Background: The
incidence of cancer among the elderly population is increasing. The aging process
can deplete functional reserve of many organ systems and thus affects the treatment
goals for this age-group.
Methods:
The pharmacologic consequences of the aging process on elderly cancer patients
are reviewed, and guidelines are suggested for assessing and treating this patient
population with antitumor drugs.
Results:
Individualized management of the older cancer patient reflects the results of
a comprehensive geriatric assessment. Factors that affect treatment decisions
include estimates of the extent of treatment toxicity, the impact of treatment
on quality of life, estimates of life expectancy, and the influence of age on
pharmacokinetic parameters.
Conclusions:
Management of older patients with cancer includes individual assessments that
consider the effects of aging on the pharmacodynamics, therapies, and complications
of treatment for this population. Treatment can be made safer and more effective
by adjusting chemotherapy dosage, maintaining hemoglobin levels, and using hemopoietic
growth factors when appropriate.
Introduction
The incidence of cancer in the older-aged person is increasing, with 50% of
all neoplasms occurring in persons over 65 years of age.1 Aging involves
a progressive depletion of the functional reserve of multiple organ systems
that may influence the pharmacology of antineoplastic drugs.2 This
process is poorly reflected by chronological age, but rather it occurs at different
rates in different individuals. Thus, the management of the older cancer patient
involves the estimate of individual functional reserve.
This article reviews some of the pharmacologic consequences of aging and provides
general guidelines for the assessment and the treatment of the older person
with cancer.
Pharmacokinetics
Age may affect most pharmacokinetics parameters, including absorption, volume
of distribution, hepatic drug metabolism, and excretion (Table 1).3,4
|
Table
1. — Influence of Age on Pharmacokinetic Parameters
|
|
Parameter
|
|
Effects
of Age
|
|
Absorption
|
Decreased
|
|
|
•
decreased gastric motility and secretions
|
|
|
•
decreased splanchnic blood flow
|
|
|
•
decreased absorptive surface
|
|
|
|
Volume
of distribution (Vd)
|
|
Decreased
for water-soluble agents
|
|
|
•
decreased water content
|
|
|
•
decreased serum albumin
|
|
|
•
decreased hemoglobin
|
|
|
|
Hepatic
drug metabolism
|
|
Reduced
|
|
|
•
decreased liver volume
|
|
|
•
decreased hepatic blood flow
|
|
|
|
Excretion:
|
|
|
|
Biliary
|
Probably
unchanged
|
|
Renal
|
Reduced
|
|
|
•
decreased glomerular filtration rate
|
| |
Diminished drug absorption may reduce the effectiveness of oral agents, but
more information is needed on this issue. A new interest in drug absorption
has been stimulated by the recent development of new oral antitumor agents such
as capecitabine, tegafur, and oral cisplatin.
The volume of distribution (Vd) is a function of body composition, serum albumin,
and hemoglobin. A progressive increase in body fat and a decline in body water
generally occur up to age 85.3,4 These changes tend to restrict the
Vd of water-soluble drugs and expand that of fat-soluble compounds. After 85
years of age, a progressive depletion of fat often occurs as well, and organ
atrophy is a common finding. Hemoglobin is a parameter of special interest,
because the levels of hemoglobin may be modulated by epoetin.5 The
majority of antineoplastic agents, including anthracyclines, anthracenediones,
epipodophyllotoxins, and taxanes, are bound to red blood cells. A reduction
in the concentration of hemoglobin may result in increased serum concentration
of free drug and increased toxicity.6
The decrement in renal excretion of drugs is the most predictable pharmacokinetic
change, and the glomerular filtration rate (GFR) declines consistently with
age. It is important to remember that compounds excreted through the bile may
give origin to active and toxic metabolites excreted through the kidneys (Table
2). Thus, renal insufficiency may enhance the toxicity of drugs that are primarily
eliminated with the bile.
|
Table
2. — Renal Excretion of Antineoplastic Agents
|
Drugs completely
excreted through the kidneys:
|
Methotrexate
Carboplatin
Bleomyci
|
Drugs partially
excreted through the kidneys:
|
|
Drugs producing
active or toxic metabolites excreted through the kidneys:
|
Anthracyclines
Cytarabine (high
doses)
|
|
|
Kintzel and Dorr7 have proposed a formula to adjust the dose of
antineoplastic agents to the GFR. The most reliable measurement of the GFR can
be obtained with the formula recently proposed by Levey et al.8 However,
the pharmacokinetics of drugs cannot be completely predicted by changes in the
GFR. Gurney9 showed how the area under the curve (AUC) of the same
drug may vary up to sevenfold in patients of comparable size receiving the same
dose of medications. Borkowski et al10 showed that the renal clearance
of dichloromethotrexate declined with the age of the patient, but the total
clearance of the drug did not. This observation suggests that yet unknown excretory
mechanisms may compensate for the decline in renal function.
Pharmacodynamics
Pharmacodynamic changes may affect both the toxicity and the effectiveness of antineoplastic agents.
The ability of aging cells to catabolize drugs or to buffer the toxic effects of drugs may become more limited than in young cells. Stein et al11 reported that the toxicity of fluorinated pyrimidines was more prevalent and more severe in older individuals and ascribed this phenomenon at least in part to a reduced intracellular concentration of dihydropyrimidine dehydrogenase. Rudd et al12 reported that cisplatin-induced DNA adducts persisted for more than 80 hours in the circulating monocytes of persons over 70 years of age but were cleared in less than 20 hours in younger individuals.
Age may also be associated with tumors that are resistant to chemotherapy. The prevalence of leukemic cells expressing the multiple drug resistance gene (MDR-1) is 67% among persons over age 60 but only 17% among younger persons.13 In addition, anoxia of neoplastic cells and reduced cell proliferation may also reduce the effectiveness of cycle-active drugs.3 It is well known that cytotoxic chemotherapy is less effective in older individuals with acute myelogenous leukemia,13 non-Hodgkin’s large-cell lymphomas,14 ovarian cancer,15 and possibly breast cancer.16 These changes in sensitivity may be explained at least in part with pharmacodynamic changes.
Therapeutic Complications
A more restricted functional reserve may enhance the susceptibility of normal
tissues to antineoplastic chemotherapy (Table 3).
|
Table
3. — Complications of Chemotherapy
That Are More Common and More Severe in Older Individuals
|
| |
•
Myelosuppression |
|
|
•
Cardiomyopathy |
| |
•
Mucositis |
|
•
Peripheral neuropathy |
| |
•
Delayed nausea and vomiting |
|
•
Central neurotoxicity |
| |
The incidence and severity
of myelotoxicity caused by moderately toxic chemotherapy increase dramatically
after age 70. In this respect, the study of patients with large-cell non-Hodgkin’s
lymphoma who were treated with cyclophosphamide, doxorubicin, vincristine, and
prednisone (CHOP) or CHOP-like chemotherapy is particularly instructive. Armitage
and Potter17 reported a 30% chemotherapy-induced death rate. Gomez
et al,18 Zinzani et al,19 and Bastion et al20
all reported that the incidence of grade 3 and 4 neutropenia and neutropenic
infections more than doubled after age 70. To a lesser extent, thrombocytopenia
and anemia were also more common. It is also well known that the risk of death
during induction chemotherapy is higher among patients with acute myelogenous
leukemia who are 60 years of age or older.13 In this case, however,
the disease may also be responsible for a restriction in hemopoietic reserve.
The incidence of chemotherapy-induced
mucositis is more common and more severe after age 65.11 The elderly
may be predisposed to this complication by a number of factors, including reduced
ability to catabolize fluorinated pyrimidines, reduced reserve of mucosal stem
cells, and increased proliferation of surface mucosal cells. Whereas the incidence
of immediate nausea and vomiting seems to decrease with the age of the patient,
the risk of delayed nausea seems to increasewith chemotherapy.3 This
complication affects the quality of life of older individuals and may seriously
compromise their treatment plans. No effective measures exist at present.
The incidence of anthracycline-related
cardiomyopathy also increases after age 70. This is likely due to a combination
of factors, including higher prevalence of preexisting conditions that restrict
the functional reserve of the myocardium.3
The issue of peripheral
neuropathy has become particularly compelling, as this complication may be dose-limiting
for two drugs of common use, cisplatin and paclitaxel.3
The cerebellar complications
of cytarabine in high doses are due to the accumulation of the toxic metabolite
ara-uridine (ara-U), which is excreted through the kidneys. Increased incidence
of cerebellar toxicity with age may be associated more with a decline in GFR
than with a reduction in the functional reserve of the cerebellum.
Cognitive complications
of chemotherapy are increasingly recognized21 and may be particularly
severe in older individuals whose cognitive function is already compromised.
Unexpectedly, the nephrotoxicity of cisplatin does not appear to be more common
among the aged.3 Seemingly, a decline in tubular reabsorption parallels
the decline in GFR and results in decreased exposure to the drug.3
Evaluation
of the Older-Aged Patient With Cancer
The individualized
management of the older-aged patient with cancer is based on the answers to
the following questions: (1) Will the patient die of cancer or with cancer?
(2) Will the patient suffer cancer-related morbidity? (3) Is the patient able
to handle the toxicity of treatment? These questions can be answered with a
multidimensional assessment that accounts for the diversity of the older population
(Table 4.22
|
Table
4. — Comprehensive Geriatric Assessment (CGA)
|
|
Domain
|
|
Instrument
|
|
Function
|
Performance Status
Activities of Daily
Living
Instrumental Activities
of Daily Living
|
|
|
|
Health
|
|
Number
of comorbid conditions
Comorbidity
Index
|
|
|
|
Cognition
|
|
Mini
Mental Status
|
|
|
|
Depression
|
|
Geriatric
Depression Scale
|
|
|
|
Nutrition
|
|
Mini
Nutritional Assessment
|
|
|
|
Pharmacy
|
|
Polypharmacy
|
|
|
|
Socio-economic
status
|
|
Income
Education
Living
conditions
Caregiver
|
|
|
|
Geriatric
syndromes
|
|
Dementia
Delirium
Depression
Falls
Osteoporosis
Incontinence
Neglect
and abuse
Failure
to thrive
|
| |
Although chronological
age is a poor reflection of physiologic age, two age landmarks have been identified:
age 70, beyond which the incidence of age-related changes increases sharply,23
and age 85, when the last stage of life (frailty) begins.24,25 No
laboratory test, including serum concentration of interleukin (IL)-6, cysteine/thiolic
groups ratio, or serum osmolarity, offers an adequate assessment of age.25
The comprehensive
geriatric assessment (CGA) allows the practitioner to establish some landmarks
(eg, frailty, life expectancy, risk of complications) in the diverse panorama
of the older population. The following components identify patient determinants
and establish guidelines for the practitioner:
• The
CGA defines patients considered to be frail, including those age 85 and older,
those dependent in one or more activities of daily living (ADLs), patients with
three or more comorbid conditions, and patients with one or more geriatric syndromes.24,25
The frail person has no functional reserve and is susceptible to the most negligible
stress. Frail patients are clearly not candidates for any form of treatment
other than palliation.
• Estimates
of life expectancy are developed based on functional status,26 the
number of comorbid conditions,27 cognition,28 depression,29
and the presence of geriatric syndromes.30,31
• Patients
at high risk for complications of cytotoxic chemotherapy are recognized. They
include patients who are dependent in one or more instrumental activities of
daily living (IADLs) and those with poor social support (eg, those who live
alone or whose main caregiver is an older spouse).32
• Unrecognized
medical problems such as malnutrition or hidden diseases may be revealed by
a CGA and properly treated. This intervention may minimize the complications
of cancer treatment.
Guidelines
for the Management of Older Patients With Cancer
A number of
reasonable guidelines aimed at making the treatment of older patients both safe
and effective may be drawn from this brief review:
1. The first
doses of chemotherapy should be adjusted to the GFR, according to the formula
of Kintzel and Dorr, in all patients age 65 and older. As the pharmacokinetics
of drugs cannot be completely predicted from GFR, successive doses should be
escalated or decreased according to the severity of treatment toxicity.
2. Hemoglobin
should be maintained to a level of 12 g/dL with epoetin alfa.
3. Hemopoietic
growth factors (G-CSF or GM-CSF) should be routinely used in persons 70 years
of age and older who are receiving moderately toxic chemotherapy (eg, CHOP,
cyclophosphamide/doxorubicin, or docetaxel/doxorubicin for breast cancer; carboplatin/
paclitaxel for non-small cell lung cancer). If no neutropenia is reported with
the first treatment, the use of growth factors may be stopped in successive
treatments.
4. The dominant
goal of treating frail patients is palliation (Figure). Palliation may include
some mild form of chemotherapy, including single-agent gemcitabine, navelbine,
mitoxantrone, and low-dose taxanes. The management of pain in older individuals
with narcotics or nonsteroidal agents may be associated with serious complications
including nausea, constipation, and delirium. In patients who are reluctant
to take analgesic medications because of these complications, chemotherapy may
represent effective palliation.
 |
|
Algorithm for the
management of cancer in the elderly. IADL = instrumental activities of
daily living; QOL = quality of life.
|
A number of
research projects are recommended for the treatment of older cancer patients,
including (1) exploring alternative mechanisms of drug excretion and determining
a simple approach to predict the AUC of drugs in older individuals, (2) analyzing
the value of new antidotes to drug toxicity, including dexrazoxane for cardiomyopathy,
keratinocyte growth factor for mucosal protection, IL-11 for thrombocytopenia
in older individuals, and amifostine for nephroprotection, myeloprotection,
and neuroprotection, and (3) studying the role of new agents — especially
oral fluorinated pyrimidines and the liposomal derivatives of anthracyclines
and cisplatin — in the management of the older and frail patients.
References
1. Yancik
R, Ries LA. Cancer in the older persons: magnitude of the problem. In: Balducci
L, Lyman GH, Ershler WB, eds. Comprehensive Geriatric Oncology. Amsterdam,
The Netherlands: Harwood Academic Publishers; 1998:95-104.
2. Balducci
L, Extermann M. Cancer chemotherapy in the older patient: what the medical oncologist
needs to know. Cancer. 1997;80:1317-1322.
3. Cova
D, Beretta G, Balducci L. Cancer chemotherapy in the older person. In: Balducci
L, Lyman GH, Ershler WB, eds. Comprehensive Geriatric Oncology. Amsterdam,
The Netherlands: Harwood Academic Publishers; 1998:429-442.
4. Grochow
L. Cancer chemotherapy in the older person. Clin Hematol Oncol. 1999.
In press.
5. Gabrilove
JL, Einhorn LH, Livingston RB, et al. Once weekly dosing of epoetin alfa is
similar to three-times weekly dosing in increasing hemoglobin and quality of
life. Proc Annu Meet Am Soc Clin Oncol. 1999;18:574A. Abstract.
6. Ratain
MJ, Schilsky RL, Choi KE, et al. Adaptive control of etoposide administration:
impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther.
1989;45:226-233.
7. Kintzel PE, Dorr RT.
Anticancer drug renal toxicity and elimination: dosing guidelines for altered
renal function. Cancer Treat Rev. 1995;21:33-64.
8. Levey AS, Bosch JP,
Lewis JB, et al. A more accurate method to estimate glomerular filtration rate
from serum creatinine: a new prediction equation: modification of diet in renal
disease study group. Ann Intern Med. 1999;130:461-470.
9. Gurney H. Dose calculation
of anticancer drugs: a review of the current practice and introduction of an
alternative. J Clin Oncol. 1996;14:2590-2611.
10. Borkowski JM, Duerr
M, Donehower RC, et al. Relation between age and clearance rate of nine investigational
anticancer drugs from phase I pharmacokinetics data. Cancer Chemother Pharmacol.
1994;33:493-496.
11. Stein BN, Petrelli
NJ, Douglass HO. Age and sex are independent predictors of 5-fluorouracil toxicity:
analysis of a large scale phase III trial. Cancer. 1995;75:11-17.
12. Rudd GN, Hartley
JA, Souhani RL. Persistence of cisplatin-induced DNA interstrand crosslinking
in peripheral blood mononuclear cells from elderly and young individuals. Cancer
Chemother Pharmacol. 1995;35:323-326.
13. Extermann M. Acute
leukemia in the elderly. Clin Geriatr Med. 1997;13:227-244.
14. Balducci L, Ballester
OF. Non-Hodgkin’s lymphoma in the elderly. Cancer Control. 1996;3(suppl):5-14.
15. Thigpen JT. Ovarian
cancer in the older patient. In: Balducci L, Lyman GH, Ershler WB, eds. Comprehensive
Geriatric Oncology. Amsterdam, The Netherlands: Harwood Academic Publishers;
1998:721-732.
16. Polychemotherapy
for early breast cancer: an overview of the randomised trials. Early Breast
Cancer Trialists’ Collaborative Group. Lancet. 1998;352:930-941.
17. Armitage JO, Potter
JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly:
increased complications with advancing age. J Am Geriatr Soc. 1984;32:269-273.
18. Gomez H, Mas L, Casanova
L, et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with
CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: identification
of two age subgroups with differing hematological toxicity. J Clin Oncol.
1998;16:2352-2358.
19. Zinzani PL, Pavone
E, Storti S, et al. Randomized trial with and without granulocyte colony-stimulating
factor as adjunct to induction VNCOP-B treatment of elderly high grade non-Hodgkin’s
lymphomas. Blood. 1997;89:3974-3979.
20. Bastion Y, Blay JY,
Divine M, et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease
presentation, response to treatment, and survival. A Groupe d’Etude des Lymphomes
de l’Adulte study on 453 patients older than 69 years. J Clin Oncol.
1997;15:2945-2953.
21. Schagen SB, van Dam
FS, Muller MJ, et al. Cognitive deficits after postoperative adjuvant chemotherapy
for breast carcinoma. Cancer. 1999;85:640-650.
22. Inoyue SK, Peduzzi
PN, Robison JT, et al. Importance of functional measures in predicting mortality
among older hospitalized patients. JAMA. 1998;279:1187-1193.
23. Balducci L, Schonwetter
R, Hescock H, et al. Decision analysis in geriatric oncology. Proc Annu Meet
Am Soc Clin Oncol. 1990;9:325. Abstract.
24. Balducci L, Extermann
M. Cancer chemotherapy in the frail patient. CRC Rev Hematol Oncol. 1999.
In press.
25. Balducci L, Stanta
G. Management of cancer in the frail person. Clin Hematol Oncol. 1999.
In press.
26. Reuben DB, Rubenstein
LV, Hirsch SH, et al. Value of functional status as predictor of mortality:
results of a prospective study. Am J Med. 1992;93:663-669.
27. Satariano WA, Ragland
DR. The effect of comorbidity on 3-year survival of women with primary breast
cancer. Ann Intern Med. 1994;120:104-110.
28. Eagles JM, Beattie
JA, Restall DB, et al. Relationship between cognitive impairment and early death
in the elderly. Br Med J. 1990;300:239-240.
29. Covinsky KE, Kahana
E, Chin MH, et al. Depressive symptoms and 3-year mortality in older hospitalized
medical patients. Ann Intern Med. 1999;130:563-569.
30. Bruce ML, Hoff RA,
Jacobs SC, et al. The effect of cognitive impairment on 9-year mortality in
a community sample. J Gerontol B Psychol Sci Soc Sci. 1995;6:289-296.
31. Fried TR, Pollack
DM, Tinetti ME. Factors associated with six-month mortality in recipients of
community-based long-term care. J Am Geriatr Soc. 1998;46:193-197.
32. Monfardini S, Ferrucci
L, Fratino L, et al. Validation of a multidimensional evaluation scale for use
in elderly cancer patients. Cancer. 1996;77:395-401
From the
Senior Adult Oncology Program at the H. Lee Moffitt Cancer Center & Research
Institute (LB), and the Division of Geriatrics at the University of South
Florida (CB), Tampa, Fla.
Address reprint
requests to Lodovico Balducci, MD, at the Senior Adult Oncology Program, H.
Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr, Tampa,
FL 33612.
No significant
relationship exists between the authors and the companies/services whose products
or services may be referenced in this article.
Back to Cancer
Control Journal Volume 6 Number 5