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Turkish Journal of Cancer
Volume 33, No. 4, 2003
Single agent oral etoposide in
recurrent or advanced solid tumors
AYTUĞ ÜNER1, UĞUR COŞKUN, ARZU YEĞİN2, DENİZ YAMAÇ1, NAZAN GÜNEL1
Gazi University Medical School, Departments of 1Medical Oncology and 2Internal Medicine, Ankara-Turkey
ABSTRACT
INTRODUCTION
Prolonged oral etoposide has antitumor activity in a variety
Etoposide is a semisynthetic epipodophyllotoxin that
causes cytotoxic effects by the inhibition of topoisomerase
II activity (1). Etoposide has been reported to have antitumor
activity in a variety of tumor types including small cell and
non-small cell lung carcinoma, ovarian, breast and germ
cell tumors and squamous cell carcinoma of head and neck
(2-7). Pharmacological studies indicated that oral administration of low dose etoposide for a prolonged period of
time may be more effective than higher dose administration
with periodic intravenous infusion (8). In clinical practice,
prolonged oral etoposide has been reported to show antitumor response in traditionally etoposide-insensitive malignancies and in traditionally etoposide-sensitive malignancies
which have already failed to prior bolus etoposide (3, 915). Oral etoposide has been tested in many solid and
hematological tumors and found to have an activitiy in
small cell carcinoma of the lung (SCLC), non-small cell
carcinoma of the lung (NSCLC), ovarian, prostate, germ
cell and breast tumors and lymphoma (3, 9-14). Beside its
efficacy, it has also several advantages in clinical practice
of physicians such as its ease administration, comperatively
lower cost and more favourable toxicity profile (16).
of solid tumors including small cell and non-small-cell lung
cancer. A total of 53 patients have been treated with prolonged oral etoposide at a dosage of 50-100 mg/day for 5,
7, 10 or 14 days in a 21 days interval. The results of these
patients were retrospectively evaluated. Twelve patients
had small cell lung carcinoma (SCLC), 11 patients had nonsmall cell lung carcinoma (NSCLC) and 30 patients had
different solid tumors including gastric, breast, ovarian and
prostate carcinoma. Fifty-two patients were evaluated for
response analysis. Objective response rate was found to
be 19,2% (1,9% complete response (CR), 17,3% partial
response (PR)). Stable disease was achieved in 30,8% of
the patients. Grade 3 and 4 neutropenia occurred in 9,3%
of the patients. We demonstrated a modest activity of single
agent oral etoposide in our heterogenous group of patients
with advanced and refractory disease. Oral etoposide may
be a treatment choice for patients with refractory disease
which there was no other alternative without supportive
care. [Turk J Cancer 2003;33(4):187-190]
KEY WORDS:
Oral etoposide, solid tumors
In this retrospective study, we analysed the results of
patients with different solid tumors treated with single
agent oral etoposide.
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MATERIALS AND METHODS
From June 1999 to February 2003, a total of 53 patients
have been treated with prolonged oral etoposide in our
center. The results were retrospectively evaluated. Twelve
patients had SCLC, 11 patients had NSCLC and 30 patients
had other malignancies including ovarian, gastric, breast
and prostate carcinoma. Characteristics of patients are
shown in tables 1 and 2. Oral etoposide was given as a
single agent in 51 patients and combined with estramustine
in 2 patients with prostate cancer. The schedule of therapy
was not standard in these patients. According to performance
status of the patients, oral etoposide was given at a dosage
of 50-100 mg/day for 5, 7, 10 or 14 days in a 21 days
interval. Dosage modification was based on Day 21 granulocyte count of preceding cycle. Dose escalation for
subsequent courses was prescribed for patients experiencing
no toxicity. Therapy was continued unless interrupted by
tumor progression or unacceptable toxicity. Response to
therapy was evaluated every cycle. Responders were defined
as complete response (CR, disappearance of assessable
disease) or partial response (PR, reduction of more than
50% of the lesion of the two largest tumor diameter). Stable
disease (SD) meant less than 25% increase in tumor size.
Progressive disease (PD) was defined by an increase of
more than 25% in tumor size. Response duration in responding patients was measured from the first day of the
chemotherapy to the first documentation of recurrence or
progression.
RESULTS
Fifty-two patients were evaluated for response. Chemotherapy was stopped in one patient before completing the
first cycle because of neutropenia. The mean number of
etoposide course was 3,2 cycles (range: 1-20). Twentyeight (52,8%) patients received one, 10 (18,9%) patients
received two and 7 (13,2%) patients received three types
of chemotherapy prior to oral etoposide. Eight (15,1%)
patients had not been treated with any chemotherapy prior
to oral etoposide. Nineteen (35,8%) patients received
etoposide-containing regimens before oral etoposide (Table
1). At the time of oral etoposide treatment, 47 (88,6%)
patients had metastatic, 2 (3,8%) had refractory disease
and 4 (7,6%) had local recurrence (Table 2). Among 52
patients, there was one complete and 9 partial responses,
for an overall response rate of 19,2%. Stable disease was
O r a l E t o p o s i d e i n A d v a n c e d S o l id Tu m o r s
the best response in 16 patients (30,8%). The remaining
26 (50%) patients had progressive disease. Details of these
results are given in table 1. The mean response duration
was 4,4 months (range: 2-10 months) in patients who had
CR and PR. The mean duration of stable disease was 3,9
months (range: 1,5-18 months) in patients who had stable
disease.
Severe neutropenia (WHO Grade 3 and 4) occurred in
5 (9,3%) patients. Two had neutropenic fever and one of
them died of sepsis. Grade 1 and 2 neutropenia occurred
in 5 (9,3%) patients. Three patients required blood transfusion during the treatment because of anemia. Only one
patient had severe nausea. Total or partial alopecia was
observed in 48 (90,5%) patients.
DISCUSSION
Etoposide is an agent with a wide spectrum of antitumor
activity in many solid tumors. It has been reported to have
an activity in SCLC and germ cell tumors as first line
therapy and in NSCLC, ovarian, breast and gastric tumors
as second line or salvage treatment (2-6, 17). Etoposide
exerts its cytotoxic activity by stabilizing the formation of
the DNA-topoisomerase-II complex that results in inhibition
of rejoining and increased DNA scission (1). It causes
double-strand DNA cleavage in cells that were entering
mitosis and is less cytotoxic for resting cells (18,19). It has
been reported that the antitumor effects of etoposide are
highly related to schedule of etoposide and the duration of
its exposure (20,21). It has been suggested that an extended
tumor exposure to pharmacologically active etoposide
levels and increased pharmacokinetic profile can be provided
by prolonged etoposide (8,15). Previous studies have
demonstrated an antitumor activity of oral etoposide both
in etoposide insensitive and sensitive tumors (3, 9-15).
These studies showed that prior treatment with intravenous
etoposide did not affect the likelihood of response to
prolonged oral etoposide.
In our center, single agent oral etoposide has been used
for the palliative treatment of patients with solid tumors
who failed to conventional treatment or could not tolerate
aggressive chemotherapy because of their poor performance
status. In different studies with single agent oral etoposide,
response rate was found 45,5% in small cell carcinoma of
the lung (SCLC), 23% in non-small cell carcinoma of the
lung (NSCLC), 6% in ovary, 9% in prostate, 18,8% in germ
Ün er e t al.
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Table 1
Patient details and diagnosis
Diagnosis
n
Number of prior
Prior
Responses
chemotherapy
etoposide
(%)
No
1
2
3
Yes
No
CR
PR
SD
PD
OR
SCLC
12
2
7
2
1
10
2
0 (0)
1 (8.3)
3 (25,0)
8 (66,7)
1 (8,3)
NSCLC*
11
1
8
1
1
1
10
0 (0)
0 (0)
4 (36,3)
6 (63,7)
0 (0)
Others**
30
5
13
7
5
8
22
1 (3,3)
8 (26,7)
9 (30,0)
12 (40,0)
9 (30,0)
TOTAL*
53
8
28
10
7
19
34
1 (1,9)
9 (17,3)
16 (30,8)
26 (50,0)
10 (19,2)
OR: Overall response (CR+PR)
*One patient was not evaluable for response
**Ovarian (n=4), Sarcoma (n=4), Gastric (n=3), Breast (n=3), Prostate (n=3), Endometrium (n=2), Pancreas (n=2), Cervix (n=1), Nasopharynx (n=1), Melanoma
(n=1), Bladder (n=1), Testicular (n=1), Germ cell (n=1), Medulloblastoma (n=1), Colon (n=1), Colon (n=1) and Thyroid (n=1) carcinoma
Table 2
Characteristics of patients
SCLC
NSCLC
Other patients
Total
n
Median age (yr)
(range)
Gender
(F/M)
12
11
30
53
58,5 (35-72)
64,0 (43-71)
51,0 (21-67)
55,0 (21-72)
2/10
4/7
18/12
24/29
cell, 35% in breast tumors and 60% in lymphoma (3, 914). In our study, objective response rate was 19,2% (1,9%
CR, 17,3% PR). One patient achieved a CR after the therapy
and his disease was mediastinal germ cell tumor. The ratio
of stable disease was 30,8%. In patients with SCLC (n=12),
only one patient achieved a PR response. No response was
observed in patients with NSCLC (n=11). This relatively
lower response rates observed in our heterogenous group
of solid tumors may be related with the dosage of oral
etoposide used in this study. The maximum tolerated dose
of oral etoposide was determined to be 50 mg/m2/day for
21 days in a 28 day cycle in a variety of neoplasms and
this schedule remains popular in clinical trials. The dosage
of oral etoposide used in our study was generally lower
compared with other studies. Adequate dose escalation
Disease status (%)
Metastatic
Local relapse Refractory
9 (75,0)
9 (81,8)
29 (96,6)
47 (88,6)
2 (16,6)
1 (9,1)
1 (3,4)
4 (7,6)
1 (8,4)
1 (9,1)
0 (0)
2 (3,8)
could not been carried out, because of the poor performance
status of the patients. Actually, in our clinic, we have usually
selected oral etoposide for patients with refractory disease
which there was no other alternative treatment without
supportive care and this approach did not give us any
possibility for dose escalation in many patients. Among
the patients, 45 (84,9%) had received prior chemotherapy
and 19 (35,8%) had received prior etoposide containing
regimen. These may have also reduced response rate of
our study.
Adverse effects were generally mild in our study. Most
common toxicity was alopecia and observed in 90,5% of
patients. Hematologic toxicity was not higher in our study
when compared to the other studies. In previous reports,
O r a l E t o p o s i d e i n A d v a n c e d S o l i d Tu m o r s
190
the ratio of grade 4 leucopenia has been reported to occur
between 16-28% (9,11,13). In our study, severe neutropenia
occurred in 5 patients (9,3%) patients. Two had neutropenic
fever and one of them died of sepsis.
An association between acute myeloid leukemias and
etoposide therapy has been reported in many studies (22,23).
These leukemias are generally found to be related with
cumulative dose of etoposide. However, leukemia was not
diagnosed in our patients. This isn’t surprising because
survival was very short in these patients and only few of
them could receive ten or more cycles of etoposide.
In conclusion, we observed that single agent etoposide
has modest activity and relatively mild toxicity in our
patients. As the patients included in this study had very
short survival expectancy and therefore were not considered
to tolerate aggressive chemotherapy, this response rate
should not be regarded as too little. Together with the
importance of its lower cost especially for the countries
with limited resources, we suggest that it can be used as
an alternative of more aggressive chemotherapy or supportive care in selected patients with advanced and refractory
cancer.
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