Download Pharmacokinetics and Toxicity of Weekly Docetaxel in Older Patients

Cancer Therapy: Clinical
Pharmacokinetics and Toxicity of Weekly Docetaxel
in Older Patients
Arti Hurria,1 Mark T. Fleming,1 Sharyn D. Baker,2 Wm. Kevin Kelly,1 Katie Cutchall,2 Katherine Panageas,1
James Caravelli,1 Henry Yeung,1 Mark G. Kris,1 Jorge Gomez,1 Vincent A. Miller,1 Gabriella D’Andrea,1
Howard I. Scher,1 Larry Norton,1 and Clifford Hudis1
Abstract
Purpose: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients
with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin
Breath Test results, age, geriatric assessment variables, and toxicity to therapy.
Experimental Design: Twenty patients ages z65 years with metastatic breast, prostate, or
lung cancer entered an Institutional Review Board ^ approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week
break. The Erythromycin Breath Test and geriatric assessment were done before the first dose.
Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel.
Results: Of the 20 patients who entered the study, 19 were evaluable.There were no age-related
differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade z3 toxicity: 16% (3 of 19) grade z3 hematologic toxicity, and 53% (10 of 19) grade
z3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test
results and docetaxel pharmacokinetic variables; however, there was no association between
Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade z3
toxicity.
Conclusions: Despite no statistically significant age-related differences in weekly docetaxel
pharmacokinetics, over half of these older patients experienced a grade z3 toxicity at the
35 mg/m2 starting dose.We advocate a starting dose of 26 mg/m2 on this weekly schedule and
dose escalating if no toxicity.
Although older individuals constitute the majority of patients
with cancer, patients over the age of 65 years have been
underrepresented in clinical trials (1 – 3). As a result, the
recommended dose and schedule of chemotherapy is often
based on clinical trials done in younger patients. Despite
known changes in the distribution, metabolism, and excretion
of drugs with aging (4, 5), there are limited data on the
pharmacokinetics and pharmacodynamics of commonly used
chemotherapies in older patients and few guidelines regarding
the optimal starting doses. In addition, even fewer studies have
included a comprehensive geriatric assessment, which might
Authors’Affiliations: 1Department of Medicine, Memorial Sloan-Kettering Cancer
Center, New York City, New York and 2Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins, Baltimore, Maryland
Received 1/27/06; revised 4/12/06; accepted 6/12/06.
Grant support: Dr. Hurria’s Merck/American Federation for Aging Research Junior
Investigator Award for Geriatric Clinical Pharmacology, K23 AG026749-01 (Paul
Beeson Career Development Award in Aging Research), American Society of
Clinical Oncology-Association of Specialty Professors-Junior Development Award
in Geriatric Oncology, and Sanofi-Aventis Pharmaceuticals.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Arti Hurria, Department of Medicine, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212639-3263; Fax: 212-717-3821; E-mail: hurriaa@ mskcc.org.
F 2006 American Association for Cancer Research.
doi:10.1158/1078-0432.CCR-06-0200
Clin Cancer Res 2006;12(20) October 15, 2006
provide an understanding of the ‘‘functional’’ versus ‘‘chronological’’ age of older patients included on clinical trials. In this
article, we investigate the relation of age, pharmacokinetics of
docetaxel, geriatric assessment variables, and toxicity in a
cohort of older patients with metastatic cancer.
Docetaxel, a widely used chemotherapy agent with broad
antitumor activity, acts as a spindle poison by promoting
tubulin assembly into microtubules and inhibiting depolymerization (6). It is administered on a weekly or every-3-week
schedule. The pharmacokinetic profile of every-3-week docetaxel in older patients has been recently reported. Although
there was no significant difference in the pharmacokinetics
between patients ages z65 years compared with those ages <65
years, there was an increased incidence of neutropenia in older
patients (7). In a phase I study of docetaxel in combination
with cisplatin (25 mg/m2 every 4 weeks), a lower dose of
weekly docetaxel was recommended for patients over the age of
75 years (docetaxel 20 mg/m2 days 1, 8, and 15 every 4 weeks)
compared with those younger than age 75 years (docetaxel
35 mg/m2 days 1, 8, and 15 every 4 weeks; ref. 8). Previous
reports have suggested that docetaxel, administered on a weekly
schedule, has been generally well tolerated and efficacious in
older patients; however, the majority of these patients had
minimal prior treatment and the toxicity profile was not
correlated to a pharmacokinetic analysis (9 – 11).
Docetaxel is primarily metabolized by the liver. The main
enzyme responsible for docetaxel metabolism is the hepatic
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Pharmacokinetics of Weekly Docetaxel in Older Patients
enzyme cytochrome 3A4 (CYP3A4), a member of the cytochrome p450 family. Although hepatic mass and blood flow
decrease with age (4, 5, 12), the effect of this decline on hepatic
enzyme activity remains controversial (13 – 16). Thus, the goal
of this study was to describe the pharmacokinetics of weekly
docetaxel in the older patient and to correlate the pharmacokinetic profile and toxicity to CYP3A4 activity as measured by
the Erythromycin Breath Test (17). Previous studies have
shown no difference in docetaxel pharmacokinetics with age.
Therefore, we chose to focus on an older cohort of patients, a
group in which age-related decline in hepatic function and
physiologic reserve might influence the pharmacokinetic
profile and toxicity.
Patients and Methods
Study design. Twenty patients ages z65 years with metastatic breast,
prostate, or lung cancer were enrolled in this study to evaluate the
pharmacokinetics of weekly docetaxel in older patients. This study was
approved by the Memorial Sloan-Kettering Cancer Center Institutional
Review Board. All study participants provided written informed consent
before enrollment. The Erythromycin Breath Test and a geriatric
assessment were performed before the first dose of docetaxel (Table 1).
Docetaxel 35 mg/m2 was administered i.v. as a 30-minute infusion
weekly for 3 weeks followed by a 1-week break. Blood samples were
collected for pharmacokinetic analysis with the first dose of docetaxel.
Patients continued on study until disease progression or unacceptable
toxicity.
Eligibility criteria. Patients were eligible if they were ages z65 years
with metastatic breast, lung, or prostate cancer. Other criteria for patient
enrollment were Karnofsky performance status (KPS) z70%; adequate
bone marrow function as defined by pre-therapy values of hemoglobin
z8.0 g/dL, absolute neutrophil count z1,500/AL, and platelet count
z100,000/AL; adequate liver function with total bilirubin within
normal limits and transaminases (aspartate aminotransferase and/
or alanine aminotransferase) up to 2.5 institutional upper limit of
normal if alkaline phosphatase was less than or equal to the upper limit
of normal, or alkaline phosphatase could be up to 4 upper limit of
normal if transaminases were less than or equal to upper limit of
normal; and peripheral neuropathy less than or equal to grade 1.
Patients were not eligible if they had a history of severe hypersensitivity
reaction to docetaxel or other drugs formulated with polysorbate 80, or
if they had an allergy to macrolide antibiotics; had untreated central
nervous system metastases or symptomatic central nervous system
metastases requiring escalating doses of corticosteroids; had a history of
untreated or unstable cardiac arrhythmias, congestive heart failure,
or myocardial infarction in the past 6 months; or were on medications
or herbal remedies that induce or inhibit CYP3A4. Patients were
advised to avoid grapefruit juice and ethanol while on study because of
potential inhibition/modulation of CYP3A4.
Patient evaluation. Pretreatment evaluation included medical history and physical examination, laboratory assessment (complete blood
count with differential, comprehensive biochemical screening profile,
lactate dehydrogenase), and electrocardiogram. Additional laboratory
assessments for patients with prostate cancer included a prostatespecific antigen, and for patients with breast cancer, a carcinoembryonic
antigen and CA15-3. Initial extent of disease staging workup for
patients with breast or prostate cancer included a bone scan and
computed tomography scan of the chest, abdomen, and pelvis. Patients
with lung cancer underwent a computed tomography scan of the chest.
The Erythromycin Breath Test was done before initiation of
docetaxel. This test involved administration of a 3 ACi dose of
radioactive erythromycin (14C N-methyl) i.v. A breath sample was
collected into a device 20 minutes later and sent to Metabolic Solutions,
Inc. (Nashua, NH), for analysis of the amount of expired 14CO2
resulting from the oxidation of 14C N-methyl-erythromycin. The data
were reported as the flux of 14CO2, expressed as a percentage of dose
exhaled per minute [C 20min (% dose/min)], assuming a CO2 output of
5 mmol/min/m2 body surface area.
A geriatric assessment was done before start of treatment consisting
of validated scales of functional status (activities of daily living,
instrumental activities of daily living, and KPS), comorbidity (via the
age-adjusted Charlson scale), and psychological state (Geriatric
Depression Scale) (Table 1).
A CBC was done before each docetaxel treatment. A history and
physical exam, KPS, and toxicity assessment were done before the first
and third docetaxel infusions of each cycle. A comprehensive metabolic
panel and tumor markers (patients with breast cancer: carcinoembryonic antigen, CA15-3; patients with prostate cancer: prostate-specific
antigen) were done before the initiation of each cycle. Restaging
computed tomography and bone scans were done every three cycles.
Patients were removed from study if they became ineligible,
developed progressive disease, had unacceptable toxicity, experienced
prolonged treatment delays (z3 weeks), or if the patient or investigator
considered it in the patient’s best interest to discontinue the study.
Drug treatment. Docetaxel was administered i.v. as a 30-minute
infusion at a dose of 35 mg/m2. A treatment cycle consisted of weekly
docetaxel for 3 weeks followed by a 1-week break. For cycle 1, week 1,
8 mg dexamethasone was administered orally the night before, the
morning of, and the evening after docetaxel administration. For
subsequent doses of docetaxel, dexamethasone was either given orally
as specified above or 10 mg i.v. pretreatment at the discretion of the
treating physician.
Pharmacokinetic sampling and assay. Blood samples were collected
for docetaxel pharmacokinetic studies during the first cycle of treatment
at the following time points: Pretreatment; 15 minutes (mid infusion);
Table 1. Geriatric assessment scores before chemotherapy
Domain
Test (maximum score)
Measurement
Functional status
Katz Activities of
Daily Living (18)
Lawton Instrumental Activities
of Daily Living (21)
Karnofsky Performance
Status (100)
Charlson Comorbidity Index
(age-adjusted)
Basic self-care skills such as ability to bathe or dress
18 (16-18)
Activities required to maintain independent daily
living in the home and in the community
Global assessment of functional status predictive of
treatment toxicity and survival in oncology patients
Medical conditions predicting an increased risk of
1-year mortality in a cohort of patients on an
internal medicine inpatient service
Validated screen for depression in the elderly
20 (14-21)
Comorbidity
Psychological state
Yeasavage Geriatric Depression
Scale (15)
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Median prechemotherapy
score (range)
80 (70-100)
3 (2-4)
2 (0-10)
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Cancer Therapy: Clinical
Table 2. Patient demographics and characteristics
Characteristics
Age, y
Sex, n (%)
Female
Male
KPS, n (%)
70
80
90
100
Tumor type, n (%)
Breast
Lung
Prostate
Prior treatments
Hormonal + cytotoxic, n (%)
0
1-3
4-5
>6
Cytotoxic, n (%)
0 Cytotoxic
1 Cytotoxic
2 Cytotoxic
3 Cytotoxic
Medications, n
No. patients
Median
Range
Age 65-74 y
Age z75 y
20
75
66-84
n = 10
n = 10
7
3
5
5
(10)
(45)
(45)
(5)
0
4 (40)
5 (50)
1 (10)
1
5 (50)
4 (40)
0
10 (50)
4 (20)
6 (30)
7 (70)
1 (10)
2 (20)
3 (30)
3 (30)
4 (40)
1
4
4
1
(10)
(40)
(40)
(10)
1
5
3
1
(10)
(50)
(30)
(10)
4
3
2
1
(40)
(30)
(20)
(10)
3
4
2
1
(30)
(40)
(20)
(10)
12 (55)
8 (45)
80
1
9
9
1
2
9
7
2
(10)
(45)
(35)
(10)
7
7
4
2
(35)
(35)
(20)
(10)
70-100
2
0-8
1
0-3
3
0-10
29 minutes (immediately before end of infusion); and after infusion:
10 minutes, 30 minutes, 1 hour, 3 hours, 7.5 hours, 24 hours, 48 hours,
and day 8 (pretreatment week 2). Total docetaxel concentrations in
plasma were measured using a validated method based on highperformance liquid chromatography with tandem mass spectrometric
detection as previously described (18). Unbound docetaxel concentrations in plasma were measured using a validated method based on
equilibrium dialysis as previously described (19). Pharmacokinetic
variables were calculated using noncompartmental analysis implemented in the computer software program WinNonlin version 5.0
(Pharsight Corporation, Mountain View, CA).
Statistical analysis. Twenty patients were accrued to the study.
Patient characteristics and prior treatment data were stratified by age
(65-74 and z75 years). Geriatric assessment was summarized using
median score and range. Docetaxel pharmacokinetic variables were
summarized as mean, SD, median, and range. Pharmacokinetic
variables, Erythromycin Breath Test results, and baseline laboratory
data were correlated with toxicity using univariate logistic regression.
Geriatric assessment variables were correlated with pharmacokinetic
variables by ordinary regression.
hormonal or cytotoxic treatments, and 16 (84%) were on
concurrent medications (median 3; range 0-10).
A baseline geriatric assessment was obtained on all patients.
Measures of functional status showed high median scores—
Katz Activities of Daily Living 18 (range 16-18), Lawton
Instrumental Activities of Daily Living 20 (range 14-21), and
KPS 80% (range 70-100%). Table 1 summarizes the prechemotherapy geriatric assessment scores.
Plasma pharmacokinetics. Docetaxel pharmacokinetic variables of the 19 assessable patients are summarized in Table 3.
Results
Between March 2003 and March 2005, 20 patients over the
age of 65 years (median age 75 years; range 66-84 years) with
metastatic breast, lung, or prostate cancer were enrolled in this
study. Baseline characteristics are shown in Table 2.
Of the 20 patients enrolled in the protocol, 19 patients were
assessable for pharmacokinetic analysis. One patient was
excluded from pharmacokinetic analysis because the data
seemed erroneous: The value for C max was 38.2 Ag/mL,
which was >15 SDs from the mean value of 4.85 Ag/mL.
Of the 19 patients assessable for pharmacokinetic analysis,
13 (68%) had received prior cytotoxic treatment (median 1;
range 0-3), 9 (47%) patients had received four or more prior
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Table 3. Docetaxel pharmacokinetic variables
Variable
Total
C max, Ag/mL
AUC, Ag/mL h
CL, L/h
CL, L/h/m2
Vss, L
Vss, L/m2
t 1/2,z , h
Unbound
C max, Ag/mL
AUC, Ag/mL h
CL, L/h
CL, L/h/m2
Vss, L
Vss, L/m2
t 1/2,z , h
Mean (SD)
4.9 (2.1)
4.1 (2.1)
18.3 (7.9)
10.3 (4.4)
579 (434.8)
319 (221)
58.9 (30.1)
286
222
330
190
8,715
5,071
61.2
(147)
(105)
(120)
(68)
(5,248)
(3,306)
(33.1)
Median (range)
4.1 (1.7-8.8)
3.6 (1.7-11.2)
17.5 (4.1-35.1)
9.9 (3.2-21.4)
424 (158.7-1,902)
270.6 (98.2-491)
57.3 (17.1-125)
231 (113-677)
212 (123-479)
323 (96.0-532)
211 (58.2-278)
7,790 (2,006-23,512)
4,889 (1,292-15,468)
54.2 (15.0-140)
Abbreviations: C max, maximum plasma concentration; AUC, area
under the concentration time curve from time 0 to infinity; CL,
systemic clearance; Vss, volume of distribution at steady-state;
t 1/2, terminal half-life.
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Pharmacokinetics of Weekly Docetaxel in Older Patients
occurred after her first dose of docetaxel. This 74-year-old
patient had a KPS of 90%, was independent in her activities
of daily living and instrumental activities of daily living. She
had received no prior chemotherapy in the past. Her only
distinguishing clinical feature was a longstanding history of
anorexia (her baseline weight was 35 kg). Pharmacokinetic
analysis revealed that this patient had an extremely high
docetaxel AUC (total AUC = 11.2 Ag/mL h) and low clearance
(total CL = 4.1 L/h), the highest and lowest, respectively, on the
study.
Overall, however, there was no association by univariate
analysis between grade z3 toxicity and pharmacokinetic
variables, baseline geriatric assessment scores, or baseline
laboratory data other than for baseline alanine aminotransferase value in which there was a trend toward significance
(P = 0.06). There was no association between increased
age and all grade z3 (P = 0.48), nonhematologic (P = 0.97),
or hematologic (P = 0.29) toxicities.
Fig. 1. Representative plasma concentration-time profiles for total (o) and
unbound (5) docetaxel.
Discussion
Mean (SD) value for total clearance (CL) was 18.3 L/h (7.85);
mean area under the curve (AUC) was 4.12 Ag/mLh (2.13);
mean C max was 4.85 Ag/mL (2.10). Despite wide variations in
docetaxel pharmacokinetics, significant associations were not
observed between increased age and increased total docetaxel
AUC (P = 0.24), decreased clearance (P = 0.24), or increased
C max (P = 0.12). In addition, there was no significant
association between increased age and unbound docetaxel
pharmacokinetic variables. Representative plasma concentration-time profiles for total and unbound docetaxel are
presented in Fig. 1. Geriatric assessment variables were
correlated with pharmacokinetic variables by ordinary regression. A lower score on the Lawton Instrumental Activities of
Daily Living scale (indicating increased need for assistance in
completing instrumental activities of daily living) correlated
with a longer terminal half-life of bound docetaxel (P = 0.02).
A higher score on the Geriatric Depression Scale correlated with
a higher volume of distribution (P = 0.01) at steady-state and
longer terminal half-life (P = 0.01) of bound docetaxel.
The Erythromycin Breath Test. The mean Erythromycin
Breath Test score was 3.01% dose/h (range 1.68-4.98; SD
0.78). By univariate analysis, no statistically significant association was observed between age and CYP3A4 activity as
measured by the Erythromycin Breath Test (P = 0.35); however,
there was an association between the Erythromycin Breath Test
score and the total pharmacokinetic variables [AUC (P = 0.02)
and clearance (P = 0.09)] and unbound pharmacokinetic
variables [AUC (P = 0.01) and clearance (P = 0.04)].
Scatterplots of associations between the Erythromycin Breath
Test variable C 20 (%dose/min), and total and unbound
docetaxel clearance and AUC are shown in Fig. 2.
Toxicity. Toxicity following docetaxel is summarized in
Table 4. Of the 11 of 19 (58%) patients who experienced
grade z3 toxicity, 3 of 19 (16%) had grade z3 hematologic
toxicity and 10 of 19 (53%) had grade z3 nonhematologic
toxicity. Diarrhea and fatigue were the most common nonhematologic toxicities, and leukopenia was the most common
hematologic toxicity (Table 5). One patient experienced a grade
5 toxicity consisting of infection without neutropenia, which
www.aacrjournals.org
In this study, we report on the pharmacokinetics of weekly
docetaxel in an older population with metastatic cancer that
incorporated geriatric assessment and assessment of CYP3A4
activity. In this cohort, we found no age-related differences in
docetaxel pharmacokinetics. These results are consistent with
other studies (7, 20, 21). Ten Tije et al. (7) evaluated the
pharmacokinetics of docetaxel at a dose of 75 mg/m2 given
once every 3 weeks and found no difference between patients
older or younger than age 65 years; however, older patients
experienced a higher rate of grade 4 and febrile neutropenia.
Minami et al. (20) evaluated docetaxel pharmacokinetics at a
Fig. 2. Scatterplots of associations between CYP3A4 activity, by assessment
of the Erythromycin BreathTest variable C 20 (%dose/min), and total (A and B) and
unbound (C and D) docetaxel clearance and AUC.
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dose of 35 mg/m2 for patients ages <65 years and 20 mg/m2 for
patients ages z65 years, in combination with cisplatin at a dose
of 25 mg/m2 given every 4 weeks. They found no age-related
differences in the pharmacokinetics of either drug; however,
older patients experienced greater neutropenia. The authors
chose a lower dose of docetaxel for older patients based on data
from a phase I study of patients above and below the age of
75 years. Slaviero et al. (21) evaluated the pharmacokinetics of
weekly docetaxel at a dose of 40 mg/m2 and found no agerelated differences.
The results of these studies are inconsistent with the results of
the pharmacokinetic study done by Bruno et al. (22), who
showed that docetaxel clearance was related to age in a cohort
of 640 patients; however, even in that study, the effect of age
was modest (estimated at a 7% decrease of mean clearance for a
71-year-old patient).
Despite studies showing no difference or modest differences in
docetaxel pharmacokinetics with age, older patients are at
increased risk of toxicity. The pharmacodynamics of the drug
differ in younger and older patients, likely because of a decreased
physiologic reserve in older compared with younger patients.
For example, older patients are more susceptible to myelosuppression and myelosuppressive-associated complications, likely
because of decreased bone marrow reserve (23 – 26).
An advantage of a weekly schedule of docetaxel compared
with an every-3-week schedule is the decreased risk of
hematologic toxicity; however, even on the weekly schedule
in our cohort, over half of patients developed a grade 3 or
higher, primarily nonhematologic, toxicity, necessitating dose
reduction. Diarrhea and fatigue were the most common
nonhematologic toxicities. A possible explanation for the
comparatively increased toxicity in our study population is
that our patients were more heavily pretreated than patients
described in previously reported studies where the range of
prior cytotoxic therapy was 0% to 51% (9, 10). In our study,
65% of patients had received prior cytotoxic therapy, and our
patients were of an older median age than patients in other
studies (27).
These data raise questions regarding the optimal starting dose
of weekly docetaxel in patients ages z65 years, especially in
those patients who have received prior therapy. Based on the
high incidence of grade 3 and higher toxicity, we advocate
starting at 26 mg/m2 and escalating the dose if the patient
tolerates therapy. Minami et al. (20) used an even lower starting
dose of docetaxel (20 mg/m2) when administered in combination with cisplatin, based on their phase I data in patients
ages >75 years. The typical geriatric adage of ‘‘start low and go
slow,’’ referring to beginning medications at a low dose and
escalating if no toxicity ensues, might be applicable to the
dosing of chemotherapy as well. Further studies are needed to
determine whether efficacy is compromised by this ‘‘start-low’’
Table 4. Grade z3 toxicity attributable to docetaxel
Any toxicity, Hematologic
Nonhematologic
n (%)
toxicity, n (%) toxicity, n (%)
All patients
Age 65-74
Age z 75
11 (58)
4 (44)
7 (70)
3 (19)
1 (11)
2 (20)
10 (53)
4 (44)
6 (60)
Clin Cancer Res 2006;12(20) October 15, 2006
Table 5. Treatment-related adverse events (n = 19)
Toxicity
Nonhematologic
Diarrhea
Fatigue
Dyspnea
Neuropathy
Arrhythmia
Confusion
Hallucination
Aphasia
Infection without neutropenia
Hypocalcemia
Hypokalemia
Hematologic
Leukopenia
Neutropenia
Liver function test
PTT
Grade 3, Grade 4, Grade 5,
n (%)
n (%)
n (%)
3 (16)
3 (16)
1 (5)
1 (5)
2 (11)
1 (5)
1 (5)
1 (5)
2 (11)
2 (11)
1 (5)
0
0
1 (5)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (5)
0
0
2 (11)
1 (5)
1 (5)
1 (5)
0
0
0
0
0
0
0
0
Abbreviation: PTT, partial thromboplastin time.
approach. In this study, we attempted to determine whether the
Erythromycin Breath Test, as a surrogate measure of CYP3A4
activity, could predict toxicity and therefore be used to
individualize dosing in the future. Our results show that
although there was an association between the Erythromycin
Breath Test results and docetaxel pharmacokinetic variables,
there was no association between either of these results and risk
of grade z3 toxicity to weekly docetaxel in this cohort. Further
studies in a larger cohort of patients are needed to explore these
relationships.
Incorporation of a geriatric assessment is being increasingly
viewed as an important aspect of clinical trial design in
geriatric oncology. Guidelines, including those from the
National Comprehensive Cancer Network and International
Society of Geriatric Oncology, advocate the use of comprehensive geriatric assessment as a tool to stratify baseline
characteristics and to predict tolerance to chemotherapy (28).
No type of geriatric assessment was included in the previously
reported papers of docetaxel pharmacokinetics and toxicity in
older patients. We can only speculate that this information
might provide insight regarding the differential incidence of
toxicity among the patients in this trial and those included in
other clinical trials. We incorporated standard measures of
geriatric assessment in our study and found that the study
participants had high mean scores, likely reflecting the
healthier older patient who is included in trials. Different
geriatric assessment measures that evaluate a broader range of
physical functioning will be needed to evaluate older
individuals included in clinical trials.
Limitations to our study include the modest sample size and
the fact that patients were accrued from a single tertiary care
cancer center. The results of the geriatric assessment might be
more informative in a group of patients with a broader range
of physical functioning. The range of tumor types represented
also limits our power to assess the clinical response within
each tumor type; therefore, based on the small subsets, we did
not report treatment efficacy. We focused our study on patients
age 65 and older, thinking that if age-related differences in
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Pharmacokinetics of Weekly Docetaxel in Older Patients
pharmacokinetics existed, they would be most pronounced in
this age group. We did not compare these results to a younger
cohort of patients.
On the other hand, our study has important strengths. We
showed the feasibility of performing a pharmacokinetic study
in older patients. In addition, we showed the feasibility of
incorporating a geriatric assessment in the baseline evaluation
of older adults on clinical trials. Through this study, we
identified barriers to accrual in pharmacokinetic studies of
older patients. Our biggest accrual barrier was lack of patient
transportation to and from the hospital for the extensive
pharmacokinetic sampling required. Our study accrual increased dramatically after amending the study to provide
housing for patients during the pharmacokinetic portion of
the study. These costs should be considered as part of the trial
design of future pharmacokinetic studies in the elderly
patient.
Ideally, within the metastatic setting, the goal of care should
be to balance efforts to prolong life with efforts to maintain
quality of life. This is particularly true in the older population,
where decreased physiologic reserve and comorbidity can lead
to increased toxicity from cancer treatment. Further studies of
chemotherapy efficacy, toxicity, and optimal dosing are needed.
A comprehensive geriatric assessment is an essential component of clinical trial design in the older patient.
Acknowledgments
We thank Carol A. Pearce, MFA, Department of Medicine, for her assistance in
the preparation of the manuscript.
References
1. Hutchins LF, Unger JM, Crowley JJ, Coltman CA, Jr.,
Albain KS. Underrepresentation of patients 65 years
of age or older in cancer-treatment trials. N Engl J
Med 1999;341:2061 ^ 7.
2. Yee KW, Pater JL, Pho L, Zee B, Siu LL. Enrollment of
older patients in cancer treatment trials in Canada:
why is age a barrier? J Clin Oncol 2003;21:1618 ^ 23.
3. Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider
RS, Friedman MA. Representation of older patients in
cancer treatment trials. Cancer 1994;74:2208 ^ 14.
4.Vestal RE. Aging and pharmacology. Cancer 1997;80:
1302 ^ 10.
5. Avorn J, Gurwitz JH. Geriatric medicine. SpringerVerlag; NewYork: 1997.
6. US Food and Drug Administration Center for Drug
Evaluation and Research. Approved claims for microtubuleinhibitors. In: OncologyTools web sitehttp://www.
accessdata.fda.gov/scripts/cder/onctools/labels.
cfm?GN=docetaxel; 2003.
7. tenTije AJ,Verweij J, Carducci MA, et al. Prospective
evaluation of the pharmacokinetics and toxicity profile
of docetaxel in the elderly. J Clin Oncol 2005;23:
1070 ^ 7.
8. Ohe Y, Niho S, Kakinuma R, et al. Phase I studies of
cisplatin and docetaxel administered by three consecutive weekly infusions for advanced non-small cell
lung cancer in elderly and non-elderly patients. Jpn J
Clin Oncol 2001;31:100 ^ 6.
9. Hainsworth JD, Burris HA III,Yardley DA, et al. Weekly docetaxel in the treatment of elderly patients with
advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 2001;19:
3500 ^ 5.
10. Maisano R, Mare M, Caristi N, et al. A modified
weekly docetaxel schedule as first-line chemotherapy
www.aacrjournals.org
in elderly metastatic breast cancer: a safety study.
J Chemother 2005;17:242 ^ 6.
11. OheY, Niho S, Kakinuma R, et al. A phase II study of
cisplatin and docetaxel administered as three consecutive weekly infusions for advanced non-small-cell
lung cancer in elderly patients. Ann Oncol 2004;15:
45 ^ 50.
12. Egorin MJ. Cancer pharmacology in the elderly.
Semin Oncol 1993;20:43 ^ 9.
13. Baker SD, van Schaik RH, Rivory LP, et al. Factors
affecting cytochrome P-450 3A activity in cancer
patients. Clin Cancer Res 2004;10:8341 ^ 50.
14. Hunt CM, Westerkam WR, Stave GM. Effect of age
and gender on the activity of human hepatic CYP3A.
Biochem Pharmacol 1992;44:275 ^ 83.
15. Schwartz JB. Race but not age affects erythromycin
breath test results in older hypertensive men. J Clin
Pharmacol 2001;41:324 ^ 9.
16. Tanaka E. In vivo age-related changes in hepatic
drug-oxidizing capacity in humans. J Clin PharmTher
1998;23:247 ^ 55.
17. Metabolic Solutions, Inc. Erythromycin breath test.
Accessed 2006.
18. Baker SD, Zhao M, He P, Carducci MA, Verweij J,
Sparreboom A. Simultaneous analysis of docetaxel
and the formulation vehicle polysorbate 80 in human
plasma by liquid chromatography/tandem mass spectrometry. Anal Biochem 2004;324:276 ^ 84.
19. Acharya MR, Baker SD, Verweij J, Figg WD,
Sparreboom A. Determination of fraction unbound
docetaxel using microequilibrium dialysis. Anal Biochem 2004;331:192 ^ 4.
20. Minami H, OheY, Niho S, et al. Comparison of pharmacokinetics and pharmacodynamics of docetaxel
and cisplatin in elderly and non-elderly patients: why
6105
is toxicity increased in elderly patients? J Clin Oncol
2004;22:2901 ^ 8.
21. Slaviero KA, Clarke SJ, McLachlan AJ, Blair EY,
Rivory LP. Population pharmacokinetics of weekly
docetaxel in patients with advanced cancer. Br J Clin
Pharmacol 2004;57:44 ^ 53.
22. Bruno R, Vivier N, Veyrat-Follet C, Montay G,
Rhodes GR. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for
docetaxel. Invest New Drugs 2001;19:163 ^ 9.
23. Gomez H, Hidalgo M, Casanova L, et al. Risk factors
for treatment-related death in elderly patients with
aggressive non-Hodgkin’s lymphoma: results of a
multivariate analysis. J Clin Oncol 1998;16:2065 ^ 9.
24. Dees EC, O’Reilly S, Goodman SN, et al. A prospective pharmacologic evaluation of age-related toxicity
of adjuvant chemotherapy in women with breast cancer. Cancer Invest 2000;18:521 ^ 9.
25. Repetto L, Carreca I, Maraninchi D, Aapro M,
Calabresi P, Balducci L. Use of growth factors in the
elderly patient with cancer: a report from the Second
International Society for Geriatric Oncology (SIOG)
2001meeting.Crit RevOncol Hematol2003;45:123 ^ 8.
26. Balducci L, Corcoran MB. Antineoplastic chemotherapy of the older cancer patient. Hematol Oncol
Clin North Am 2000;14:193 ^ 212, x ^ xi.
27. D’Hondt R, Paridaens R,Wildiers H, et al. Safety and
efficacy of weekly docetaxel in frail and/or elderly
patients with metastatic breast cancer: a phase II
study. Anticancer Drugs 2004;15:341 ^ 6.
28. Extermann M, Aapro M, Bernabei R, et al. Use of
comprehensive geriatric assessment in older cancer
patients: recommendations from the task force on
CGA of the International Society of Geriatric Oncology
(SIOG). Crit Rev Oncol Hematol 2005;55:241 ^ 52.
Clin Cancer Res 2006;12(20) October 15, 2006
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Pharmacokinetics and Toxicity of Weekly Docetaxel in Older
Patients
Arti Hurria, Mark T. Fleming, Sharyn D. Baker, et al.
Clin Cancer Res 2006;12:6100-6105.
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