty. It appears reasonable to screen persons
aged 85 and older for frailty very thoroughly, as the inci-
dence of geriatric syndromes and functional dependence
increases after this age [59, 100, 101].
The previous classification of aging into three groups of
individuals of different functional reserve and comorbidity
may be used as the basis for an algorithm for the treatment
of cancer in older patients (Fig. 4). Classification and algo-
rithm are meant as models for future studies, not as defini-
tive constructs. As our understanding of aging evolves, new
populations of patients may be defined that better reflect
life expectancy and tolerance of stress [62, 63].
After exploring the benefits of a CGA, a number of
practical questions need to be addressed: How are patients
selected for whom the CGA is indicated? Who should per-
form the CGA? What kind of time investment is involved?
As the prevalence of age-related changes increases
sharply between age 70 and 75 [58], it is reasonable to
233
ASSESSMENT
GROUP GROUP GROUP
1 2 3
LIFE
< CANCER < CANCER
TREATMENT
TOLERANCE
YES NO
PALLIATION
LIFE
PROLONGING
TREATMENT
Figure 4. Algorithm for the management of the older cancer patient
based on CGA. Patients who are totally independent and have no
serious comorbidity (group 1) should receive full-dose treatment, as
long as their average life expectancy is longer than the life
expectancy from cancer. Patients dependent in one or more IADLs or
with some comorbidity (group 2) should be subject to some precau-
tions, such as dose reduction of chemotherapy at first administration.
Frail patients (group 3) are mainly candidates for supportive care.
recommend that all cancer patients aged 70 and older
receive some form of geriatric evaluation, just as a complete
review of system and physical exam are obtained in all
patients who come to a clinic for the first time. In addition,
CGA may be indicated in those persons younger than 70
with clear signs of aging (functional dependence, memory
disorders, history of falls, etc). The experience of the Senior
Adult Oncology Program at the H. Lee Moffitt Cancer
Center and Research Institute in Tampa (http://www.mof-
fitt.usf.edu) supports this recommendation [87]. Among the
first 200 patients aged 70 and older processed by this pro-
gram, 18% were dependent in one or more ADLs; 72% in
one or more IADLs; 36% had significant comorbidity
according to the Charlson scale and 94% according to the
CIRS-G scale; 22% had memory disorders, 19% malnutri-
tion, and 41% polypharmacy. Many of these problems
would have been missed in the absence of a CGA.
The CGA can be performed by any trained health pro-
fessional. Whereas the ideal setting for a CGA is primary
care, a large number of older individuals may reach an
oncologist without any form of geriatric evaluation.
The time commitment for the CGA is a serious problem,
given the current trend to process patients in shorter and
234
shorter time. Whereas the information related to function,
living condition, depression, polypharmacy and comorbidity
may be obtained from questionnaires completed by the
patient or family member, the record and interpretation of the
information is time-consuming. Furthermore, the minimental
status needs to be administered by a professional and takes
approximately 15 minutes. The average oncology practice
cannot afford this time investment until the CGA is properly
compensated by third-party payers. A reasonable compro-
mise, endorsed by the NCCN task force for the management
of cancer in the older person, involves the use of a short
screening instrument (Table 6) to unearth potential problems
in the various domains of the CGA and perform a complete
assessment of that particular domain only for patients who
screen positive. This screening instrument is an adaptation to
cancer patients of the instruments proposed by Lachs et al.
for the general geriatric population [102].
CONCLUSIONS AND PERSPECTIVES
This review has highlighted two aspects of aging:
• Aging is associated with a progressive reduction in
the functional reserve of multiple organ systems and
reduced tolerance of physical, emotional, and social
stress.
• Aging is multidimensional and individualized. The
physiologic, medical, social, emotional, and cognitive
changes of aging are poorly reflected in chronologic age
and can be best appreciated with a multidimensional
assessment of the older person.
This finding suggests two special provisions in the
management of the older cancer patient:
• Prevention of chemotherapy-related toxicity in
patients aged 70 and over with prophylactic use of
hemopoietic growth factors, prevention and manage-
ment of anemia, and proper adjustment of drug
dosages to individual GFR.
• A comprehensive assessment of the older person to
unearth and address individual problems that may
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