Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes.

Abstract

The role of first-line trastuzumab-based therapy has been firmly established in patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. In this trial, we evaluated the efficacy and safety of a vinorelbine and trastuzumab combination chemotherapy in patients who were pretreated with anthracyclines and taxanes.
Thirty-three patients with HER2 overexpressing metastatic breast cancer, all of whom had previously been treated with anthracyclines and taxanes, were included in this study. The patients were treated with 25 mg/m(2) of vinorelbine (over a 15-minute infusion) on days 1 and 8 every 3 weeks. Additionally, trastuzumab was administered at an initial dose of 4 mg/kg over 90 minutes, and was subsequently administered at weekly doses of 2 mg/kg (over 30 minutes).
The median age of the patients was 53 years (range, 39-72 years). The overall response rate was 30.3% (10 patients; 95% confidence interval [CI], 23-57%). The median time to progression was 6.8 months (95% CI, 5.3-8.2 months). The median overall survival was 12.4 months (95% CI, 10.3-14.6 months). In the 194 cycles of treatment, the incidence rates of grade ≥3 neutropenia and anemia were 7.2% and 1.0%, respectively. Neutropenic fever was detected in three cycles (1.5%). The non-hematological toxicities were not severe: grade 1 or 2 nausea or vomiting was detected in 15.2%, and grade 2 neuropathy was noted in 6.1% of patients. None of the patients experienced any serious cardiac toxicity, and no treatment-related deaths occurred.
These results show that a combination chemotherapy consisting of vinorelbine and trastuzumab is useful in patients with HER2-overexpressing metastatic breast cancer who were pretreated with anthracyclines and taxanes, with a favorable toxicity profile.

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© 2011 Korean Breast Cancer Society
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INTRODUCTION
Human epidermal growth factor receptor-2 (HER2) is a key
contributor to normal cell growth and differentiation [1]. How-
ever, HER2 is associated with neoplastic transformation of cells
when overexpressed. Approximately 15-20% of breast cancers
overexpress HER2 (3+ by immunohistochemistry [IHC]) and/
or amplification of the HER2 gene. HER2 overexpression is
generally associated with a more aggressive tumor phenotype,
and women with HER2 positive disease tend to have poor over-
all prognoses and faster relapse times at all stages of cancer de-
velopment [2]. The advent of trastuzumab, a humanized mono-
clonal antibody against the extracellular domain of HER2, rep-
resents a major breakthrough in the treatment of women suf-
fering from HER2 positive metastatic breast cancer (MBC).
As a first-line, single-agent therapy, trastuzumab has an over-
all response rate of 26% [3]. Among patients treated previous-
ly with chemotherapy for MBC, trastuzumab monotherapy
resulted in an overall response rate of 15% [4]. Trastuzumab
exerts synergistic effects with vinorelbine, cisplatin, docetaxel,
thiotepa, cyclophosphamide, and etoposide; exerts additive ef-
fects with doxorubicin, paclitaxel, methotrexate, and vinblas-
tine; and exerts antagonistic effects with 5-fluorouracil [5]. In
two randomized trials, the addition of trastzumab to either pa-
clitaxel [6] or docetaxel [7] yielded a significant survival benefit
in patients with previously untreated MBC. The results of these
two trials have firmly established the combination of trastu-
zumab with a taxane as standard first-line treatment for patients
with HER2-overexpressing MBC. However, when first-line
Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing
Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes
Yu Rim Lee1, Seok Jae Huh1, Dong Hyun Lee1, Hyun Hwa Yoon1, Young-Mi Seol2, Young-Jin Choi2, Kyung A Kwon1,
Suee Lee1, Sung Yong Oh1,3, Sung-Hyun Kim1, Hyo-Jin Kim1, Hyuk-Chan Kwon1,3
1Department of Internal Medicine, Dong-A University College of Medicine, Busan; 2Department of Internal Medicine, Pusan National University Hospital
Medical Research Institute, Pusan National University School of Medicine, Busan; 3Medical Research Center for Cancer Molecular Therapy, Dong-A
University College of Medicine, Busan, Korea
ORIGINAL ARTICLE
J Breast Cancer 2011 June; 14(2): 140-146 DOI: 10.4048/jbc.2011.14.2.140
Purpose: The role of first-line trastuzumab-based therapy has
been firmly established in patients with human epidermal growth
factor receptor-2 (HER2) positive metastatic breast cancer. In this
trial, we evaluated the efficacy and safety of a vinorelbine and
trastuzumab combination chemotherapy in patients who were
pretreated with anthracyclines and taxanes. Methods: Thirty-three
patients with HER2 overexpressing metastatic breast cancer, all
of whom had previously been treated with anthracyclines and
taxanes, were included in this study. The patients were treated
with 25 mg/m2 of vinorelbine (over a 15-minute infusion) on days
1 and 8 every 3 weeks. Additionally, trastuzumab was adminis-
tered at an initial dose of 4 mg/kg over 90 minutes, and was sub-
sequently administered at weekly doses of 2 mg/kg (over 30 min-
utes). Results: The median age of the patients was 53 years (range,
39-72 years). The overall response rate was 30.3% (10 patients;
95% confidence interval [CI], 23-57%). The median time to pro-
gression was 6.8 months (95% CI, 5.3-8.2 months). The median
overall survival was 12.4 months (95% CI, 10.3-14.6 months). In
the 194 cycles of treatment, the incidence rates of grade ≥3 neu-
tropenia and anemia were 7.2% and 1.0%, respectively. Neutro-
penic fever was detected in three cycles (1.5%). The non-hema-
tological toxicities were not severe: grade 1 or 2 nausea or vom-
iting was detected in 15.2%, and grade 2 neuropathy was noted
in 6.1% of patients. None of the patients experienced any serious
cardiac toxicity, and no treatment-related deaths occurred. Conclu-
sion: These results show that a combination chemotherapy con-
sisting of vinorelbine and trastuzumab is useful in patients with
HER2-overexpressing metastatic breast cancer who were pre-
treated with anthracyclines and taxanes, with a favorable toxicity
profile.
Key Words: Breast neoplasms, Metastasis, Trastuzumab, Vinorelbine
Correspondence: Hyuk-Chan Kwon
Department of Internal Medicine, Dong-A University College of Medicine,
3-1 Dongdaesin-dong, Seo-gu, Busan 602-715, Korea
Tel: +82-51-240-2887, Fax: +82-51-246-5044
E-mail: hckwon@dau.ac.kr
This paper was supported by Dong-A University Research Fund.
Received: January 31, 2011 Accepted: May 2, 2011
Journal of
Breast
Cancer

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chemotherapy fails, non-crossresistant treatments with mini-
mal toxic effects that could be readily administered on an out-
patient basis are warranted.
Vinorelbine is a semisynthetic vinca alkaloid, with higher li-
posolubility and a higher tissue concentration than its analogues
[8]. When employed as a single agent against MBC, vinorel-
bine exhibits response rates ranging from 32% to 50% as a first-
line treatment, and from 15% to 36% as a second-line treat-
ment [9]. In the preclinical setting, a synergism has been de-
tected between trastuzumab and vinorelbine. The mean com-
bination index value for trastuzumab and vinorelbine ranged
from 0.24 (p<0.001) to 0.78 (p=0.034), in which a statistical-
ly significant value of <1.0 indicated synergy [5].
The use of trastuzumab and vinorelbine to treat MBC results
in objective response rates for the combination in the range of
44-86% (51-86% as first-line treatment), and a median dura-
tion of response of 10-17.5 months [10]. However, no previous
reports have assessed the efficacy of a therapy consisting of
vinorelbine plus trastruzumab in cases of heavily treated MBC.
The treatment for intensively pretreated MBC is basically pal-
liative, and the objective is to provide antitumor activity and
prolong survival, but without any significant deterioration in
quality of life.
Therefore, we conducted a phase II study to evaluate the ef-
ficacy and toxicity of vinorelbine plus trastuzumab in patients
with HER2-positive MBC who had been treated previously
with anthracyclines and taxanes.
METHODS
Eligibility
To be eligible for this study, patients were required to have a
histologically confirmed diagnosis of MBC, in addition to at
least one measurable lesion. All patients were ≥18 years and
were required to have previously treated with anthracycline
and taxane-based chemotherapy. Only patients with an East-
ern Cooperative Oncology Group (ECOG) performance sta-
tus of grade 0-2 were enrolled in this study. Adequate bone mar-
row function (an absolute neutrophil count ≥1,500×103/μL
and a platelet count ≥100,000×103/μL), adequate renal func-
tion (a serum creatinine level ≤1.5 mg/dL), and adequate he-
patic function (aspartate aminotransferase and alanine amino-
transferase levels ≤3×upper limit of normal and a total bili-
rubin level ≤1.5×upper limit of normal) were required for
the patients enrolled in this study. Patients were also required
to have a left ventricular ejection fraction (LVEF) of ≥50%.
Patients were allowed to have received prior adjuvant chemo-
therapy (including taxane- or anthracycline-containing regi-
mens), as long as chemotherapy was received ≥6 weeks prior
to entry into the study. Patients were also allowed to have received
adjuvant trastuzumab if the final dose was received ≥12 months
prior to study entry.
Patients were ineligible if they had local relapse only, tumor
in the contralateral breast only, symptoms of brain metastases
or leptomeningeal involvement, peripheral neuropathy of at
least grade 2 (according to National Cancer Institute Common
Toxicity Criteria, NCI-CTC) or serious conditions including
cardiac disease, symptomatic dyspnea, uncontrolled hypercal-
cemia, or clinically relevant active infection. Patients were also
excluded if they were pregnant or breast-feeding, had partici-
pated in another clinical trial within 30 days prior to inclusion
in this study, had a history of another malignancy, except for
adequately treated basal cell carcinoma of the skin or in situ cer-
vical carcinoma, or previously exposed to trastuzumab or lap-
atinib. All patients provided informed consent, and this study
was approved by the Institutional Review Board of Dong-A
University Medical Center (No.11-32).
HER2 status
A primary antibody directed against HER2 (Neo Markers,
Fremont, USA) was used. Patients overexpressing HER2 at the
3+ level of IHC staining were immediately eligible for inclu-
sion. HER2 expression at the 2+ level required confirmation
by HER2 gene amplification using fluorescent in situ hybrid-
ization (FISH) with PathVision® HER2 DNA probe kit (Vysis
Inc., Downers Grove, USA). HER2 testing was conducted on
a primary tumor sample or a biopsy from the metastatic site.
Treatment protocol
The patients were treated with 25 mg/m2 of vinorelbine (over
a 15-minute infusion period) on days 1 and 8, at 3-week inter-
vals. The vinorelbine dose was adjusted each week on the day
of therapy, based on hematological and/or non-hematological
toxicity. Adjustments were made in the dose of vinorelbine (25%
dose reduction) in patients who experienced grade ≥3 hema-
tological toxicity, grade 4 febrile neutropenia, grade 4 neutrope-
nia persisting for 7 days, or grade 4 thrombocytopenia. The gran-
ulocyte colony stimulating factor was used for cases in which
treatment was delayed for more than 2 weeks because of neu-
tropenia or febrile neutropenia. One-week delays in vinorel-
bine dosing were applied in cases of grade 2 or higher neutro-
penia and thrombocytopenia. The vinorelbine dosage was re-
duced by 25% in cases of grade 2 neurologic toxicity, until it
resolved to grade 1 or lower. In cases of non-hematologic grade
3, vinorelbine administration was delayed until the side effects
were resolved to grade 1 or lower. If toxicity persisted for more
than 3 weeks, patients were dismissed from the study, as were
patients with grade 4 non-hematologic toxicity.

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Trastuzumab was administered at an initial dose of 4 mg/kg
over 90 minutes, and was subsequently administered at weekly
doses of 2 mg/kg (over a 30-minute period). If patients expe-
rienced an infusion syndrome characterized by rigor, fever, or
other symptoms of hypersensitivity to trastuzumab, treatment
was halted, and patients were assessed and treated with support-
ive measures (acetaminophen, diphenhydramine, H2 antago-
nists, dexamethasone, or meperidine) as needed. Treatment
was reinstituted when vital signs stabilized. The study protocol
did not include dose adaptations or delays for trastuzumab. All
patients received electrocardiograms and LVEF measurements
upon enrollment, and every 9 weeks thereafter or more fre-
quently when dictated by clinical circumstances. Trastuzumab
application was paused when LVEF was reduced by >20% from
baseline or was reduced to >10% below the lower limit of nor-
mal. If a reevaluation conducted after 1 month reflected stabi-
lized cardiac function, trastuzumab treatment was resumed,
albeit accompanied by short-term controls. Otherwise, trastu-
zumab treatment was halted. Trastuzumab was immediately
halted in New York Heart Association (NYHA) III or IV car-
diac dysfunction. Vinorelbine and trastuzumab were admin-
istered until disease progression, unacceptable toxicity, or pa-
tient refusal.
Assessment of response
A physical examination, complete blood counts, blood chem-
istry, and chest X-rays were acquired after each cycle. Com-
puted tomography scans were repeated every three cycles or
earlier for cases in which clinical deterioration was detected.
The primary endpoint of this study was the tumor response
rate, and the secondary endpoints included the time to progres-
sion (TTP), overall survival (OS), and toxicities. Patients who
had been treated with at least two cycles of therapy were assess-
able for response; all patients who received treatment were as-
sessable for toxicity.
Tumor responses were evaluated using the Response Evalu-
ation Criteria in Solid Tumors criteria. A complete response
(CR) was defined as the disappearance of all measurable lesions
for a minimum duration of 8 weeks. Partial response (PR) was
defined as a reduction of 30% or more in the sum of products
of the greatest diameters of measurable lesions, no increase in
lesion size, and no new lesions. Stable disease (SD) was defined
as a reduction of less than 30% and an increase of less than 20%
without any appearance of new lesions. Progressive disease (PD)
was defined as an increase of greater than 20% in tumor size or
the appearance of new lesions. Toxicity was evaluated using the
NCI-CTC criteria (version 3.0), and was recorded per patient
as the worst episode that appeared during a treatment cycle.
Statistical methods
This trial was designed to detect a response rate of 35%, as
compared to a minimal clinically meaningful response rate of
20%. The two-stage optimal design devised by Simon was ad-
opted, with a statistical power of 80% to accept the hypothesis
and 5% significance to reject it. Allowing for a follow-up loss
rate of up to 10%, the total required sample size was 31 patients
with measurable disease. The TTP and the OS were calculated
from treatment initiation to the initial observation of disease
progression or death, respectively. The Kaplan-Meier method
Table 1. Patient characteristics (n=33)
Characteristic Median (range)No. (%)
Age (yr)
Stage at diagnosis
I
II
III
IV
Grading
1
2
3
Hormone receptor status
Estrogen receptor positive
Progesterone receptor positive
Adjuvant endocrine therapy
Adjuvant chemotherapy
Type of adjuvant chemotherapy
CMF
AC
AC followed by T
Adjuvant radiotherapy
No. of prior chemotherapy regimen
2
3
4
5
ECOG performance status
0-1
2
Time to recurrence (mo)
<24
≥24
No. of metastases localizations
1
2
≥3
Localization of metastases
Liver
Lung
Bone
Lymph nodes
Skin, soft tissue
Other
53 (39-72)

4 (12.1)
16 (48.5)
9 (27.3)
4 (12.1)

1 (3.0)
16 (48.5)
16 (48.5)

20 (60.6)
22 (66.7)
22 (66.7)
28 (84.8)

10 (30.3)
10 (30.3)
8 (24.2)
19 (57.6)

15 (45.5)
9 (27.3)
8 (24.2)
1 (3.0)

30 (90.9)
3 (9.1)

8 (24.2)
25 (75.8)

18 (54.5)
9 (27.3)
6 (18.2)

9 (27.2)
13 (39.4)
12 (36.4)
10 (30.3)
5 (15.2)
5 (15.2)

CMF=cyclophosphamide, methotrexate, 5-fluorouracil; AC=adriamycin,
cyclophosphamide; T=taxol; ECOG=Eastern Cooperative Oncology
Group.

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was applied to estimate overall and progression-free survival
outcomes. No multivariate analyses were conducted, due to the
limited sample size. All data were analyzed with SPSS software
version 14.0 (SPSS Inc., Chicago, USA).
RESULTS
Patient characteristics
Between August 2004 and August 2008, 33 patients with
MBC, who were pretreated with anthracycline and taxane-
based therapy, were scheduled for treatment at the Dong-A
University Medical Center, Busan, South Korea. The charac-
teristics of the 33 patients enrolled in this study are described
in Table 1. The median patient age was 53 years (range, 39-72
years). The performance status (ECOG) was grade 0-1 in the
majority of the patients; three patients (9.1%) were grade 2.
Estrogen receptor (ER) expression was positive in 20 patients
(60.6%) and progesterone receptor (PR) expression was posi-
tive in 22 patients (66.7%). All patients with hormone recep-
tor-positive tumors had received adjuvant hormonal therapy,
but only six of the 22 patients (27.3%) had previously received
palliative hormonal therapy. Twenty-nine of the patients (88%)
were +3 overexpression of HER-2 IHC, four possessed tumors
with +2 overexpression and were FISH-positive.
One organ was involved in 18 patients (54.5%), two organs
were involved in nine (27.3%) and three or more organs were
involved in six (18.2%). The lung was the most common met-
astatic site (13 patients, 39.4%), and bone (12 patients, 36.4%),
lymph nodes (ten patients, 30.3%), liver (nine patients, 27.2%)
and skin and soft tissue (five patients, 15.2%) were involved in
a combined fashion. Fifteen patients (45.5%) received vinorel-
bine plus trastuzumab treatment as a third-line chemotherapy,
nine patients (27.3%) as a fourth-line, and nine patients (27.3%)
as a fifth (or more)-line therapy. Enrolled patients were previ-
ously treated with doxorubicin and cyclophosphamide, pacli-
taxel or docetaxel, capecitabine, and gemcitabine. None of the
patients received prior adjuvant or metaststic setting.
Tumor response and survival
Of the 33 patients who were assessed for responses, PR was
noted in ten patients (30.3%; 95% confidence interval [CI], 23-
37%), SD was detected in 12 patients (36.4%), and PD was ob-
served in 11 patients (33.3%). The response rate of third line
treatment was not better than that of later line therapy (46.7%
vs. 16.7%, p=0.062). The median follow-up duration was 12.9
months. The median TTP was 6.8 months (95% CI, 5.3-8.2
months) (Figure 1). The median OS was 12.4 months (95%
CI, 10.3-14.6 months) (Figure 2). The OS of third line therapy
tended to be longer than that of later line therapy, but the dif-
ference was not significant (13.5 vs. 8.9 months, p=0.192). At
the time of study analysis, four patients remained in treatment,
and 29 patients had discontinued the study. Twenty-seven pa-
tients had experienced tumor progression. Of those patients
with PD, four (12.1%) were discovered to have new central
nervous system metastases as sites of disease progression. An
additional two patients withdrew their consent for physician
or patient preference.
Dose administration and toxicity
A total of 194 treatment cycles were administered to 33 pa-
tients, with a median number of three cycles (range, 2-12 cycles).
The number of dose-reduced cycles was 74 (38.1%) among the
194 cycles. The reasons for dose reduction were neutropenia
and/or febrile neutropenia. The relative dose intensities were
Figure 1. Time to progression curve.
Time to progression
Months
0.0 5.0 10.0 15.0 20.0
1.0
0.8
0.6
0.4
0.2
0.0
Figure 2. Overall survival curve.
Overall survival
Months
0.0 20.0 40.0 60.0
1.0
0.8
0.6
0.4
0.2
0.0

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Yu Rim Lee, et al.
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15 mg/m2/wk (90.6%) for vinorelbine and 1.9 mg/kg/wk (95.0%)
for trastuzumab.
The incidence and severity of acute toxicity associated with
combined vinorelbine and trastuzumab therapy was quite low.
All treatment-related toxicities noted in this study are shown
in Table 2. Grade 3 or 4 neutropenia was observed in 14 cycles
of treatment (7.2%), but only three episodes of non-fatal neu-
tropenic fever were detected. Grade 1 or 2 vomiting was noted
in five patients (15.2%), and grade 1 or 2 peripheral sensory
neuropathy was detected in two patients (6.1%). Many of the
women with neuropathy had pre-existing symptoms from pre-
vious taxane-based treatments. Fewer than one-third of pa-
tients showed any alopecia, and the observed gastrointestinal
symptoms were also mild, with less than 10% of patients ex-
hibiting grade 2 constipation and no patients exhibiting grade
3 or 4 gastrointestinal toxicities. Notably, no case of congestive
heart failure or asymptomatic reductions in LVEF ≥20% oc-
curred in the study population. Additionally, no treatment-re-
lated deaths occurred during this study.
DISCUSSION
After the pioneering research of Slamon et al. [6], as well as
another report by Marty et al. [7], the combination of trastu-
zumab and taxane is currently the standard first-line treatment
for patients with HER2-positive MBC. However, such combi-
nations are not reasonable for patients who have already re-
ceived taxanes and trastuzumab as an adjuvant treatment, a
group whose numbers will undoubtedly increase.
Trastuzumab has also proven clinically beneficial in combi-
nation with other chemotherapeutic agents, including vinorel-
bine, capecitabine, gemcitabine, liposomal doxorubicin, and
platinum salts [11]. Among them, vinorelbine rarely induces
total alopecia or severe gastrointestinal events or symptomatic
cardiac events. The most frequent dose-limiting hematological
toxicity associated with vinorelbine is neutropenia. Common
non-hematological side-effects include grade 1/2 peripheral neu-
ropathy, constipation, and phlebitis [9]. Several phase II trials
of trastuzumab in combination with vinorelbine have been con-
ducted [12-16]. The overall response rates (ORRs) were gener-
ally highest in patients who received the trastuzumab-vinorel-
bine combination as a first-line treatment for MBC (range, 51-
86%). Encouraging ORRs were also observed after prior che-
motherapy for MBC, and the use of adjuvant chemotherapy
does not appear to influence clinical efficacy [13,14]. Trastu-
zumab-vinorelbine has yielded progression-free survival (PFS)
and OS results comparable to other trastuzumab-chemother-
apy combination [12-16].
A phase III, multicenter, randomized trial was conducted to
assess the efficacy of trastuzumab in combination with either
vinorelbine or a taxane for treating of HER2-positive MBC: this
was called the trastuzumab and vinorelbine or taxane (TRAV-
IOTA) study [17]. The available results reflect at least compa-
rable activity between the treatment arms: the ORR was 51%
for trastuzumab-vinorelbine and 40% for trastuzumab-taxane,
and the median TTPs were 8.5 and 6.0 months, respectively.
Notably, that study did not possess power sufficient to detect
statistically significant treatment differences, due to its early
closure. In another retrospective comparison, the combination
of docetaxel and trastuzumab was associated with higher ORR
(77% vs. 57%, p=0.01), and longer OS relative to vinorelbine
and trastuzumab (35 vs. 23 months, p=0.04), with no differ-
ence in TTP (12 vs. 10 months, p=0.53) [18]. Obviously, be-
cause of the retrospective nature of our study, several biases
must be considered when interpreting our findings.
The selection of chemotherapeutic regimens is a challenging
issue for MBC whose disease has failed to respond to anthra-
cyclines and/or taxanes. In particular, treating patients who are
experiencing severe myelosuppression with these cytotoxic ther-
apies has been particularly problematic. In a previous report,
the efficacies of gemcitabine and trastuzumab after previous
exposure to anthracyclines, docetaxel, and/or vinorelbine and
trastuzumab were assessed [19]. The RR was 19.2%, the TTP
was 3 months, and the OS was 17 months. Other results of the
phase II trial demonstrated that capecitabine administered in
combination with trastuzumab is highly effective (RR 45%, PFS
6.7 months, OS 28 months) in patients with anthracycline- and
taxane-pretreated HER2 overexpressing MBC [20].
In this study, the RR was 30.3%, the TTP was 6.8 months,
and the OS was 12.4 months, which were lower than in many
previous reports; this might be attributable to the fact that all
enrolled patients had received both anthracylines and taxanes,
Table 2. Hematologic (per cycle) and non-hematologic (per patient) tox-
icities
NCI-CTC grade, No. (%)
1234
Hematologic toxicities
Anemia
Neutropenia
Thrombocytopenia
Non-hematologic toxicities
Nausea
Vomiting
Constipation
Myalgia
Peripheral neuropathy
Alopecia
Edema

7 (3.6)

4 (2.0)

1 (3.0)
1 (3.0)
2 (6.1)



1 (3.0)

3 (1.5)
2 (1.0)

2 (1.0)
10 (5.2)


4 (2.0)

2 (6.1)
1 (3.0)
1 (3.0)
2 (6.1)
2 (6.1)
1 (3.0)

NCI-CTC=National Cancer Institute-Common Toxicity Criteria.

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that >50% of the patients enrolled received vinorelbine and
trastuzumab as fourth-line and fifth-line chemotherapy. Four
patients (12.1%) developed cerebral metastases as initial pro-
gression sites while on therapy, a problem frequently encoun-
tered in HER2-positive disease [21]. This phenomenon is prob-
ably attributable to the prolonged survival due to trastuzumab
treatment, in connection with the observation that antibodies
are unable to pass the blood-brain-barrier.
The toxicity observed when using trastuzumab in combina-
tion with vinorelbine did not differ appreciably from that antic-
ipated from previous studies [12-16]. Neutropenia was the grade
3/4 adverse event most frequently associated with combination
therapy. Grade 3/4 neutropenia was noted in 7.2% of treatment
courses; however, the duration of neutropenia was both brief
and noncumulative. Few non-hematological grade 3/4 adverse
effects were observed in this study. Although patients should be
monitored for cardiac toxicity while on trastuzumab therapy,
vinorelbine does not appear to enhance trastuzumab-induced
cardiac toxicity. It is worth noting that no cardiac dysfunction
was observed in conjunction with heart failure symptoms in
this study, which constitutes an improvement even upon the
excellent cardiac tolerance observed in other phase II studies
using similar combinations. Finally, none of the patients in this
study died of any treatment-related complications.
The number of cases with a reduced dose of vinorebine was
74 (38.1%) among the total of 194 cycles, which was due to neu-
tropenia and/or febrile neutropenia. Therefore, the dose and
schedule of vinorelbine employed in this phase II trial appears
feasible for use in heavily pretreated populations.
Although this study enrolled only a small number of patients
and its duration was relatively short, the combination treatment
consisting of trastuzumab and vinorelbine generated a response
rate of 30.3% as a more than third-line therapy with a median
OS of 12.4 months. It is difficult to compare this current phase
II study of trastuzumab and vinorelbine directly with other var-
ious phase II/III studies due to different patient selection cri-
teria, particularly differences in previous therapies and deter-
minations of HER2 overexpression. Although it would clearly
be inappropriate to consider this combination as a standard
treatment for patients with HER2-overexpressing MBC before
more controlled trials are conducted, this schedule may be re-
garded as an acceptable option for MBC who have previously
undergone heavy treatment.
We conclude that the combination of vinorelbine plus trastu-
zumab appears to be a feasible and safe treatment option for
HER2 positive MBC who have previously undergone heavy
treatment.
CONFLICT OF INTEREST
Conflict of interest relevant to this article was not reported.
REFERENCES
1.?Hynes?NE,?Stern?DF.?The?biology?of?erbB-2/neu/HER-2?and?its?role?in?
cancer.?Biochim?Biophys?Acta?1994;1198:165-84.?
2.?Ménard?S,?Fortis?S,?Castiglioni?F,?Agresti?R,?Balsari?A.?HER2?as?a?prog-
nostic?factor?in?breast?cancer.?Oncology?2001;61?Suppl?2:67-72.?
3.?Vogel?CL,?Cobleigh?MA,?Tripathy?D,?Gutheil?JC,?Harris?LN,?Fehren-
bacher?L,?et?al.?Efficacy?and?safety?of?trastuzumab?as?a?single?agent?in?
first-line?treatment?of?HER2-overexpressing?metastatic?breast?cancer.?J?
Clin?Oncol?2002;20:719-26.?
4.?Cobleigh?MA,?Vogel?CL,?Tripathy?D,?Robert?NJ,?Scholl?S,?Fehrenbacher?
L,?et?al.?Multinational?study?of?the?efficacy?and?safety?of?humanized?anti-
HER2?monoclonal?antibody?in?women?who?have?HER2-overexpress-
ing?metastatic?breast?cancer?that?has?progressed?after?chemotherapy?for?
metastatic?disease.?J?Clin?Oncol?1999;17:2639-48.?
5.?Pegram?MD,?Konecny?GE,?O’Callaghan?C,?Beryt?M,?Pietras?R,?Slamon?
DJ.?Rational?combinations?of?trastuzumab?with?chemotherapeutic?drugs?
used?in?the?treatment?of?breast?cancer.?J?Natl?Cancer?Inst?2004;96:739-49.?
6.?Slamon?DJ,?Leyland-Jones?B,?Shak?S,?Fuchs?H,?Paton?V,?Bajamonde?A,?
et?al.?Use?of?chemotherapy?plus?a?monoclonal?antibody?against?HER2?
for?metastatic?breast?cancer?that?overexpresses?HER2.?N?Engl?J?Med?
2001;344:783-92.?
7.?Marty?M,?Cognetti?F,?Maraninchi?D,?Snyder?R,?Mauriac?L,?Tubiana-Hu-
lin?M,?et?al.?Randomized?phase?II?trial?of?the?efficacy?and?safety?of?trastu-
zumab?combined?with?docetaxel?in?patients?with?human?epidermal?
growth?factor?receptor?2-positive?metastatic?breast?cancer?administered?
as?first-line?treatment:?the?M77001?study?group.?J?Clin?Oncol?2005;23:?
4265-74.?
8.?Krikorian?A,?Rahmani?R,?Bromet?M,?Bore?P,?Cano?JP.?Pharmacokinetics?
and?metabolism?of?Navelbine.?Semin?Oncol?1989;16(2?Suppl?4):21-5.?
9.?Bonneterre?J,?Penel?N.?Vinorelbine?in?breast?cancer.?Expert?Opin?Phar-
macother?2008;9:2901-10.?
10.?Chan?A.?A?review?of?the?use?of?trastuzumab?(Herceptin)?plus?vinorel-
bine?in?metastatic?breast?cancer.?Ann?Oncol?2007;18:1152-8.?
11.?Bell?R,?Verma?S,?Untch?M,?Cameron?D,?Smith?I.?Maximizing?clinical?
benefit?with?trastuzumab.?Semin?Oncol?2004;31(5?Suppl?10):35-44.?
12.?Chan?A,?Martin?M,?Untch?M,?Gil?MG,?Guillem-Porta?V,?Wojtukiewicz?
M,?et?al.?Vinorelbine?plus?trastuzumab?combination?as?first-line?therapy?
for?HER?2-positive?metastatic?breast?cancer?patients:?an?international?
phase?II?trial.?Br?J?Cancer?2006;95:788-93.?
13.?Burstein?HJ,?Harris?LN,?Marcom?PK,?Lambert-Falls?R,?Havlin?K,?Over-
moyer?B,?et?al.?Trastuzumab?and?vinorelbine?as?first-line?therapy?for?
HER2-overexpressing?metastatic?breast?cancer:?multicenter?phase?II?
trial?with?clinical?outcomes,?analysis?of?serum?tumor?markers?as?predic-
tive?factors,?and?cardiac?surveillance?algorithm.?J?Clin?Oncol?2003;21:?
2889-95.?
14.?Papaldo?P,?Fabi?A,?Ferretti?G,?Mottolese?M,?Cianciulli?AM,?Di?Cocco?B,?
et?al.?A?phase?II?study?on?metastatic?breast?cancer?patients?treated?with?
weekly?vinorelbine?with?or?without?trastuzumab?according?to?HER2?
expression:?changing?the?natural?history?of?HER2-positive?disease.?Ann?

Page 7

146
Yu Rim Lee, et al.
http://ejbc.kr DOI: 10.4048/jbc.2011.14.2.140
Oncol?2006;17:630-6.?
15.?Schilling?G,?Bruweleit?M,?Harbeck?N,?Thomssen?C,?Becker?K,?Hoffmann?
R,?et?al.?Phase?II?trial?of?vinorelbine?and?trastuzumab?in?patients?with?
HER2-positive?metastatic?breast?cancer.?A?prospective,?open?label,?non-
controlled,?multicenter?phase?II?trial?(to?investigate?efficacy?and?safety?of?
this?combination?chemotherapy).?Invest?New?Drugs?2009;27:166-72.?
16.?De?Maio?E,?Pacilio?C,?Gravina?A,?Morabito?A,?Di?Rella?F,?Labonia?V,?et?
al.?Vinorelbine?plus?3-weekly?trastuzumab?in?metastatic?breast?cancer:?a?
single-centre?phase?2?trial.?BMC?Cancer?2007;7:50.
17.?Burstein?HJ,?Keshaviah?A,?Baron?AD,?Hart?RD,?Lambert-Falls?R,?Mar-
com?PK,?et?al.?Trastuzumab?plus?vinorelbine?or?taxane?chemotherapy?
for?HER2-overexpressing?metastatic?breast?cancer:?the?trastuzumab?and?
vinorelbine?or?taxane?study.?Cancer?2007;110:965-72.?
18.?Redana?S,?Donadio?M,?Nolè?F,?Jacomuzzi?ME,?Beano?A,?Martinello?R,?
et?al.?Trastuzumab?with?either?docetaxel?or?vinorelbine?as?first-line?treat-
ment?for?patients?with?HER2-positive?advanced?breast?cancer:?a?retro-
spective?comparison.?BMC?Cancer?2010;10:28.?
19.?Bartsch?R,?Wenzel?C,?Gampenrieder?SP,?Pluschnig?U,?Altorjai?G,?Rudas?
M,?et?al.?Trastuzumab?and?gemcitabine?as?salvage?therapy?in?heavily?pre-
treated?patients?with?metastatic?breast?cancer.?Cancer?Chemother?Phar-
macol?2008;62:903-10.?
20.?Schaller?G,?Fuchs?I,?Gonsch?T,?Weber?J,?Kleine-Tebbe?A,?Klare?P,?et?al.?
Phase?II?study?of?capecitabine?plus?trastuzumab?in?human?epidermal?
growth?factor?receptor?2?overexpressing?metastatic?breast?cancer?pre-
treated?with?anthracyclines?or?taxanes.?J?Clin?Oncol?2007;25:3246-50.?
21.?Clayton?AJ,?Danson?S,?Jolly?S,?Ryder?WD,?Burt?PA,?Stewart?AL,?et?al.?In-
cidence?of?cerebral?metastases?in?patients?treated?with?trastuzumab?for?
metastatic?breast?cancer.?Br?J?Cancer?2004;91:639-43.