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Greater Risks of Chemotherapy Toxicity in Elderly Patients With Cancer

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Complications of cytotoxic chemotherapy are more common in older patients (65 years of age and older) with cancer than in younger patients, and the occurrence of myelo suppression, mucositis, cardiodepression, peripheral neuropathy, and central neurotoxicity can complicate treatment. Age-related physiologic changes that can increase the toxicity of chemotherapy are decreased stem-cell reserves, decreased ability to repair cell damage, progressive loss of body protein, and accumulation of body fat. A decline in organ function can alter the pharmacokinetics of many of the commonly used chemotherapeutic agents in some elderly patients, making toxicity less predictable.
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R E V I E W
Greater Risks of Chemotherapy Toxicity
in Elderly Patients With Cancer
Lazzaro Repetto, MD, PhD
cal trials, little is known about the influence of co-
Abstract Complications of cytotoxic chemotherapy are more common
morbidities on the toxicity of chemotherapy [4].
in older patients (65 years of age and older) with cancer than in younger
The uncertain relation between age, comorbidi-
patients, and the occurrence of myelosuppression, mucositis, cardiode-
ties, and toxicity is a major impediment to the in-
pression, peripheral neuropathy, and central neurotoxicity can complicate
clusion of older patients in trials of drug safety and
treatment. Age-related physiologic changes that can increase the toxicity
efficacy [5, 6]. The lack of evidence-based guide-
of chemotherapy are decreased stem-cell reserves, decreased ability to
lines on managing drug toxicity in older patients
repair cell damage, progressive loss of body protein, and accumulation of
may also influence what therapy is prescribed or
body fat. A decline in organ function can alter the pharmacokinetics of
result in suboptimal dosing [7]. It is particularly
many of the commonly used chemotherapeutic agents in some elderly
important to minimize the undertreatment of eld-
patients, making toxicity less predictable. Comorbidities increase the risk
erly patients, as they can benefit from standard
of toxicity through their effects on the body. Furthermore, the drugs used
treatment as well as younger patients [8]. Appro-
to treat comorbidities may interact with chemotherapeutic drugs, poten-
priate supportive care to manage the toxicity of
tially increasing toxicity in elderly patients. Prospective trials in older pa-
chemotherapy, such as the use of growth factors,
tients with lymphoma or solid tumors have found that age is a risk factor
is particularly important in older patients, who are
for chemotherapy-induced neutropenia and its complications. Anemia
at greater risk for the toxicity associated with che-
may be present because of the disease or its treatment, and, if left uncor-
motherapy [9, 10]. This article reviews age and
rected, it can alter drug activity and increase toxicity. Being able to pre-
comorbidities as risk factors for toxicity and dis-
dict which elderly patients are at greater risk of toxicity on the basis of
cusses newer, less toxic therapeutic options for old-
pretreatment factors would be valuable, and there is a need for prospec-
er patients.
tive trials to determine regimen- and patient-specific prognostic factors.
Effective management of the toxicity associated with chemotherapy with
Age-Related Physiologic Changes and
appropriate supportive care is crucial, especially in the elderly popula-
Susceptibility to Chemotherapy-
tion, to give them the best chance of cure and survival, or to provide pal-
Related Toxicity
liation. For example, management of neutropenic complications with col-
Aging is highly individualized, and certain com-
ony-stimulating factors makes treatment with standard-dose
mon physiologic changes increase the likelihood
chemotherapy possible, which can lead to better outcomes. A better un-
of toxicity with chemotherapy (Table 1). The de-
derstanding of drug activity and toxicity in older patients is necessary for
clining ability of senescent cells to repair DNA
developing guidelines for safe and effective treatment. Few randomized
damage may prolong toxicity [11]. Reduced he-
controlled trials of antitumor drugs in older patients with cancer have
matopoietic stem-cell mass and reduced ability to
been conducted, but a number of agents with favorable efficacy and tox-
mobilize these cells from the marrow in older per-
icity profiles in elderly patients have been identified.
sons may slow their recovery after cytotoxic che-
motherapy [12–14]. Similarly, increased destruc-
tion of and lower numbers of rapidly renewing
Dr. Repetto is Director
he incidence and severity of the toxicity of
of Oncology, Istituto
chemotherapy are greater in older patients
Nazionale di Riposo e
Cura per Anziani,
with cancer than in younger patients and
Rome, Italy.
T
mucosal stem cells increase susceptibility to mu-
cositis. The functional reserve of organ systems may
be seriously reduced in older persons, so that the
can complicate their treatment [1]. Re-
damage by chemotherapy to nontumor tissue leads
search on the effects of age on drug metabolism,
drug effects, and toxicity has become more impor-
Correspondence to: Lazzaro Repetto, MD, PhD, Unità Oper-
tant as the number of elderly patients with cancer
ativa Geriatria Oncologica, Istituto Nazionale di Riposo e Cura
continues to increase [2]. Comorbidities are prev-
per Anziani, Rome, Italy; telephone: +39 (06) 3034-2610;
fax: +39 (06) 3034 2529; e-mail: l.repetto@inrca.it
alent in elderly patients with cancer [3], and, since
such patients are frequently excluded from clini-
J Support Oncol 2003;1(suppl 2):18–24
© 2003 BioLink Communications
18
www.SupportiveOncology.net
THE JOURNAL OF SUPPORTIVE ONCOLOGY

to organ failure, such as cardiomyopathy, and neu-
rotoxicity [15, 16].
Table 1
Age-related differences in pharmacokinetics
Physiologic Changes and Consequences of Chemotherapy
can increase the toxicity of antineoplastic drugs
Associated With Aging in Elderly Patients With Cancer
and their metabolites [17]. Oral chemotherapy
PHYSIOLOGIC CHANGE
CONSEQUENCE OF CHEMOTHERAPY
agents have drawn attention to age-related changes
Slower repair of DNA damage
Prolonged toxicity
that may affect drug absorption, including less ab-
Reduced stem-cell mass and
Slow recovery of blood and mucosal cells
sorptive surfaces of the small bowel and splanch-
hematopoiesis
nic circulation, reduced gastric motility, and re-
Reduced functional reserve of organ
Risk of organ failure with additional
duced gastric secretion [18].
systems
tissue loss
Over time, the body progressively accumulates
Reduced gastrointestinal absorptive
Reduced drug absorption
more fat, and this can alter drug distribution in
surfaces, gastric motility, and gastric
secretion
older persons. Higher proportions of body fat may
Reduced fat–free mass
Altered drug distribution
increase the volume of distribution of lipid-solu-
Greater anemia
Increased levels of circulating drugs
ble drugs, but other changes, such as reduced to-
Decreased liver mass
Reduced drug metabolism
tal body water and reduced concentrations of plas-
Decreased nephron mass
Reduced drug excretion
ma proteins and hemoglobin, may decrease the
volume of distribution and increase the plasma
concentrations of hydrophilic drugs [19]. Because
at lower doses. Furthermore, adequate dosing is
several of the common chemotherapeutic agents
necessary for therapeutic effectiveness [31].
Repetto
bind to red blood cells and because anemia is prev-
alent in the elderly, the influence of hemoglobin
Comorbidities
levels on drug toxicity is of particular interest [20–
Chronic comorbidities affect most elderly pa-
22]. For those drugs that are highly bound to red
tients; persons 65 years of age and older have on
blood cells, such as taxanes and anthracyclines,
average three different diseases [32, 33]. Common
anemia is associated with a greater concentration
comorbidities are cardiovascular disease, hyperten-
of free drug in the circulation, and it is an inde-
sion, chronic bronchial obstruction, arthritis, be-
pendent risk factor for myelosuppression [20, 22–
nign prostatic hypertrophy, and depression [34].
24]. Correcting anemia both before and after cy-
Comorbidity indexes have shown that comorbidi-
totoxic chemotherapy is therefore advocated, to
ties have a negative effect on survival in patients
avoid unpredictable drug toxicity and the conse-
with cancer [35]. A recent study found that hos-
quences of anemia, such as fatigue [1].
pitalization for chemotherapy-induced toxicity in
Drugs are metabolized primarily in the liver, and
older patients with breast cancer increased signif-
their metabolism may decrease with declining
icantly with their comorbidity score [36].
splanchnic circulation and hepatocyte mass. Au-
Few prospective studies have reported the ef-
topsy studies indicate that the mass of the liver
fect of multiple comorbidities, or of specific comor-
decreases over time and has decreased by 20% to
bid conditions, on the safety and efficacy of che-
50% at age 80 years, thus decreasing the amount of
motherapy [4, 37]. Comorbid conditions are often
drug-metabolizing enzymes [25]. In addition, the
used to exclude patients from trials of cancer ther-
activity of reactions that are mediated by the cyto-
apies, and, as a result, few guidelines exist for adapt-
chrome P-450 system is approximately 30% less in
ing the results of earlier trials to suit those with
healthy older persons than in younger persons [26].
other health problems, other than dose adjustment
Loss of nephron mass is an important and pre-
for renal [29] and hepatic [38] dysfunction.
dictable feature of aging [27]. It reduces the rate
A recent large randomized trial by Meyerhardt
of glomerular filtration by approximately 1 mL/min
and colleagues [39] evaluated the effects of diabe-
for every year over 40 years of age [17]. With cy-
tes mellitus on the treatment outcomes and toxic-
totoxic agents (and their metabolites) that are
ity in patients with high-risk stage II and III colon
nephrotoxic or that undergo primarily renal ex-
cancer treated with adjuvant chemotherapy, find-
cretion, renal dysfunction is an important consid-
ing that the recurrence of cancer and mortality
eration that may require dose adjustment [28–30].
were higher in patients with diabetes. The inci-
The pharmacology of many drugs is not entirely
dence of treatment-related grade 3 or 4 diarrhea
predictable, however, and they may still be toxic
was higher in those with diabetes than in those
VOLUME 1, SUPPLEMENT 2 n NOVEMBER/DECEMBER 2003
www.SupportiveOncology.net
19

without diabetes (29% vs 20%, P < 0.001) but was
regimens [28, 50–53]. These retrospective studies
Risks of Toxicity
not associated with greater mortality. There were
show that age itself should not be a contraindica-
no differences in the incidences of severe nausea,
tion for cancer therapy. These studies were in high-
vomiting, stomatitis, or leukopenia [39]. Risk fac-
ly selected populations, however, and their find-
tors for oral mucositis (the dose-limiting toxicity
ings may not apply to the broader geriatric
of 5-fluorouracil) were evaluated in a prospective
population [1]. Forty percent of all malignancies
study in patients with cancer of the digestive tract
occur in persons older than 70 years, but only 10%
[40]. Xerostomia and lower neutrophil counts were
to 15% of the patients in these trials were in that
associated with a greater risk of mucositis, but di-
age group. Furthermore, there were very few pa-
abetes was not. The role of cardiac risk factors,
tients 80 years old or older. Conventional enroll-
including hypertension and diabetes, in the devel-
ment criteria ensured that the older patients had
opment of congestive heart failure (CHF) was as-
disproportionately few comorbidities and good per-
sessed in patients with metastatic breast cancer
formance status. Additionally, the dose intensities
who were treated with epirubicin (Ellence) and
used in most of the drug trials were not as high as
paclitaxel [41]. The incidence of CHF was 13% in
those with the current regimens [1].
patients with cardiac risk factors and 4% in those
In contrast, age was found to be a definite in-
without such risk factors. The risk of CHF was low
dependent risk factor for neutropenia in patients
until the cumulative dose of epirubicin exceeded
older than 60 years with lymphoma in a number of
990 mg/m², after which the risk increased with the
prospective clinical trials of CHOP (cyclophospha-
presence of an additional cardiac risk factor.
mide, doxorubicin, Oncovin [vincristine], and
Polypharmacy and high drug use are common
prednisone) or regimens with equivalent toxicity
in older patients, and the drugs that are used to
[54–60]. These studies found that age is clearly
treat health problems other than cancer may in-
associated with a greater risk of grade 4 neutrope-
teract with those in chemotherapy regimens. These
nia, neutropenia-related infection, and mortality.
adverse drug reactions may be related more to the
Myelosuppression is not only more common in the
number of medications used or the severity of the
elderly but also more severe, resulting in longer
medical problem than to the age of the patient [42].
hospital stays [61, 62] and higher inpatient mor-
For example, antibiotics, which may induce diar-
tality [63]. The risk of neutropenia and its compli-
rhea, or opioids and certain antipsychotics, which
cations, including death, is highest in the early
can cause constipation, may interfere with the
cycles of chemotherapy [54, 64, 65]. Because of
absorption of oral chemotherapy agents [43–45].
this risk and the potential for better outcomes,
Another consideration in the use of chemothera-
prophylaxis with a colony-stimulating factor be-
py is that its toxicity may be exacerbated by the side
ginning in the first cycle should be considered in
effects of the drugs that are used to treat comorbidi-
elderly patients [66]. Prospective evaluation of
ties [16]. Many anticancer agents are metabolized by
hematologic toxicity in women 65 years old or older
cytochrome P-450 enzymes, which can be induced
with breast cancer treated with CMF (cyclophos-
or inhibited by many commonly prescribed medica-
phamide, methotrexate, and 5-fluorouracil) [67]
tions, such as opioids, antidepressants, and antipsy-
and patients 70 years old or older with non–small-
chotics [46, 47]. The metabolism of the chemother-
cell lung cancer (NSCLC) treated with gemcita-
apy may also be altered by the concurrent use of beta
bine (Gemzar) and vinorelbine [68] found that age
blockers and vasodilators, which alter blood flow to
was a risk factor for myelosuppression. The risk of
the liver, resulting in an increase in toxicity [48, 49].
grade 3 thrombocytopenia was also higher in older
Drug interactions, therefore, can be a particular con-
patients with breast cancer. The influence of age
cern in polypharmacy.
on the risk of chemotherapy-induced anemia has
received little attention, despite the prevalence of
Age as a Risk Factor for Toxicity
this condition in older patients with cancer.
MYELOSUPPRESSION
MUCOSITIS
Retrospective analyses of data from clinical tri-
Older persons may be more susceptible to mu-
als in patients with solid tumors show no correla-
cosal toxicities, such as cystitis, gastritis, and sto-
tion between age and myelosuppression, the ma-
matitis, which often lead to diarrhea [19, 67, 69].
jor dose-limiting toxicity of modern chemotherapy
In studies of 5-fluorouracil-containing regimens for
20
www.SupportiveOncology.net
THE JOURNAL OF SUPPORTIVE ONCOLOGY

colon or colorectal cancer or CMF for breast can-
febrile neutropenia [77, 78], and anemia [79]. The
cer, advanced age predicted more frequent and
need for prospective models of chemotherapy tol-
Repetto
more severe diarrhea and stomatitis [67, 69–71].
erance that incorporate clinical measures such as
Mucositis requires prompt treatment to prevent
comorbidities, cognition, depression, and nutrition
potentially fatal dehydration and failure of vascu-
(which have high relevance in older patients) has
lar support [67, 69].
been emphasized [21].
A pilot study was conducted in 80 patients aged
OTHER TOXICITIES
70 years or older with solid tumors or non-leuke-
The risk of anthracycline-induced cardiotoxic
mic hematologic malignancies who were treated
effects increases with age but does not appear to be
with various chemotherapy regimens, to determine
relevant until a threshold dose of drug equivalent
overall predictors of both hematologic and non-
to doxorubicin 450 mg/m² or greater has been ad-
hematologic toxicity. After adjustment for the
ministered [1]. Also, both advanced age and re-
published toxic effects of the regimen, the pretreat-
duced glomerular filtration rate appear to be risk
ment diastolic blood pressure and marrow inva-
factors for peripheral and central neuropathy. Cer-
sion correlated independently with toxicity. Pre-
ebellar toxicity with cytarabine may result from
vious treatment with chemotherapy, lower body
accumulation of the catabolic product arauridine,
mass index, low red blood cell counts, and low
which occurs if the rate of renal excretion decreas-
platelet counts predicted lower chemotherapy dose
es [1, 72, 73]. Age appears, however, to have no
intensity [21].
influence on the frequency or severity of nephro-
toxicity [19].
Development of Less-Toxic
The greater incidence and severity of toxicity
Chemotherapy Regimens
in the elderly mean that they require more sup-
The development and use of elderly-specific
portive care. The aggressive and effective manage-
regimens may produce better outcomes than would
ment of toxicity associated with chemotherapy is,
using an empirically reduced dose of a standard
therefore, crucial in this population, as chemother-
regimen [16]. Few agents have been tested in phase
apy doses are frequently reduced to minimize tox-
II or phase III trials in older patients, however. One
icity [7]. With the availability of growth factors,
example is vinorelbine, which has a similar vol-
the greater risk of myelosuppression need not be a
ume of distribution, terminal half-life, and system-
barrier to treatment [74]. A cure for mucositis has
ic clearance rate in patients older and younger than
yet to be approved, but keratinocyte growth factor
65 years [80]. A pivotal randomized trial in pa-
has shown promise in ameliorating this toxicity in
tients with NSCLC who were older than 70 years
clinical trials [75]. Although cardiotoxicity is an-
and did not have impaired bone marrow, hepatic,
other risk in elderly patients, routine use of pro-
or renal function confirmed the favorable toxicity
tective measures is not advised [31]. A more de-
profile of vinorelbine and found that survival with
tailed discussion of and guidelines for supportive
treatment was better than with supportive care
care are provided in the article by Balducci in this
alone [81]. Gemcitabine has also shown efficacy
supplement [10].
and minimal toxicity in a phase III trial in 21 pa-
tients with NSCLC older than 70 years [82]. In a
Predictors of Tolerance to
retrospective analysis of data from four clinical tri-
Chemotherapy
als of gemcitabine, the response rates in patients
Being able to predict which older patients are
older than 65 years were higher than those in
at greatest risk of toxicity associated with chemo-
younger patients [83]. A recent phase III trial in
therapy would be clinically valuable. Pharmacoki-
698 patients older than 70 years with advanced
netic modeling is useful for predicting the toxicity
NSCLC compared the efficacy and toxicity of the
of some drugs, but it may be impractical in clinical
combination of vinorelbine and gemcitabine with
practice, may be difficult to determine with multi-
those of each drug given alone. The combination
drug regimens, and may be inadequate with non-
treatment not only did not increase survival over
pharmacokinetic mechanisms of toxicity such as
that achieved with each drug alone but was also
reduced stem-cell reserves. Multifactorial predic-
more toxic [84].
tive models thus far have focused primarily on he-
Weekly docetaxel (Taxotere) can be tolerated,
matologic end points, such as neutropenia [23,76],
with minimal myelosuppression, in patients older
VOLUME 1, SUPPLEMENT 2 n NOVEMBER/DECEMBER 2003
www.SupportiveOncology.net
21

than 65 years with advanced breast cancer, includ-
toxicity by concomitant use of the cardioprotec-
Risks of Toxicity
ing those with poor performance status [85]. The
tive drug dexrazoxane (Zinecard); schedule chang-
efficacy of this regimen has not been compared
es, such as continuous intravenous infusion or low
with that of the standard dosing (once every
weekly doses; and encapsulation in liposomes [17].
3 weeks), but it provides an additional option for
The incidence of mucositis can be lowered by
treatment in the elderly. Carboplatin (Paraplatin)
using oral fluoropyrimidines (eg, capecitabine [Xe-
is preferable to cisplatin because it causes less re-
loda]) rather than intravenous 5-fluorouracil. Sim-
nal toxicity and thrombocytopenia and requires a
ilarly, epirubicin or mitoxantrone (Novantrone)
smaller volume of fluid for intravenous adminis-
can be substituted for doxorubicin, but there are
tration (the administration of large volumes is con-
few data on their efficacy in elderly patients [19].
traindicated in patients with cardiac decompen-
sation) [16, 17]. An outpatient regimen of
Conclusions
paclitaxel and carboplatin was safely administered
The physiologic changes associated with aging
in a cohort with a high proportion of older patients
may increase the susceptibility of older patients to
(median age, 70 years) with advanced carcinoma
the toxicity of chemotherapy. Chronologic age is
of the urothelium [86].
a risk factor for toxicities such as neutropenia and
Newer anthracyclines, such as idarubicin and
mucositis, and older patients may require more
epirubicin, are thought to be less cardiotoxic than
supportive care. Determining the patient- and reg-
traditional anthracyclines and may be useful in
imen-specific factors that predict the risk for toxic
older patients [17]. Weekly low-dose epirubicin is
effects of chemotherapy would be clinically rele-
tolerated, with negligible toxicity, in women older
vant. Developing new chemotherapy regimens
than 75 years with breast cancer [87]. Furthermore,
with similar efficacy but less toxicity in elderly pa-
the anthracyclines can be manipulated for lower
tients should be a priority for future research.
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