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Oral etoposide monotherapy is effective for metastatic breast cancer
with heavy prior therapy
Authors: Peng YUAN, Binghe XU, Jiayu WANG, Fei MA, Ying FAN, Qing LI
and Pin ZHANG
Affiliations:
Department of Medical Oncology, Cancer Hospital (Institute), Chinese
Academy of Medical Science & Peking Union Medical College, Beijing 100021,
1
China
Requests for reprints
Dr. Binghe Xu,
Department of Medical Oncology, Cancer Hospital (Institute), Chinese
Academy of Medical Science & Peking Union Medical College, Beijing 100021,
China;
TEL: 8610-8778-8826
FAX: 8610-8771-5711
2
E-mail: [email protected]
Key words: etoposide; oral;metastatic breast cancer ; chemotherapy
PS: The abstract of this paper was presented as a poster at the 2011 ASCO (American Society
of Clinical Oncology) Meeting (Abstract ID: 1107).
3
Abstract
Purpose
Treatment option for metastatic breast cancer (MBC) patients
pretreated with chemotherapy is limited. Oral etopside has shown some
promises in these patients. However, patients who received heavy prior
4
chemotherapy may have poor tolerance to prolonged oral etoposide exposure.
This study is a single-arm clinical trial that evaluates the efficacy and safety of
short-term oral etoposide in Chinese patients with MBC who had received
heavy prior therapy.
Methods
MBC patients receiving at least 2 chemotherapy regimens prior to
the enrollment were treated with repeated cycles of oral etoposide (60 mg/m 2/d
on days 1-10, followed by 11-day of rest). The primary end point was the
progression free survival (PFS). The secondary end points were objective
response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and
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toxicity profiles.
Results Thirty-two patients received 230 cycles with a median of 6 cycles
(range: 2 to 20 cycles) per patient. Eight patients (25%) had partial response
(PR), 14 patients achieved stable disease (SD). The ORR was 25%. Nine
patients achieved SD for more than 24 weeks and CBR was 53%. The median
PFS and OS were 5 (range: 1.5-17.0 months) and 16 months (range: 3.0-51.0
months), respectively. The patients who achieved clinical benefit had longer
survival time than those who did not (25.0 verses 11.0 months, P<.01). Among
the 16 patients who received more than 4 regimens prior to this study, 4
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patients achieved PR, and 4 achieved SD for more than 24 weeks, with a CBR
of 50%. The most common hematologic adverse events were anemia (43.8%)
and neutropenia (38.5%). Nausea/vomiting (75.0%) and alopecia (62.5%)
were the most frequent non-hematologic toxicity.
Conclusions
Oral etoposide is effective and well tolerated in Chinese women
with heavily pretreated MBC.
INTRODUCTION
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Progresses in early detection and comprehensive treatment in recent years
have improved the survival of breast cancer patients worldwide. Hormone
treatment plays important roles in the treatment of breast cancer. For
metastatic breast cancer (MBS) not sensitive to hormone therapy, novel
agents that target specific tumor signaling pathways are important
breakthroughs. However, at least 30% of patients initially diagnosed with early
stage breast cancer will eventually develop MBC.
Anthracycline, taxane and trastuzumab are preferred drugs for MBC. Other
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drugs,
e.g.,
capecitabine[1],
vinorelbine[2-4],
gemcitabine[5-7]
and
platinum-based antineoplastics[8-10] also demonstrated some efficacy, and
can be used in cases that are resistant to anthracycline and taxanes. For
patients treated previously with three or more chemotherapy regimens, there
are no standard therapeutic schedules. Most guidelines suggest best
supportive therapy or participating in clinical trials[11,12].
Etoposide is a semi-synthetic derivatives of podophyllotoxin, and arrest cell
cycle at the late S phase and early G2 phase[13]. Etoposide injection has
weak efficacy on MBC[14]. However, a phase I clinical trial indicated that a
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variety of solid tumors respond to prolonged exposure to etoposide[15].
Sensitivity to oral etoposide has been demonstrated n small cell lung cancer,
non-small-cell
lung
cancer
and
non-Hodgkin
lymphoma[16].
The
maximum-tolerated dosage upon oral administration (each cycle consisted of
21 consecutive days of treatment followed by 7-day “drug holiday”) was 50
mg/m2/day[17]. In a phase II clinical trial for recurrent breast carcinoma,
however, poor tolerance at this dosage was noticed[18]. In summary, optimal
dosage and duration of the treatment remain unknown. Also, there is lack of
data for oral etoposide in Chinese patients with MBC.
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In the current study, we investigated the efficacy and safety of short-term
oral etoposide in a group of Chinese patients with MBC whose disease
progressed despite extensive prior chemotherapy.
METHODS
Patients
Written informed consent was obtained from all participants. The inclusion
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criteria were: (1) histologically confirmed MBC; (2) aged between 18 and 80
years; (3) At least two previous chemotherapeutic regimens for MBC; (4)
ECOG performance status (PS) score ≤2; (5) adequate bone marrow reserve
(hemoglobin≥10.0g/dl, neutrophils≥1.5×109 /L, platelet≥100×109 /L; (6)
relatively normal liver (serum bilirubin 1.5×upper limits of normal [ULN], AKP,
AST and ALT  2.5×ULN or 5.0  ULN if liver metastasis was present) and
renal function (serum creatinine <1.5 times the upper limit of normal [ULN] or a
creatinine clearance of ≥60 ml/minute); (7) normal cardiac function (assessed
by electrocardiogram or thoracic radiography).
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The exclusion criteria included: previous chemotherapy or radiotherapy not
completed at least 4 weeks prior to the enrollment; patients not recovered from
the toxic effects of previous chemotherapy or radiotherapy (except alopecia);
previous radiation therapy targeted more than 25% of whole body bone; known
or suspected brain metastasis or second primary malignancy (except basal cell
carcinoma and in situ cervical carcinoma).
Treatment Plan
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In this single site, one arm clinical trial, patients received oral etoposide (60
mg/m2/d, given in single dose) on days 1-10 at home. Treatment cycle was
repeated every 3 weeks until confirmed disease progression, or intolerable
toxicity. Dose modification was pre-planned as following: reduction to 75%
after the first episode of grade 3 hematologic toxicity and/or grade 2
non-hematologic toxicity; reduction to 50% after the second episode of grade 3
hematological
toxicity
and/or
grade
2
non-hematological
toxicity;
discontinuation upon the third episode of grade 3 hematologic toxicity and/or
grade 2 non-hematologic toxicity, or a second episode of grade 4 toxicity.
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Efficacy and Safety Assessment
Prior to the enrollment, all the patients received baseline assessment that
included medical history, somatoscopy, chest X-ray or CT, complete blood
count, and full clinical chemistry workups. Whole blood cell counts and full
clinical chemistry workups were carried out during each cycle. CT scanning
(with magnetic resonance imaging [MRI] as indicated) was performed every 2
cycles.
15
The primary end point was progression free survival (PFS). The secondary
end points included objective response rate (ORR), clinical benefit rate (CBR),
overall survival (OS), and toxicity profiles. Tumor evaluation was performed
every two cycles according to the RECIST criteria (version 1.0). PFS was
defined as the period from the start of the treatment until disease progression.
OS was calculated from the start of the treatment to death by any cause or to
the last date the patient was known to be alive. Objective response was
defined as complete response (CR) plus partial response (PR). Objective
responses, stable disease (SD), and disease progression (PD) were evaluated
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in accordance with RECIST criteria. Clinical benefit rate (CBR) was defined as
CR+PR+SD≥24 weeks.
Safety was assessed on the basis of reported adverse events and laboratory
abnormalities. All toxicities were graded according to the National Cancer
Institute Common Toxicity Criteria (version 3.0).
Statistics
Intention-to-treat（ITT）analyses were carried out for both efficacy and safety
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measures. Descriptive statistics were used to summarize safety and laboratory
observations. Median PFS and OS, with 95% confidence interval (CI), were
estimated by Kaplan-Meier method. Response rate in subgroups was
analyzed by cross-tabulation and Chi-squared testing.
RESULTS
Patient population
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Thirty two patients were enrolled between May 2005 and May 2008. Patient
demographics at baseline are summarized in Table 1. Median follow-up was
17.2 months with a range from 3.2 to 51.2 months. Majority of the patients
(75.0%) had visceral disease involving the lung and/or liver. The cancer had
metastasized to at least two distant sites in 78.0% of the patients. Half of the
patients had received four chemotherapeutic regimens for MBC. Most of the
patients (31/32) received anthracycline and/or taxane-containing regimen as
adjuvant or metastatic therapy. 84% of the patients received capecitabine, two
third of the patients received venorelbine and platinum-containing regimen,
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and a quarter of the patients received gemcitabine as metastatic therapy.
Treatment Compliance
A total of 230 treatment cycles were given, with a median of 6 cycles (range 2
-20 cycles). A total of 3 treatment cycles were delayed for 3 to 10 days (median,
7 days), as a result of grade 2 leukopenia or neutropenia (2 patients) and liver
dysfunction (1 patient). The median time of the delay was 5 days with a range
from 2 to 10 days. Etoposide dosage was reduced in one patient. 97% of
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patients received full dosage.
Response and survival
Of the 32 patients, 8 (25%) patients achieved PR, 14 patients (44%) achieved
SD, 9 patients (28%) had SD for more than 24 weeks (long SD); and 10
patients (31%) experienced PD during treatment. The median PFS was 5.0
months with a range from 1.5 to 17 months. The median OS was 16.0 months
(range: 3-51 months) (Table 2). The CBR was 53% (17/32). Eight patients are
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still alive at the latest follow-up. Of the 16 patients who received ≥4 regimens
prior to this study, 4 patients had PR, 6 patients had SD, and 4 patients had
long SD, with a CBR of 50%. The median OS was 25.0 months (range:
16.9-33.0 months) in patients who had clinical benefit versus 11.0 months
(range: 9.1-12.9 months) in patients without ( P=.000) (Figure 1).
Safety
Hematological and non-hematological toxicities are summarized in Table 3.
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There were no treatment-related deaths. The most common hematologic
adverse events were leucopenia (31%), neutropenia (38%) and anemia (42%).
Treatment-related hematologic adverse events were grade1/2 and reversible.
No grade 3 or grade 4 hematological adverse events were observed.
Nausea/vomiting were the most frequent non-hematologic adverse events,
with an incidence of 75%. Grade 3 nausea/vomiting occurred in one patient.
No grade 4 non-hematologic adverse events were observed. Peripheral
neuropathy was observed in 34% (11/32) of the patients (grade Ⅰ, 8 patients;
grade Ⅱ, 3 patients). Other treatment-related non-hematologic adverse events
23
are summarized in Table 3.
DISCUSSION
In the first reported phase I clinical trial of oral etoposide, Hainsworth et al. [17]
demonstrated that etoposide could be tolerated at up to 50 mg/m 2/d upon 21
consecutive days of treatment followed by 7-day break. Such a regiment has
since then been adopted for patients with MBC by many investigators [19-23].
Martin et al. [23] and Palombo et al [24] reported an objective response rate of
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30% and 22% in patients who had received one prior chemotherapy regimen,
respectively. Neskovic-Konstantinovic et al. [19] observed a response rate of
33% in previously untreated MBC patients. Atienza et al. [22] reported 19%
objective response rate; approximately 25% of their patients were
chemotherapy naive, and fewer than 10% had failed two previous
chemotherapy regimens. In contrast, Bontenbal et al. [20] observed a
response rate of only 10% in patients who had failed one previous
chemotherapy regimen. Pusztai et al. [21] reported only one partial response
in 24 patients when oral etoposide was given as third- or fourth-line therapy in
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heavily pretreated patients and a 25% dose reduction was required in four
patients because of hematologic toxicity. The most common non-hematologic
toxicities included alopecia, nausea, and mucositis. Grade 2 or greater
alopecia, nausea, and mucositis affected 80%, 53%, and 40% of patients,
respectively. Pusztai et al. concluded oral etoposide has limited activity and
may cause severe toxicity as a third- or fourth-line therapy in heavily
pretreated MBC patients. In another phase II trial, Saphner et al. [18] observed
higher response rate in patients who never received chemotherapy vs. those
who had received prior chemotherapy (57% vs. 6%, P = 0.004). There were
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two treatment-related deaths, both owing to myelosuppression and infection.
In our study, oral etoposide was given for 10 consecutive days in a 21-day
cycle. Most patients received prior treatments with anthracycline and
taxane-containing regimens. Half of the patients received four regimens after
establishing a diagnosis of MBC, and a quarter of the patients received more
than 5 regimens. The current study achieved a partial response rate of 25%,
CBR of 53%, median PFS of 5.0 months and OS of 16.0 months. These
outcomes are compare to that of capecitabine monotherapy in MBC as third
line treatment and indicate relatively higher control rate and longer tumor
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control time of oral etopside than that of capecitabine monotherapy[22,25-27].
Leukopenia, neutropenia and anemia were the most common hematologic
toxicities in our study, with 31%, 38% and 42% patients developing grade I/II
toxicities, respectively. No grade 3 or grade 4 hematological adverse events
was observed. Nausea/vomiting was the most frequent non-hematologic
toxicity, with an incidence of 75%, but grade 3 nausea/vomiting occurred in
only one patient only, and no grade 4 non-hematologic toxicities were
observed. Peripheral neuropathy was observed in 34% (11/32) of the patients
(grade Ⅰ, 8 patients; grade Ⅱ, 3 patients). The safety profile of the etoposide
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regimen used in this study seems to be better than that with 21 days of
treatment in 28-day cycle. An obvious explanation for this finding is shorter
exposure time.
CONCLUSION
This study demonstrated efficacy and an acceptable toxicity profile of oral
etoposide administered at home in heavily pretreated Chinese patients with
MBC. Based on our findings, oral etoposide is an option for heavily pretreated
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MBC patients with good performance status and adequate organ reserve.
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