The Importance of Drug Scheduling in Cancer Chemotherapy:
Etoposide as an Example
Kenneth R. Hande
Vanderbilt University School of Medicine, Nashville VA Medical Center, Nashville, Tennessee, USA
Key Words. Etoposide • Administration schedule • Cancer pharmacology • Bioavailability • Pharmacodynamics
• Pharmacokinetics
Concise Review
Abstract. Etoposide is a drug whose antineoplastic
activity is dependent on the schedule of drug admin-
istration. This article reviews the rationale for a
prolonged schedule of etoposide administration and
the therapeutic results of use of such a schedule in
the treatment of cancer. The pharmacology of
etoposide is also reviewed, with particular atten-
tion paid to the pharmacokinetics of oral etoposide
and etoposide plasma concentrations associated
with cytotoxicity. Stem Cells 1996;14:18-24
Introduction
Most drugs with recognized administration
schedule dependence are antimetabolites. In the
1960s, cytosine arabinoside was shown to be
inactive unless given as a prolonged infusion or
on a multiple-day administration schedule [1].
Toxicity from methotrexate is related to the dura-
tion of time a plasma concentration adequate to
inhibit dihydrofolate reductase is maintained
[2]. The toxicity of 5-fluorouracil depends on
its administration schedule, with weekly bolus
doses producing more myelosuppression and
infusions of several days producing greater gas-
trointestinal toxicity [3]. For other antineoplas-
tic agents, however, the schedule of drug
administration has not been felt to be as impor-
tant in determining cytotoxicity. However, clin-
ical studies performed over the past few years
have shown that the schedule of drug adminis-
tration is important in altering the cytotoxicity of
Correspondence: Dr. Kenneth R. Hande,
Vanderbilt University School of Medicine, Medical
Oncology, 1956 The Vanderbilt Clinic, Nashville, TN
37232, USA.
Received June 16, 1995; accepted for publication
June 16, 1995. ©AlphaMed Press 1066-5099/96/$5.00/0
STEM CELLS 1996;14:18-24
several antineoplastic drugs, including etopo-
side and Taxol ® , which are not classical
antimetabolites. The effect of the administra-
tion schedule on etoposide cytotoxicity is the
subject of this review.
Rationale for Chronic Etoposide Therapy
Several preclinical and clinical findings
suggest that the duration of exposure of neo-
plastic cells to etoposide is important in pro-
ducing maximal antitumor activity. Mammalian
DNA topoisomerase II is the target site for
etoposide action. This enzyme normally func-
tions within the cell to carry out necessary
breakage-reunion reactions of mammalian
DNA. It is a constituent of the mitotic chro-
mosome scaffold. One of the primary physio-
logic activities of topoisomerase II is the
untangling of daughter chromosomes during
mitosis. This process requires passage of an
intact double-stranded DNA (dsDNA) helix
through a transiently-formed break made in
the backbone of a second helix molecule by
topoisomerase II [4]. Etoposide inhibits topoi-
somerase II’s ability to reseal these transiently
formed DNA strand breaks [5]. It causes dose-
dependent single-strand and dsDNA breaks
when incubated with cells. When etoposide is
removed, DNA breakage is quickly repaired.
The interaction of etoposide and DNA leads
to cell cycle arrest in G 2 and subsequent trig-
gering of apoptosis (programmed cell death)
[6]. Apoptosis, induced by etoposide, is
enhanced by the presence of certain oncogene
products, growth factors (such as transform-
ing growth factor α) and the p53 gene, while it
is inhibited by the bcl-2 protein [7, 8].
Hande
Etoposide’s target, topoisomerase II, is sig-
nificantly expressed only in dividing cells dur-
ing selected mitotic phases of the cell cycle [9].
Chronic scheduling may therefore be advanta-
geous because it maximizes the likelihood of
exposing malignant cells to etoposide during
sensitive periods of the cell cycle. Cytotoxicity
of topoisomerase II-targeting drugs relates not
only to the magnitude of formation of drug-
induced, enzyme-mediated DNA strand breaks,
but also to the intracellular half-life of these
lesions [10]. Therefore, antineoplastic agents
or protracted scheduling schemes that prolong
the presence of DNA strand breaks in the cell
would be expected to result in superior efficacy.
In vitro, lymphoma cells exposed to less than
1 µ g/ml etoposide for 30 h can be completely
killed [11]. Finally, high and low etoposide con-
centrations exhibit differential effects on cell
cycle events. Though not clearly understood,
the combination of high concentrations and brief
duration of exposure to etoposide appears to
result in a relatively protective effect by “freez-
ing” a proportion of cells in phases of the cell
cycle during which the drug is nonlethal. In cel-
lular studies with etoposide, Drewinko and
Barlogie [12] demonstrated that a 1 h exposure
to 10 µg/ml etoposide resulted in 100-fold less
cytotoxicity when compared to prolonged expo-
sure to 1 µ g/ml concentrations.
Although the importance of drug admin-
istration schedule on etoposide’s antineoplastic
activity was suggested in early preclinical and
clinical trials, the most informative studies on
the importance of schedule dependence have
been conducted by investigators from St.
Bartholomew’s Hospital in London. In two con-
secutive studies, the effect of changing the
administration schedule of 500 mg etoposide
on antineoplastic activity and toxicity was
determined. In the first study [13], patients with
Table 1. Schedule dependency of 500 mg etoposide in small cell lung cancer
(from Slevin et al. [13] and Clark et al. [14])
Study 1
(1 Day)
Response Rate 10%
Median Survival (Months) 6.3
Neutrophil Nadir 2,600/µ l
Plasma Concentration >10 µ g/ml 23 h
Plasma Concentration >5 µ g/ml 32 h
Plasma Concentration >1 µ g/ml 46 h
AUC (µ g/ml h) 458
19
previously untreated small cell lung cancer
(SCLC) were randomized to receive 500 mg/m2
etoposide either as a 24 h i.v. infusion or as five
daily 2 h infusions. Though both patient groups
received the same total drug dose, differences in
response rates were dramatic. In the one day
treatment arm, 10% of patients responded to
therapy, compared to an 89% response rate in
the five day treatment arm (Table 1).
Pharmacokinetic data from this trial revealed no
significant difference in area under the concen-
tration time curve (AUC) measurements between
these two treatment arms. However, prolonged
maintenance of low serum etoposide concentra-
tions (≥1 µ g/ml) was associated with superior
efficacy in the five day treatment arm. High
etoposide concentrations (>10 µg/ml) were main-
tained for considerably longer periods in the less
effective one day arm than in the superior five
day arm (23 versus 11 h, respectively). In a sub-
sequent study in SCLC [14], a five day sched-
ule was compared to an eight day schedule for
administration of 500 mg etoposide. In this sec-
ond study, patients were of poorer performance
status than in the initial study and toxicity from
etoposide was greater than that seen in the ini-
tial trial. The five and eight day schedules were
found to have equivalent antineoplastic activity
(Table 1). Hematologic toxicity was greater in
the five day arm. Duration of time with plasma
etoposide concentrations >3 µg/ml was associ-
ated with the degree of myelosuppression. These
two studies suggest that prolonged exposure to
low concentrations of etoposide may improve
the therapeutic ratio of this drug.
Chronic, Oral Etoposide Administration
In an attempt to determine if an adminis-
tration schedule longer than the standard 3 to
Study 1 Study 2 Study 2
(5 Day) (5 Day) (8 Day)
89% 81% 87%
10 7.1 9.4
2,600/µ l 800/µ l 1,700/µ l
11 h 11 h 4h
34 h 32 h 26 h
94 h 98 h 106 h
480 495 453
20
5-day regimens would improve the therapeu-
tic index of etoposide, a Phase I study was con-
ducted at Vanderbilt using oral etoposide
administered daily for 21 days [15]. An oral
administration regimen was chosen for the prac-
tical reason of making long-term administra-
tion simple, and a 21-day duration was chosen to
be significantly longer than standard regimens.
Myelosuppression was found to be the dose-
limiting toxicity. The maximal tolerated dose
of etoposide on this schedule was 50 mg/m2/day.
With this regimen, blood counts were checked
weekly and etoposide was discontinued when
the WBC count fell below 2,000/µl or platelets
below 75,000/µ l. Etoposide was not restarted
until the WBC was >3,000/µl. In patients having
a leukocyte nadir <1,000/µ l or who needed to
stop the drug before 21 days, a 75% dose reduc-
tion was used during the subsequent cycle. With
this schedule, leukocyte nadirs occurred
between day 21 and 28 of therapy and recov-
ered by day 28-36, in most cases. Toxicity was
greater in previously treated patients (Table 2).
Other than myelosuppression, this treatment
regimen was well-tolerated. Red cell transfu-
sions were often needed following multiple
cycles of therapy. Alopecia was universal.
Nausea, vomiting, mucositis or diarrhea were
uncommon or very mild.
Several Phase II studies using either 50 mg or
50 mg/m2 etoposide once or twice daily for 14 to
21 days have now been conducted involving
patients with both previously treated and untreated
lung cancer [16-18], lymphoma [19], previously
treated germ cell tumors [20, 21], soft tissue sar-
comas [21], ovarian cancer [22, 23], breast cancer
[24, 25], melanoma and renal cell carcinoma.
Responses have been seen in all tumor types but
were uncommon in melanoma, sarcoma and renal
cell carcinomas. Responses have been noteworthy
in SCLC, germ cell tumors, and non-Hodgkin’s
lymphoma (Table 3). Overall, response rates have
been equal to or greater than expected from his-
torical data from similar patient populations given
Table 2. Hematologic toxicity of 50 mg/m2/day × 21 days oral etoposide (from [15, 17–19])
Previously Treated
Toxicity
Patients
Leukocytes <1.0 × 109/l
Platelets <50 × 109/l
Erythrocyte Transfusion
Etoposide
standard doses and schedules of etoposide. In
addition, several patients with SCLC, lymphomas
and germ cell tumors who responded to the
chronic schedule were previously clinically resis-
tant to standard doses and schedules.
While daily oral etoposide has significant
activity, is easy to administer, has tolerable tox-
icity and produces responses in patients who
have previously received drugs in other sched-
ules, it does not necessarily improve response
rates over standard etoposide-containing regi-
mens in every situation. In a recent study by
the Cancer and Leukemia Group B, patients
with SCLC were randomized to receive cisplatin
with three days of etoposide i.v., or low-dose
etoposide p.o. for 21 days [26]. Response rates
and median survival were equivalent in the two
arms. When used in combination chemother-
apy as initial therapy, the administration sched-
ule did not produce significant changes in the
therapeutic index of etoposide.
Etoposide Pharmacology
Kinetic parameters associated with i.v. etopo-
side administration, as determined at Vanderbilt,
are shown in Table 4 [27]. The AUC and peak
plasma concentrations following i.v. etoposide
administration are linearly related to dose [28].
Thirty to 40% of an administered dose of drug is
excreted unchanged in the urine [28, 29]. Direct
biliary excretion of etoposide appears to be a
minor route of drug elimination [30].
Obstructive jaundice does not alter the clear-
ance rate of etoposide. Etoposide is highly
bound to plasma proteins with an average free
plasma fraction of 6%. The etoposide plasma-
binding ratio (the amount of bound drug/the
amount of free drug) is directly related to the
serum albumin level [31]. Many patients with
cancer have reduced serum albumin levels and,
therefore, a higher free etoposide fraction (13%)
than normal volunteers (4%). Since the free
Untreated Patients
20% 6%
20% 0%
45% 36%
Hande
Table 3. Activity of chronic, low-dose oral etoposide
Disease
Small Cell Lung Cancer
Non-Small Cell Lung Cancer
Lymphoma
Germinal Tumors
Ovarian Cancer
Breast Cancer
drug is biologically active, conditions which
decrease protein binding may increase the phar-
macologic effect of a given dose.
The use of oral etoposide provides a con-
venient, tolerable treatment regimen which
avoids the need for hospitalization. Depending
on the cost of intravenous fluids, supplies used
for chemotherapy administration and drug
costs, oral etoposide therapy may be more eco-
nomical than the use of an intravenous regi-
men [32]. There are, however, drawbacks to
oral etoposide therapy. One disadvantage of
oral etoposide is the wide variability from
patient to patient in oral etoposide absorption.
Table 5 summarizes a series of studies from
Vanderbilt and compares the variability in
apparent drug clearance as a function of the
route of drug administration. Between patient
variability is significantly greater than within
patient variability. However, administration of
drug by the oral route increases variability both
within and between patients. As a drug’s clear-
ance is equal to the dose of drug given divided
by the AUC (Cl = Dose/AUC), the significant
interpatient and intrapatient variability in oral
etoposide absorption makes it difficult to pre-
dict the AUC for any individual oral dose of
drug. Careful monitoring of blood counts is
thus critical in each patient to assume adequate,
but not excessive, drug exposure.
Table 4. Etoposide pharmacokinetic parameters
(from Hande [27])
Volume of Distribution 13.8 ± 7.4 l/min
Clearance (plasma) 26.5 ± 9.6 ml/min/m2
Clearance (renal) 9.3 ± 3.9 ml/min/m2
Half-life 6.4 ± 2.4 h
21
Response Rate Reference
45% (n = 22) [16]
60% (n = 27) [17]
20% (n = 25) [18]
60% (n = 25) [19]
19% (n = 17) [20]
60% (n = 5) [21]
18% (n = 17) [21]
6% (n = 18) [22]
26% (n = 28) [23]
35% (n = 43) [24]
20% (n = 36) [25]
The bioavailability of oral etoposide ranges
from 40%-75% with, as mentioned, significant
within and between patient variability. The
absorption of etoposide varies with dose. Table 6
compares kinetic parameters seen following a
100 mg and a 400 mg oral dose of etoposide
with those seen following intravenous adminis-
tration. Oral absorption is linear to doses up to
250 mg. Bioavailability decreases with doses
greater than 300 mg. Once absorbed, there is no
pharmacologic difference between oral and intra-
venous etoposide with respect to mechanism of
action, half-life or mode of drug elimination.
Low-Dose Infusional Etoposide
As previously noted, oral etoposide admin-
istration, while convenient, is compromised by
variable drug absorption. In addition, adminis-
tration of 100 mg oral drug produces peak
plasma concentrations of 2-4 µ g/ml. Since
myelosuppression may be dependent on peak
etoposide serum levels, while antitumor effect
may be related to duration of exposure to a rel-
atively low serum level, the chronic schedul-
ing of etoposide using a long-term low-dose
continuous infusion has been investigated as a
means of avoiding high peak serum etoposide
levels. In a Phase I/II clinical trial, etoposide
was administered as a continuous infusion by
portable infusion pump; the drug was mixed in
normal saline at a maximum concentration of
0.4 mg/ml. Twenty-five mg/m2/day was selected
as the initial dose level. Initially, a 21-day infu-
sion was planned, followed by a one week rest.
It soon became evident that infusions of more
than 21 consecutive days were possible in most
22
Table 5. Variation in etoposide clearance with different routes of administration
Group Administration
Within Same Patient i.v.
Within Same Patient p.o.
Between Patients i.v.
Between Patients p.o.
patients and subsequent patients were treated
continuously as long as their WBC remained
>2,000/mm2, platelets >75,000/mm2 and tumor
progression was not evident. Patients receiving
infusions of 25 mg/m2/d who developed myelo-
toxicity necessitating an interruption of ther-
apy were restarted at a 75% dose reduction.
Forty patients were treated in this Phase I
study [34]. Continuous etoposide infusions could
be given for prolonged periods. The duration of
etoposide therapy ranged from 2 to 80 weeks
(median 17 weeks). The total etoposide dose
administered ranged from 375-8,838 mg/m 2
(median 1,620 mg/m2). Myelosuppression was
the major toxicity produced by infusional
etoposide. Moderate leukopenia (WBC
2,000-3,000/µ l) was seen in most patients but
precipitous drops in counts from week to week
were not seen. A leukocyte count of less than
1,000/µ l was experienced in five patients
accounting for only 5 of 353 total weeks on ther-
apy. Following discontinuation of therapy, the
WBC recovered quickly (2-6 days). Two patients
developed thrombocytopenia. Anemia requir-
ing a transfusion was observed in 21 patients.
Alopecia was universal. Other side effects
(anorexia, nausea, fatigue) were mild.
Objective responses were seen in 5 of 10
patients with previously treated non-Hodgkin’s
lymphoma and two of three patents with previ-
ously untreated SCLC [35]. The mean plasma
etoposide concentration in patients receiving
25 mg/m 2 /day was 0.78 ± 0.4 µ g/ml (range
Table 6. Etoposide kinetics (from [30, 33])
Intravenous
Dose
Peak Plasma Concentration
Time to Peak
Half-life 6.4 ± 1.8 h
Clearance 2.7 ± 1.0 l/h
Bioavailability
Etoposide
Coefficient of Variation
10.7% (n = 12)
15.7% (n = 11)
29.8% (n = 48)
38.6% (n = 16)
0.2-2.1 µg/ml). This study suggests that plasma
etoposide concentration of roughly 1 µg/ml can
be maintained with minimal myelosuppression
and that these concentrations are sufficient for
antineoplastic activity, at least against SCLC
and lymphoma.
Other investigators have also administered
infusional etoposide and have attempted to cor-
relate steady-state plasma etoposide concentra-
tions with tumor response. In SCLC, Sarkar et al.
[36] found no responses in six patients who main-
tained etoposide plasma concentrations of <0.75
µg/ml, while 6 of 10 patients with plasma etopo-
side concentrations of 0.75-1.5 µg/ml responded
to infusional etoposide. In non-SCLC, responses
were seen in 1 of 10 patients with plasma etopo-
side concentrations less than 1.0 µg/ml while 7
of 17 patients with plasma concentrations of 1.0-
2.0 µg/ml responded [37]. This data suggests that
etoposide concentrations of 0.5-2.0 µ g/ml are
required for cytotoxicity but that the specific
threshold may vary depending upon tumor type.
Summary
Preclinical and clinical studies have demon-
strated the importance of a more prolonged
administration schedule for maximizing the ther-
apeutic index of etoposide. While an optimal
treatment regimen remains unknown, a 21-day
low-dose oral etoposide regimen has demon-
strated significant antitumor activity against a
100 mg 400 mg
Oral Dose Oral Dose
3.0 ± 1.8 µ g/ml 8.6 ± 2.5 µg/ml
2.8 ± 1.8 h 2.9 ± 1.7 h
6.6 ± 1.6 h 6.6 ± 1.6 h
3.8 ± 1.5 l/h 5.1 ± 1.6 l/h
76 ± 22% 48 ± 18%
Hande
variety of neoplasms. This regimen is convenient
to administer and well-tolerated when myelo-
suppression is carefully monitored. It can pro-
duce responses in patients who have previously
been treated with other etoposide administration
regimens. Disadvantages of oral etoposide
include the significant variability in drug clear-
ance and the potential for development of a treat-
ment-related leukemia [38-40], although this has
not been seen with this treatment regimen to date.
Plasma etoposide concentrations of 0.7-2.0 µg/ml
appear to be associated with cytotoxicity. Higher
plasma concentrations may lead to additional
myelosuppression.
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