pharmacology of 21-day oral etoposide given in combination ...auc3 of etoposide and hematological...
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Vol. 3, 719-725, May 1997 Clinical Cancer Research 719
Pharmacology of 21-Day Oral Etoposide Given in Combination with
i.v. Cisplatin in Patients with Extensive-Stage Small Cell Lung
Cancer: A Cancer and Leukemia Group B Study
(CALGB 9062)’
Antonius A. Miller,2 Gary L. Rosner,
Mark J. Ratain, Donna R. Hoffis, Mark R. Green,
and Richard L. SchilskyUniversity of Tennessee, Memphis, Tennessee 38163 [A. A. M.];Duke University, Durham, North Carolina 27710 [0. L. R., D. R. H.];University of Chicago, Chicago, illinois 60604 [M. J. R., R. L. S.];and University of California, San Diego, California 92103 [M. R. 0.]
ABSTRACTThis was a pharmacological companion study to a ran-
domized Phase ifi trial comparing 21-day oral versus 3-day
i.v. etoposide in combination with i.v. cisplatin in patients
with extensive-stage small cell lung cancer. Etoposide
plasma concentrations were measured in patients random-
ized to the 21-day schedule and correlated with toxicity and
tumor response.
Patients were treated with etoposide (50 mg/m2/day)
orally for 21 days and cisplatin (33 mglm2/day) i.v. for 3
consecutive days every 28 days for 6 courses. Plasma sam-
plea before the daily etoposide dose (trough concentrations)
and complete blood counts were obtained weekly during
treatment. The average of three etoposide concentrations
(Er) per course was calculated.
Of 158 patients registered to this schedule of the study,
150 were eligible. In 106 patients, etoposide samples wereobtained at least in the first course in which the mean E�
was 039 �ml (SD 0.29). In 102 patients (missing albu-
mm values in 4 of 106 patients), the concentration of etopo-
side not bound to protein (E�) was estimated based on the
following equation: percentage unbound = (1.4 x total bil-
irubin) - (6.8 x albumin) + 34.4. Regression analysis re-
vealed that increasing age was correlated with higher E�
(r 0.27; two-tailed P< 0.01) and E� (r 0.31; two-tailed
P < 0.01). Higher E� and Ef� values were associated with
lower WBC counts and absolute neutrophil counts after the
Received 8/29/96; revised 1/24/97; accepted 1/24/97.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.1 Supported by National Cancer Institute (Bethesda, MD) GrantsCA47555, CA33601, CA41287, CA11789, and CA44691 and by theBristol-Myers Oncology Division. Conducted by the Cancer and Leu-kemia Group B (R. L. S., chairman; central office, Chicago, IL).2 To whom requests for reprints should be addressed, at University ofTennessee, 3 North Dunlap, Memphis, TN 38163. Phone: (901) 448-5817; Fax: (901) 448-5033; E-mail: [email protected].
first treatment course in 83 patients with nadir counts. Usingmultiple linear regression, a pharmacodynamic model was
developed that included E� or E�, age, and alkaline phos-
phatase. An interaction with bone marrow results at Wag-
nosis was found, indicating a sharper decline in nadir counts
with increasing E� or E� when the marrow was involvedwith small cell lung cancer. This model explained 29% of the
variation for WBC nadirs (P < 0.001) and 31 % of thevariation for absolute neutrophil count nadirs (P < 0.001).
Neither E� nor E� showed a significant correlation with
tumor response.
A pharmacokinetic relationship between E� or E�
and age was found. A pharmacodynamic model could bedeveloped for toxicity but not for tumor response.
INTRODUCTION
Clinical oncologists are well aware of the narrow therapeu-
tic index of most antineoplastic drugs, yet our understanding of
the pharmacodynamics of cancer therapy is limited (1). The
desired effect is a reduction in tumor volume, which is generally
optimized by maximizing the dose. Because of the narrow
therapeutic index, most dosing strategies focus on the dose-
related adverse effects of treatment, especially myelosuppres-
sion. Pharmacodynamic studies of antineoplastic drugs are corn-
plicated by the temporal discrepancy between measured drug
concentrations and clinical outcome. Furthermore, patients gen-
erally cannot be observed daily, leading to the maximum ob-
served effect being less than the true maximum effect. Despite
these difficulties, insight into pharmacodynamic relationships
may improve our therapeutic strategies.
Studies of the pharmacokinetics (study of drug concentra-
tion versus time) and pharmacodynamics (study of drug dose or
concentration versus clinical effects) of etoposide have recently
shown promising results. After i.v. administration, relationships
have been noted between steady-state concentrations or the
AUC3 of etoposide and hematological toxicities, particularly
leukopenia and neutropenia (2-7). One study also examined the
duration of exposure to various concentrations of etoposide;
antitumor activity was associated with the maintenance of lower
levels than those found to be associated with hematological
toxicity (7). This led to the hypothesis that the schedule of
etoposide administration may affect efficacy and toxicity and
3 The abbreviations listed are: AUC, area under the curve; CALGB,Cancer and Leukemia Group B; E#{128}�,average of three etoposide concen-trations per course; � the concentration of etoposide not bound toprotein; ANC, absolute neutrophil count; ANC�, ANC (at nadir); WBC,,WBC count (at nadir); Em,,�, sigmoid maximum response model.
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720 Pharmacology of 21-Day Oral Etoposide
that prolonged exposure to low concentrations may improve the
therapeutic index for this phase-specific cytotoxic drug. Because
etoposide is also available in an oral formulation, prolonged
administration (for instance, for 2 1 days) is feasible without the
need for infusion pumps (8). Disadvantages of this approach are
the variable bioavailability of oral etoposide (9-12) and the
availability of only one capsule size (50 mg) in the United
States. Some dose approximations on a schedule of 50 mg/m2/
day for 21 days are therefore necessary. Phase II studies in small
cell lung cancer suggested that the 21-day oral schedule of
etoposide might be more efficacious (13-15). Pharmacody-
namic relationships between etoposide levels and hematological
toxicity (leukopenia and neutropenia) have also been demon-
strated for the 21-day schedule (16-19). Statistically significant
correlations between weekly measurements of E� before a once-
daily dose (trough concentrations) and the nadir leukocyte or
neutrophil counts have been found and expressed in pharmaco-
dynamic models (16-18).
In 1990, the CALOB designed a study that asked the
following questions: (a) Does etoposide have schedule-depen-
dent effects in small cell lung cancer? and (b) Do measurements
of E� during prolonged exposure yield clinically important
correlations with hematological toxicity and tumor response?
This resulted in a randomized Phase III trial testing the schedule
dependency of 2 1-day oral versus 3-day i.v. etoposide in com-
bination with iv. cisplatin in extensive-stage small cell lung
cancer. All patients randomized to the 21-day schedule had
plasma samples taken to measure E�. Pharmacological ap-
proaches, if proven superior, could replace our current practice
of dose normalized for body surface area. Dose normalization
based on body weight or predicted surface area fails to achieve
consistent drug exposure (20, 21). All patients received combi-
nation chemotherapy with etoposide and cisplatin. Although the
cisplatin may have confounded the results regarding clinical and
pharmacological questions about etoposide, a trial of single-
agent etoposide in untreated extensive-stage small cell lung
cancer would not have received wide acceptance in the cooper-
ative group at the time and was subsequently found to be
inferior to combination chemotherapy (22, 23).
The two schedules of etoposide did not result in differences
in treatment outcome with respect to tumor response and sur-
vival (24). A significantly greater rate of severe or life-threat-
ening hematological toxicity was noted on the 21-day oral
etoposide schedule; 83% of patients on this schedule experi-
enced grade 3 or 4 leukopenia during treatment compared to
62% of patients on the 3-day i.v. etoposide schedule (24). This
report provides the results of the pharmacological component of
the study.
PATIENTS AND METHODSEligibility criteria and treatment schedules were published
previously (24). When patients were randomized to the 21-day
schedule, they were also registered to the pharmacological com-
panion trial. Treatment on this schedule consisted of etoposide
(50 mg/m2/day) orally for 2 1 days and cisplatin (33 mg/m2/day)
on days 1, 2, and 3 by i.v. infusion over 1 h in 250 ml of normal
saline or 3% sodium chloride solution (after hydration with at
least I liter of normal saline over 1-2 h) every 28 days for 6
courses. The commercially available, soft gelatin capsules of
etoposide (VePesid) were used for all patients as a once-daily
dose. Bristol-Myers Oncology Division (Princeton, NJ) pro-
vided the drug free of charge for 15 patients who could not
otherwise afford it (IND 38,375). Because etoposide is available
in the United States only in 50-mg capsules, it was necessary to
make some approximations in the calculated daily dose. For
example, if a patient was calculated to receive 85 mg/day, the
amount of etoposide given was 100, 100, and 50 mg on 3
consecutive days, respectively, and the schedule was repeated
for 21 days (i.e., average daily dose = 83.3 mg). Patients
received a calendar with the number of capsules to be taken
written in for each treatment day to insure accuracy and corn-
pliance. No radiation therapy except for brain metastases was
administered while patients received chemotherapy.
Weekly samples were obtained for complete blood counts
and determination of etoposide plasma concentrations. Proce-
dures developed in a previous study at one institution (16) were
followed in this cooperative group study. The time period be-
tween the previous day’s drug administration and blood sam-
pling was 24 h. Blood was collected before the daily dose of
etoposide in heparinized green-top tubes and immediately cen-
trifuged at 1000 x g (2000-3000 rpm in a tabletop centrifuge)
for 10 mm. Plasma was transferred into a polypropylene tube,
stored at -20#{176}C, batched, and sent on dry ice by overnight
express mail to the laboratory at the University of Tennessee.
Plasma was analyzed for E� by high-performance liquid chro-
matography according to a previously published method (16).
The lower limit of detection was 0.05 p.g/ml. The day-to-day
coefficients of variation for etoposide measurements were less
than 10%, as in the previous study (16). The measured values
for the E� in microgram/milliliter plasma were entered into the
central CALOB database that also contained all the clinical
information for this trial. E� was estimated based on an
equation developed by Stewart et a!. (25): percentage un-
bound = (1.4 X total bilirubin) - (6.8 X albumin) + 34.4.
Statistics. Total E� and Ef�� for a given course were
computed by averaging the available data for each patient. We
also generated an adjusted trough concentration to account for
the fact that patients varied the number of 50-mg tablets each
day to approximate a dose of 50 mg/m2. This adjusted concen-
tration statistic, produced by dividing each measured concentra-
tion by the oral dose of etoposide taken by the patient the
previous day, estimated the trough concentration of etoposide
per milligram of oral etoposide. The adjusted average daily
trough concentration of oral etoposide, standardized for body
surface area, was estimated by averaging these adjusted concen-
trations computed for a patient in a given cycle and multiplying
the result by 50, giving an estimated trough concentration during
a treatment cycle for each patient, based on the prescribed daily
dose of 50 mg. Thus, the adjusted average daily trough concen-
tration of etoposide is an estimate of total E� expected for the
patient for every 50 mg of oral etoposide. Furthermore, multi-
plying these latter estimates of a patient’s daily average trough
concentration by the patient’s body surface area produced an
estimate of the average daily trough concentration expected for
that patient if receiving a constant daily dose of 50 mg/m2.
Although daily concentrations correlated with the previous
day’s dose, the average concentration of the cycle exhibited
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Clinical Cancer Research 721
much lower correlation. In addition, pharmacodynamic analyses
using adjusted trough concentrations did not differ appreciably
from analyses based on the unadjusted average concentrations,
so we only report results using the average of measured con-
centrations.
The coefficient of variation, expressed as a percentage, was
defined as 100 times the SD divided by the mean. Interpatient
variability for each treatment course summarizes the variability
in patient-specific average concentrations within the course and
was estimated by the coefficient of variation for the patient-
specific average concentrations within the course. Intrapatient
variability across courses, calculated using data from patients
with concentrations from at least three courses, was estimated
by computing for each patient the coefficient of variation of
his/her course-specific average concentrations.
Means are presented with SDs or SEs as indicated. All
statistical significance tests are two-sided, and significance is
assessed at the 5% level. Some analyses used logarithms of data,
such as concentrations or nadir blood counts. Measured concen-
trations equal to 0 p.g/ml were changed to 0.03 before taking
logs, because the lowest detectable value was 0.05 p.g/ml. Nadir
neutrophil counts equal to zero were set to 0.05 X l03/p.1 if the
logarithm was used. Linear regression was used to model rela-
tionships. The E� model was fit using nonlinear regression
with the logarithm of the parameters to ensure positive values.
Nonparametric group comparisons were tested for statistical
significance using the Wilcoxon rank-sum test if examining two
groups and the Kruskal-Wallis test if examining three or more
groups. Correlations across cycles were estimated nonparametri-
cally, based on the ranks of the data (Spearman’s rank correla-
tion).
Pharmacodynamic analyses of nadir counts excluded pa-
tients without monitored blood counts recorded after day 14 of
cycle 1 because the nadir occurred around day 21 . Furthermore,
analyses of concentrations within a cycle or over multiple cycles
of chemotherapy accounted for within-patient correlation using
a linear mixed-effects model (26) fit with the function Ime
written in the S programming language (27). All analyses were
carried out using the S-Plus statistical package (28).
RESULTS
Of 158 patients registered to the oral etoposide schedule,
150 were eligible, and 106 of these had samples for E� available
at least for the first course (Table 1). The mean E� for 106
patients in the first course was 0.39 p.g/ml (SD = 0.29; range,
0.03-1.54 p.g/ml). The mean � for 102 patients for whom
albumin concentrations were recorded was 0.044 p.g/ml (SD =
0.039; range, 0.002-0.220 p.g/ml) in the first course (Table 2).
Interpatient variability in course 1 was 75% for E� and 90% for
� Because dose adjustments could have introduced more
interpatient variability, the study prohibited dose adjustments
for etoposide; only cisplatin doses were adjusted based on
toxicity, including hematological toxicity. Nevertheless, courses
2-6 exhibited higher interpatient variability, ranging from 86-
99% for E� and from 106-125% for � with the greatest
variability occurring in the second treatment course. Overall, the
median interpatient coefficient of variability was 93% for E�
and 109% for Ef�e for courses 1-6. The mean intrapatient
Table 1 Characteristics of 106 patients with E� at least in the firstcourse
Characteristic No.
GenderMale 81Female 25
Age (yrs)<50 650-59 2960-69 4270+ 29
Performance status0 231 442 39
RaceWhite 95Black 10
Other 1Bone marrow involvement
Positive 35Negative 69Unknown 2
Laboratory values recordedBilirubin 106Alkaline phosphatase 106Creatimne 106Albumin 102Neutrophil nadir counts 83
Tumor responseComplete 17Partial, regression 50Stable disease 15Progression 7Unevaluable 17
variability in the first course, expressed as the coefficient of
variation, was 52% (median, 39%; range, 6-173%) for both E�
and Efree. The mean intrapatient variability across courses was
50% (median, 39%; range, 12-198%), examining patients with
at least 3 treatment courses (72 patients for E� and 69 patients
for Ef�e). Correlations for E� and Ef�e averaged 0.60 and 0.64,
respectively, between consecutive courses.
Age was significantly correlated with E� (r = 0.27; P =
0.006) and Efr� (r = 0.31; P = 0.002) in the first course (Fig.
1). An analysis using only the first concentration among patients
receiving 100 mg of oral etoposide on the previous day (73
patients) confirmed this result, indicating that this correlation
was independent of the dose administered on the day before the
E� was determined. Age did not correlate significantly with
measures of renal (i.e. , serum creatinine) or hepatic function
(i.e., bilirubin, aspartate aminotransferase, and alkaline phos-
phatase). E� was not significantly correlated with other meas-
ured patient characteristics (height, weight, body surface area, or
body mass index) or with clinical laboratory values (bilirubin,
aspartate aminotransferase, alkaline phosphatase, or serum crc-
atinine). Liver metastases were detected in 44 of 106 patients
and were correlated with higher alkaline phosphatase values
(P < 0.001). Bone metastases were diagnosed in 51 patients but
did not correlate with alkaline phosphatase values (P 0.46).
E� did not differ significantly by sites of metastatic disease.
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In
Fig. 1 Relationship between age (years) and E� or E� (microgram/milliliter plasma).
722 Pharmacology of 21-Day Oral Etoposide
Table 2 Median, mm imum, and max imum E� by course
Course
Total etopos ide E� Efr,,,
n Median Mm” Max n Median Mm Max
1234S6
1068573634324
0.310.340.340.350.370.32
000000
1.542.702.042.262.761.80
1028170614324
0.0310.0310.0310.0340.0350.027
000000
0.2200.3720.2910.3230.3940.210
a Mm, minim um; Max, maximum.
The median (range) E� values for performance status 0, 1,
and 2 were 0.23 (0-1.08), 0.30 (0-1.26), and 0.39 (0-1.54)
p.g/ml, respectively. For Ef�, the corresponding values were
0.027 (0-0. 13), 0.023 (0-0. 12), and 0.045 (0-0.22) p.g/ml.
These differences by performance status were statistically sig-
nificant for E� (P = 0.023) and Ef� (P = 0.009) when
analyzed without adjustment for administered dose. An analysis
comparing the first concentration across levels of performancestatus among patients who received 100 mg of etoposide the
previous day (73 patients) showed that only E� was signifi-
candy higher among patients with a performance status of 2
versus those with a lower performance status. However, this
finding may be attributable to a confounding relationship be-
tween performance status and albumin. The albumin values
were significantly (P = 0.017) lower in patients with a perform-
ance status of 2. No significant relationship existed between
albumin values and age.
The effects of the previous day’s dose and course among
patients receiving up to six courses (Table 2) of oral etoposide
were explored to answer the question of whether concentrations
tended to change systematically by week within a given course,
by course, or by dose. The results showed only that the concen-
trations increased slightly but significantly (P < 0.01) with
increasing course.
Higher E� and Ef� values were associated with lower
WBCn and ANC� values after the first treatment course in 83
patients in whom weekly counts allowed an estimate of the
nadir. A pharmacodynamic model, using multiple linear regres-
sion, showed that age, drug concentration (E� or E�), and
alkaline phosphatase were significant correlates with observed
WBCn and ANC�. An example of the predictor equations fol-
lows, and details of the model are given in Table 3:
log10(WBC,) = -0.030 - 0.007 X age - 0.0330 X E�
E� was compared by race and gender. Median (range) E�
during the first course among white patients was 0.30 (0-1.54)
�i.g/rnl and was 0.42 (0.16-1.26) among African-American pa-
tients (P = 0.17). For Ef�, the corresponding values were 0.03
(0-0.22) p.g/ml among whites and 0.05 (0.022-0.13) p.g/ml
among African-American patients (P = 0.06). Median (range)
E� during the first course among males was 0.30 (0-1.54)
ii.g/ml and was 0.35 (0. 12-1 .26) among females (P = 0.33). ForE�, the corresponding values were 0.03 (0-0.22) p.g/ml
among males and 0.03 (0.01-0.13) p.g/ml among females (P =
0.72).
+ 0.379 X log10(alkaline phosphatase)
Adjusted average daily trough concentrations were significantly
associated with WBCn and ANC� (multiple R2 = 0.26 for both;
P < 0.01 and P = 0.02, respectively). Using only a single
etoposide concentration obtained 1 week from the start of treat-
ment gave similar results (multiple R2 between 0.23 and 0.27),
although the sample size was smaller. No significant association
between the pretreatment counts and nadir counts for WBC
count and ANC was found. The correlations between the loga-
rithms of pretreatment and nadir counts were 0.12 ( P = 0.289)
and 0. 12 (P = 0.302) for WBC count and ANC, respectively.
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Clinical Cancer Research 723
Table 3 Pharmacodyn amic models
Variable Estimate SE PRegression
R2
Model for log10 (WBC�)InterceptAgeBclog,0 (alk. phos.Y’
Model for log10 (WBC�)InterceptAgeE�log,0 (alk. phos.)
Model for log10 (ANC�)Intercept
AgeE�
log10 (alk. phos.)Model for log10 (ANC�)
InterceptAgeE�log10 (alk. phos.)
-0.030-0.007-0.330
0.379
-0.127-0.007
-0.3320.409
-0.153
-0.017-0.363
0.530
-0.312-0.017-2.973
0.583
0.3660.0040.1050.145
0.3800.004
0.8090.151
0.583
0.0060.159
0.222
0.5930.0061.2070.225
0.9360.0440.0020.011
0.7390.0580.0050.008
0.7940.0030.026
0.020
0.6000.0050.0160.012
0.25
0.23
0.25
0.27
a a&. phos., alkaline phosphatase.
Significantly different relationships between E� and E�
and nadir counts existed in the data set, depending on whether
the patient did or did not have bone marrow involvement. An
interaction term in the phannacodynamic model indicated that
patients with bone marrow involvement from small cell lung
cancer exhibited steeper declines in WBC count (P = 0.032)
and ANC (P = 0.021) as E� increased. The model using E� is
shown in Table 4 and is graphically illustrated in Fig. 2.
Previous efforts to describe the pharmacodynamics of i.v.
etoposide included sigmoid E,,,,� models (3, 6, 29). A sigrnoid
E,,,.,� model fit to our data of trough concentrations after oral
etoposide and surviving fractions of WBC count or ANC (i.e.,
nadir divided by pretreatment counts) resulted in curves that
seemed linear over the range of average concentrations studied.
The R2 (1 - residual variation/total variation) values corre-
sponding to the fitted E,,.� models ranged between 0.05 and
0.07. The linear regression of the log of the nadir count on E�
alone had an R2 of 0.14 (WBC count) and 0.10 (ANC). There-
fore, we saw no advantage in using an E,,,� model over simple
linear regression. Other previously published pharrnacodynamic
models for 21-day oral etoposide (16-18) were also evaluated
but resulted in regression R2 � 0.07; these models were there-
fore inferior to the models in Tables 3 and 4.
E� and E� were correlated with the various categories of
tumor response, but no significant relationships were found.
Exposure to etoposide above threshold concentrations of 0.1,
0.3, and 0.5 p.g/ml was also evaluated in relation to tumor
response, but without statistically significant results.
DISCUSSIONThis study was conducted in the cooperative group setting
in which 24 member institutions in CALGB submitted plasma
samples to a central laboratory for etoposide measurement.
Although complete data were not available on all 150 eligible
patients, a substantial number of patients had at least 3 samples
Table 4 Pharmacodynamic models with interaction term foruninvolved versus involved bone marrow
Variable Estimate SE PRegression
R2
Model for log10 (WBC�) 0.29
Intercept -0.076 0.387 0.845Age -0.008 0.004 0.032Etree -0.617 1.092 0.574log10 (alk. phos.)aMarrow involved”
0.3820.132
0.1580.098
0.0180.182
Interaction term -3.487 1.534 0.026Model for log,0 (ANC�) 0.31
Intercept -0.068 0.600 0.910Age -0.019 0.006 0.002EfrCI, -0.764 1.624 0.640
log,0 (alk. phos.)Marrow involved”
0.4790.224
0.2350.146
0.0460.130
Interaction term -4.630 2.279 0.046
a alk. phos., alkaline phosphatase.b 1 = yes, 0 = no.
for E� taken in the first course (n = 106), and the corresponding
nadir count was recorded (n = 83). Limitations to the study are
that: (a) etoposide doses varied in patients alternating 50 and
100 mg/day; (b) only trough concentrations of etoposide were
measured; (c) cisplatin may have confounded the pharmacolog-
ical results; and (d) blood counts and E� were only obtained
once a week. Nevertheless, we find the following results re-
markable: a pharmacokinetic relationship between E� or Ef�
and age was found, and a pharmacodynamic model could be
developed for toxicity but not for tumor response.
A consistent finding in pharmacological reports on etopo-
side administered i.v. (2-7) or p.o. (16-19) is the moderate
intrapatient and pronounced interpatient variability in concen-
trations. On the other hand, results from this and other trials
have demonstrated large interpatient variability in clinical re-
sults (24). Therefore, it seemed logical to investigate what
impact the pharmacological variability has on clinical outcomes.
The desired result is turnbr response. Clark et aL were able to
relate the AUC for etoposide to tumor response; however, their
regimen consisted of 5 or 8 days of daily i.v. etoposide (7). The
duration of exposure to concentrations between 0.5 and 2.0
1j.g/ml was correlated with tumor response, whereas the duration
of concentrations above 3.0 p.g/ml was correlated with neutro-
penia. In our trial, trough concentrations between 0.03 and 1.54
1j.g/ml were maintained for 21 days, and a significant correlation
with tumor response could not be demonstrated.
The dose-limiting toxicity for etoposide is leukopenia and
neutropenia. In this CALGB study, 83% of patients treated with
21-day oral etoposide experienced treatment-related leukopenia
and neutropenia of grade 3 or 4 severity (24). Various previous
reports have demonstrated correlations between leukopenia or
neutropenia and concentrations at steady state (2-5) or the AUC
(6, 7) of infusional etoposide. Studies of prolonged oral etopo-
side relied more on trough levels (16-18) or a calculated mean
concentration (19). Indeed, in one study of 21-day oral etopo-
side, the trough concentrations did show a pharmacodynamic
relationship with neutropenia, but the AUC did not (18). In a
preliminary single-institution study, the following pharmacody-
namic model was developed in 27 evaluable patients:
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1.0� 0.8
� 0.60.5
0.4
0.3
0.2
0.1
0.0 0.05 0.10 0.15 0.20
Average Free Etoposide
724 Pharmacology of 21-Day Oral Etoposide
6.0
5.0
4.0
3.0
2.0
Fig. 2 Relationship betweenWBC� and E� depending onbone marrow involvement.
ANC� = 0.32(1 + ANC� X e247 X Ec)
in which ANC� is the pretreatment neutrophil count (16). This
model was subsequently validated in an additional 21 evaluable
patients (17). Zucchetti et a!. (18) independently validated this
model in 39 patients and compared it to their following modi-
fication:
ANC� = 0.44(1 + ANC� x e_2M X EC)
This larger cooperative group study arrived at different
models based on multiple regression of the data accumulated in
the central data base (Tables 3 and 4). Age, which had pharma-
cokinetic importance, was also incorporated in the pharmaco-
dynamic model. The relationship between E� and race reached
borderline significance (P = 0.06), although only 10 African-
American patients were enrolled in the study (Table 1). This
observation warrants attention in future studies. Neither E� nor
Efrec differed significantly by gender or sites of metastatic
disease. Performance status was related to E�, but this relation-
ship was not independent of dose. E� was related to perform-
ance status independent of dose, but this relationship was prob-
ably confounded by albumin concentrations that determined
how much etoposide was bound. This may explain why per-
formance status did not contribute to our pharmacodynamic
model, which is different from a model for i.v. etoposide in
which performance status did play a role (2). Pretreatment
counts also did not explain a significant amount of the residual
variation, contrary to previous models (16-18).
Using the estimated E� in the model generally resulted in
an improvement over using the measured E#{128},.E� was calcu-
lated based on a formula validated by Stewart et a!. that includes
bilirubin and albumin (25). Joel et al. have confirmed that E�
is correlated with measures of liver function, including bilirubin,
albumin, and alkaline phosphatase (30). They also found that
etoposide clearance was significantly correlated with alkaline
phosphatase and bilirubin. In our study, E� was not related to
sites of metastatic disease. However, liver metastasis was asso-
ciated with significantly higher alkaline phosphatase levels. This
may explain why alkaline phosphatase contributed to our phar-
rnacodynamic model.
The fact that significantly different models existed in the
data base depending upon whether the patient was diagnosed
with or without bone marrow involvement from small cell lung
cancer is a novel observation. Although all patients had exten-
sive-stage disease, bone marrow involvement may be an mdi-
cator of total metastatic tumor burden. Alternatively, the steeper
decline of WBC count and ANC with increasing E� in patients
with marrow involvement may indeed reflect a limited capacity
of the residual normal bone marrow to regenerate after chemo-
therapy. Although all these pharmacodynamic models described
statistically significant relationships, the multiple R2 values and
visual inspection of Figs. 2 and 3 indicate that application to an
individual patient is severely limited. Even the model with and
without bone marrow involvement explained only 29 and 31%
of the variation in WBC� and ANC�, respectively. Although the
mathematical models are statistically significant, plasma level
monitoring of etoposide is unlikely to be clinically beneficial.
The National Cancer Institute of Canada recently con-
ducted a retrospective analysis of data on 608 patients with
limited-stage small cell lung cancer to evaluate the prognostic
importance of age (31). Patients were treated with cyclophos-
phamide, doxorubicin and vincristine, and etoposide plus cis-
platin in an immediate or delayed alternating fashion. Response
rates, survival, and hematological toxicity were not influenced
by age. In our previous report ofthe clinical results of this study,
logistic regression was used to examine the joint effect of age,
Research. on January 19, 2021. © 1997 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
Clinical Cancer Research 725
gender, and performance status and their interactions with treat-
ment on grade 4 toxicity (24). Older patients and patients with
poorer performance status had a significantly greater chance of
experiencing grade 4 toxicity, whereas gender had no significant
impact. We now report a pharmacokinetic relationship between
E� and age that has not been observed before and warrants
further study. In the future, it may be possible to make dosing
recommendations based on age. CALGB is currently conducting
a Phase H study of 21-day oral etoposide in relapsed non-
Hodgkin’s lymphoma with an accrual goal of 82 eligible pa-
tients. This study has the advantage of using oral etoposide as
the single agent. This should allow us to further evaluate the
pharmacodynamic models without the confounding influence of
cisplatin on toxicity and tumor response.
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lungwith i.v. cisplatin in patients with extensive-stage small cell Pharmacology of 21-day oral etoposide given in combination
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