Download Article PDF - Open Access Peer Reviewed Medical

Clinical Medicine: Therapeutics
Review
Open Access
Full open access to this and
thousands of other papers at
http://www.la-press.com.
A Review of Vinorelbine in the Treatment of Advanced Breast
Cancer
A. Brunello, A. Roma, U. Basso and A. Jirillo
Istituto Oncologico Veneto, Division of Medical Oncology, 35126 Padova, Italy. Email: [email protected]
Abstract: Vinorelbine is a semi-synthetic vinca alkaloid that has been shown active in many tumor types and is currently registered
for the treatment of advanced breast cancer (ABC) and non-small cell lung cancer (NSCLC), and it is used in other cancer type such as
prostate cancer, lymphomas, gynecologic malignancies. This agent has a generally favorable safety profile, and may be suitable for
use in special populations such as the elderly and/or frail patient. However, with the taxanes established as standard second line treatment for ABC after failure of an anthracycline, Vinorelbine has been generally relegated for use as third line therapy, in competition
with the oral compound Capecitabine. Combination regimens of Vinorelbine and Gemcitabine have been indeed widely studied, and
have been demonstrated to be safe and effective. More recently, the exciting results observed with the combination of Vinorelbine and
Trastuzumab in patients with Her-2 overexpressing tumors, as well as the development of a reliable formulation and revised schedule
of oral Vinorelbine appear to have revived the interest in this compound in the management of this disease. Yet, data from properly
designed randomized clinical trials are eagerly awaited to confirm the amount of available data which are mostly based on phase II
studies.
Keywords: vinorelbine, advanced breast cancer, vinca alkaloid, trastuzumab, oral
Clinical Medicine: Therapeutics 2009:1 1715–1726
This article is available from http://www.la-press.com.
© Libertas Academica Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License
(http://www.creativecommons.org/licenses/by/2.0) which permits unrestricted use, distribution and reproduction
provided the original work is properly cited.
The authors grant exclusive rights to all commercial reproduction and distribution to Libertas Academica. Commercial
reproduction and distribution rights are reserved by Libertas Academica. No unauthorised commercial use permitted
without express consent of Libertas Academica. Contact [email protected] for further information.
Clinical Medicine: Therapeutics 2009:1
1715
Brunello et al
Introduction
These structural modifications give highly specific
antimitotic properties to Vinorelbine, as well as enhanced
lipophilicity.
Similarly to other vinca alkaloids, Vinorelbine
induces cytotoxic effects by inhibiting polymerization
of tubulin dimers into microtubules, disrupting mitotic
spindle formation and preventing cell division. Thus, its
activity is cell cycle specific. Vinorelbine is selective
for mitotic microtubules; it has minimal to no activity
(except in higher concentrations) on axonal or other
microtubule classes, with a reduction in the frequency
and severity of neuro-toxicity, typically observed
with other microtubule agents.3 Vinorelbine is extensively metabolized in the liver through cytochrome
P450 iso-enzymes of the CYP3A subfamily. Biliary
excretion is the predominant route of elimination,
accounting for at least 50% of an intravenous dose.
Extensive biliary excretion of metabolites also
appears to occur.4,5 The elimination half-life after intravenous administration is 42 to 45 hours and 24 to
56 hours after oral administration.5,6 Pharmacokinetics
in elderly patients (older than 65 years) is similar to
those reported in younger people.7
This report reviews the most important studies
involving Vinorelbine in ABC with particular regard
to the results of randomized trials in order to evaluate
its role in this subset of patients.
Vinorelbine represents both an active and a well
tolerated treatment for metastatic breast cancer in
patients who display anthracycline and/or taxanesrefractory disease, or who are not suitable for such
treatments. Some concerns, though, have been raised
Despite the recent trend toward treatment of early
stage breast cancer aggressively with anthracyclines
and taxanes, nearly half of those women will have
metastatic recurrence. Advanced breast cancer (ABC)
generally responds to chemotherapy yet, given the
usual prior exposure to these drugs, many women
facing first-line therapy for recurrent disease will now
have developed anthracycline- and taxane-refractory
metastatic breast cancer, presenting a major therapeutic challenge. A number of established drugs have
proved to be effective in this setting: Capecitabine;
Gemcitabine; Vinorelbine; and new drugs are currently
being developed, such as camptothecins, epothilones,
mitosis inhibitor E7389, the ascidian-derived anticancer
compound trabectedin and others.
ABC is however an incurable disease, with a
median survival of 2–3 years, with response rates
to mono­therapy ranging from about 20%–75% in
chemotherapy-naïve patients.1 Moreover, the quantity and quality of the available evidence regarding
the efficacy of currently used drugs in patients with
locally advanced or metastatic breast cancer previously treated with both a taxane and an anthracycline
are extremely limited.2
Vinorelbine (5’-noranhydrovinblastine) is a semisynthetic vinca alkaloid, from the Catharanthus alkaloid family. The clinical development of Vinorelbine
started in the 1980s and, although a derivative of
Vinblastine, Vinorelbine is structurally different, with an
8-membered ring as opposed to the 9-membered ring
characteristic of naturally occurring vinca alkaloids.
VINBLASTINE
VINORELBINE
OH
N
N
CH3
H
H
N
H
N
H
C
O
CH3
N
OCH3
C
O
OCH3
N
H3CO
H3CO
CH3
H
N
H3C
O
O
H
C
OH
OCH3
C
N
O
CH3
CH3
H
H3C
O
O
H
C
O
C
O
CH3
OCH3
Figure 1.
1716
Clinical Medicine: Therapeutics 2009:1
Vinorelbine in ABC
about a potential cross-resistance between taxanes
and Vinorelbine, and contradictory evidence exists
on the use of Vinorelbine in patients with disease
refractory to taxanes. In a phase II trial, no responses
were seen with Vinorelbine among 14 patients with
ABC refractory to taxanes,8 whereas other studies
indicate possible responses in patients treated with
Vinorelbine for ABC judged taxane-refractory.9–11
In the next paragraphs single agent activity and combinations regimens with Vinorelbine are discussed,
as well as combinations with targeted therapy, namely
Trastuzumab.
Vinorelbine: single agent activity
Many phase II studies have demonstrated the activity
and tolerability of intravenous administration of
Vinorelbine, with response rates ranging from 40%–
60% in chemo-naïve disease and with good tolerability,12 Table 1. Vinorelbine rarely induces total
alopecia or severe gastrointestinal events or symptomatic cardiac events. The major dose-limiting
hematological toxicity associated with Vinorelbine is
neutropenia. Common non-hematological side-effects
include G1–G2 peripheral neuropathy, constipation
and phlebitis.
Because of its clinical activity and its mild toxicity
profile and, in particular, the absence of alopecia could
be particularly attractive for women.
Indeed, for all the above mentioned reasons,
Vinorelbine as single agent represents a valid alternative in the treatment of metastatic breast cancer in
elderly patients.
Sorio and colleagues demonstrated that Vinorelbine
administered intravenously at the dose of 30 mg/m2
on days 1 and 8 every 3 weeks was well tolerated.
Responses were observed in 6 out of 20 evaluable
patients (ORR 30%) and no correlation between
dosage, age and toxicity was observed.7 In another
study, Vinorelbine was administered weekly at the
same dosage (30 mg/m2). The dose-limiting toxicity
observed was hematologic, easily recovered with
dose adjustment. Asthenia, gastroenteric toxicity and
injection site reactions were the predominant nonhematologic adverse events. Neurotoxicity and alopecia
were relatively infrequent and mild.13–15
Only two randomized phase III trials are available
testing Vinorelbine single agent,16,17 Table 2. Vinorelbine given with schedule 30 mg/m2 (days 1 and 8)16
has been shown to be as effective as single agent as in
the combination with Gemcitabine as for overall survival, whereas the combination significantly improves
progression-free survival (PFS), when toxicity was
significantly higher in the combination arm.
The study by Jones and colleagues explored Vinorelbine with schedule 30 mg/m2 weekly,17 showing a survival benefit in anthracycline-refractory ABC with use
Table 1. Phase II studies involving Vinorelbine in ABC patients.
Authors
N
Route
Setting
ORR
PFS months
OS months
145
i.v.
1st line
41
5.8
18
50
i.v.
1st line
50
5
15
44
i.v.
1st line
41
6
NA
Weber et al
60
i.v.
1st line
35
4.5
15.5
Bruno et al
63
i.v.
1st line
44
3
11.7
56
i.v.
1st line
38
9
NA
27
i.v.
1st line
59
NA
19
34
i.v.
1st line
50
4.4
10
100
i.v.
2nd line
16%
NA
NA
60
i.v.
1st line, 2nd line
12%
3.0
10.3
50
i.v.
1st line
20%
3.4
NA
131
oral
2nd line
11%
NA
9.9
72
oral
1st line
24%
NA
NA
Fumoleau et al
18
Garcia-Conde et al
Romero et al
20
21
22
Vogel et al
13
Terenziani et al
Twelves et al
23
24
Degardin et al
Langkjer et al
25
26
Toi et al27
Winer et al28
Amadori et al
29
19
Clinical Medicine: Therapeutics 2009:1
1717
Brunello et al
Table 2. Phase III randomized studies involving single agent Vinorelbine in ABC patients.
Authors
Arms
Martin et al
ORR
PFS months
OS months
26%
4.0
16.4
36%
6.0
15.9
Vinorelbine 30 mg/m weekly
46%
2.8
8.7
Melphalan 25 mg/m every 4 weeks i.v
28%
2.0
7.7
PLD
10%
2.9
11
V (or MC + Vbt)*
12%
2.5
9
Vinorelbine 30 mg/m
16
2
Vinorelbine + Gemcitabine 30/1200 mg/m
Jones et al
17
2
2
2
Keller et al
11
*14% of patients in the V arm actually received Mitomicin (MC) and Vinblastine (Vbt).
of Vinorelbine versus Melphalan, with comparable
toxicity and quality of life.
In a more recent trial performed in a population of
301 women with ABC who had failed a taxane as first
or second line therapy, Vinorelbine (which was the
chosen comparator in 85% of the cases; n = 129) was
shown equivalent to Pegylated Liposomal Doxorubicin
(PLD), a novel Doxorubicin formulation with comparable efficacy and better safety profile.11 Only the
subgroup of patients without previous exposure to
anthracyclines (17% of the study population) had a
somewhat better PFS with PLD.
Combination regimens with Vinorelbine
One of the virtues of Vinorelbine is the fact that,
in view of its mild toxicity profile, it can be easily
combined with virtually any other cytotoxic. A large
number of phase II trials have been performed
which have generally shown encouraging activity
with an acceptable safety profile (Table 3). Examples
include Paclitaxel30–37 Docetaxel;38–46 Doxorubicin;47–51
Epirubicin52–54 Mitoxantrone;55–57 Pegylated Liposomal
Doxorubicin;14,58–61 Gemcitabine;62–73 5-Fluorouracil;74–79
platinum compounds;80–83 and Capecitabine,84–88 which
will be separately discussed. Several triplets have
also been investigated but increased toxicity should
be expected.89–92
Some of these combinations were eventually
investigated in phase III trials, and will be discussed
in more detail in the following section.
The combination of Vinorelbine and 5-Fluorouracil,
one of the most extensively studied in patients with
ABC, was compared to Docetaxel in a small randomized
phase III trial (sample size 176 patients).93 Although
there were no differences in terms of efficacy, the combination resulted in more toxicity, with also toxic deaths
registered, as compared to single agent Docetaxel.
Yet, it must be noticed that high doses of 5-Fluouracil
(750 mg/m2/day for 5 days) have been administered
in this trial. Randomized trials have evaluated the addition of Vinorelbine to an anthracycline such as Mitoxantrone,94 Doxorubicin,95,96 and Epirubicin97 against
Table 3. Combination regimens with Vinorelbine.
Authors
Arms
Setting
ORR
PFS months
OS months
Toxicity
V + 5FU
Docetaxel
Previous
anthracyclines
43%
39%
5.1
6.5
15
16
More
Namer et al94
V + Mitoxantrone
FAC/FEC
1st line
35%
33%
8
5
20
16
More
Blajman et al95
V + Doxorubicin
FAC
1st line
75%
74%
7.5
9
17.8
17.3
Similar
Norris et al96
V + Doxorubicin
Doxorubicin
1st/2nd line
38%
30%
6.2
6.1
13.8
14.4
More
Ejlertsen et al97
V + Epirubicin
Epirubicin
1st line
50%
42%
10.1
8.2
19.1
18.0
More
Bonneterre et al
1718
93
Clinical Medicine: Therapeutics 2009:1
Vinorelbine in ABC
standard anthracycline arms. Only one of these trials
suggested an advantage for the combination in terms
of response rates and progression-free survival, at
the price of higher toxicities for the combination
arms. Generally, toxicities for the combination arms
were statistically increased in the combination arms
in trials comparing single agent versus combination
with Vinorelbine.
These results are in line with those of other
randomized clinical trials in ABC, showing that combination chemotherapy is usually not superior to
optimal sequential treatment, and is likely to result
in more toxicity, therefore the use of combination
chemotherapy regimens in advanced settings should
be limited to those patients requiring rapid shrinking
of life-threatening tumors.
Vinorelbine and Capecitabine,
Phase II studies
Vinorelbine is currently occupying a delicate place
in the management of ABC especially for third
line therapy after failure of anthracyclines and taxanes, in open competition with the oral compound
Capecitabine, an oral fluoropyrimidine carbamate
which is enzymatically converted via a 3 enzymatic
step to 5’-deoxy-5-fluorocytidine (5’-DFCR), 5’-deoxy5-fluorouridine (5’-DFUR), and finally 5-FU. To date,
no randomized phase III trial comparing directly
Vinorelbine vs. Capecitabine has been performed.
The limited data coming from a phase II study98 and
retrospective data sets99,100 show similar activity of the
two agents or, in the case of retrospective data, higher
activity for Capecitabine. In particular, safety profiles are different, with more G3–G4 hematological
toxicity for Vinorelbine, and more grade 3 cutaneous
toxicity for Capecitabine. In addition, Capecitabine
and Vinorelbine have been compared in a pharmacoeconomic analysis performed in the United States.
Mean monthly cost for patients with advanced breast
cancer was higher for patients receiving Vinorelbine when compared to matched patients receiving
Capecitabine and the main difference in cost was
dictated by management of treatment related toxicity
and chemotherapy i.v. administration.101
Capecitabine is an attractive combination partner
since it displays a high single agent activity and a
non overlapping toxicity profile, with only minimal
myelodepression and no alopecia. Moreover, there
Clinical Medicine: Therapeutics 2009:1
is a synergistic effect due to Vinorelbine mediated
up-regulation of thymidine phosphorilase (TP), which
has a crucial role in the 3-step conversion of Capecitabine
to 5-FU at tumor site.102
The combination of Capecitabine and Vinorelbine
has been investigated in a variety of phase I studies
and phase II studies, which are illustrated in Table 4.
Recently, an oral formulation of Vinorelbine has
become available. Some studies also evaluated an all
oral combination of Vinorelbine and Capecitabine,
which could represent an attractive option in particular
subsets of patients, such as elderly patients.
Oral Vinorelbine
Among the options for treatment of anthracycline- and
taxanes-pretreated advanced breast cancer, Capecitabine
has been generally preferred by patients because of
the convenience of the oral route, but recently a novel
oral formulation of Vinorelbine (ONVB) which has
apparently overcome the problem of erratic absorption has become available. In patients with NSCLC,
oral and intravenous Vinorelbine have been shown to
have comparable activity.115
In pharmacokinetic studies, equivalence in bioavailability has been demonstrated between the oral
and intravenous formulation.116 Oral Vinorelbine is
rapidly absorbed, with a Tmax of 0.75–1.4 hours.116,117
Bioavailability of soft-gelatine capsules, the
third and most recent oral formulation of Vinorelbine, is 33%–43%,116,117 with 38% inter-individual
variability.116 Low bioavailability may be attributed
to both incomplete absorption and to a first-pass
effect (intestinal and hepatic). The problems with
hematologic toxicity observed in earlier trials,118
have been managed by administering the first
course of ONVB at the dose of 60 mg/m2 days 1
and 8, and only if no toxicity is observed escalating to a dose of 80 mg/m2 days 1 and 8. This helped
reducing the severe toxicity which was typically
observed at first cycle, with the occurrence of even
toxic deaths in the earlier trials.118 This schedule
has demonstrated moderate efficacy but is characterized by a high rate of neutropenia, the risk of
which increases after dose escalation to 80 mg/m2.119
Consequently close hematological monitoring is
essential.118 Furthermore, differently from intravenous formulation, oral Vinorelbine has been shown
to be associated with frequent nausea, vomiting and
1719
Brunello et al
Table 4. Phase II studies in first and subsequent lines of Vinorelbine and Capecitabine for ABC.
Author
N
Dose (mg/m2)
C days 1–14
V days 1 and 8
ORR
TTP
OS
Elghazaly et al103
45
C 2000
V 25
64%
9
NA
Ghosn et al85
30
C 1700
V 25
70%
10
30.4
Ghosn et ala,104
40
C 1700
V 25
55%
12.3
35.8
Köler et alb,105
30
C 2000
V 25
77%
NA
NA
Hess et alb,106
70
C 1000/1300
V 20
43%–57%
4.3/7.0
NA
Iodice et alb,107
53
C 2000–2500
V 20–25
62%
12.1
21.3
Palumbo et al108
32
C 2000
V 25
72%
9.1
NA
Stuart et al88
58
C 2000
V 25
43%
NA
NA
Davis et al109
22
C 2000
V 25
33%
5.8
3.5
Orphanos et al110
30
C 2000
V 20
50%
NA
NA
Estévez et al111
31
C 2000
V 20
49%
7.6
27.2
Lorusso et al112
38
C 2000
V 25
37%
6.8
11.3
Xu B et al113
77
C 1900
V 25
47%
6
NA
Ahn et al114
44
C 2500
V 25
50%
5.3
17
1st line
2nd line
a
b
Sequential Docetaxel.
Studies specifically addressed to elderly patients.
diarrhea,118,119 and prophylactic antiemetics are
recommended.118 Nonetheless, oral formulation may
be attractive for patients not willing to be treated with
i.v. drugs and for elderly patients, a subset of patients
in which it has been demonstrated fair safety of this
formulation, though activity raises concerns.120
Although experience with oral Vinorelbine is less
extensive than with the intravenous formulation, the
pivotal phase II trial that has investigated the new
schedule in patients with ABC resulted in response rates
of 31% and median duration of response of 4 months
in previously untreated patients.119 Furthermore, it has
1720
been shown that ONVB brings added value in terms of
patients’ convenience allowing improved quality of
life and reduced hospital stays while keeping optimal compliance to treatment schedule in a French
experience.121
All oral combinations of Vinorelbine and Capecitabine have been investigated in phase I and II studies,
with overall response rates ranging from 26%–61%,
median progression-free survival 6–10.5 months and
median overall survival 10–48 months.87,122
In particular, when used in first line settings,
response rates are in the range of 44%–51% with median
Clinical Medicine: Therapeutics 2009:1
Vinorelbine in ABC
progression free survival of 8.4 months.86,123 Among
the major benefits for these combination regimens
is the possibility of continuing therapy for prolonged periods in patients with controlled disease,
whereas this would not be possible for anthracycline
and/or taxanes containing regimens due to cumulative toxicity.
Recently, new metronomic schedules have been
proposed, which can be appealing for the low toxicities
and manageable side effects that render the schedule
easily applicable to vulnerable populations such as
elderly patients oral Vinorelbine 80 mg/m2 fractionated in days 1, 3, and 5, three week on-one week off,
every 4 weeks. ORR 41%, with median time to disease progression was 7.1 months and median overall
survival was 12.7 months.124
with a taxane (e.g. prior exposure to taxanes,
pre-existing peripheral neuropathy, patient’s choice
depending on potential side effects), Vinorelbine has
been demonstrated an effective option.
In the preclinical setting, synergism between Trastuzumab and Vinorelbine has been demonstrated.127
Vinorelbine and Trastuzumab have no overlapping
toxic effects, which contrast with the use of Trastuzumab in combination with anthracyclines.128
A phase I dose-finding study evaluated escalating
doses of Vinorelbine in 12 patients.129
Vinorelbine was given at doses of 20, 25 and
30 mg/m2 in successive cohorts, on a day 1 and 8 schedule every 21 days, in combination with Trastuzumab.
Toxic effects were primarily hematological; one
case of febrile neutropenia and one episode of acute
cholecystitis were noted among six assessable patients
receiving Vinorelbine 30 mg/m2 and this was therefore
determined as the maximum tolerated dose.
Several phase II trials (Table 5) and one phase III
trial130 have now reported data for Trastuzumab in
combination with Vinorelbine in the HER2-positive
MBC setting. The trials have included 450 assess­
able patients, the majority (94%) having HER2positive status, defined as an immunohistochemistry
(IHC) score of 3+ or by FISH. In particular, in
the phase III trial,130 the Vinorelbine-Trastuzumab
combination showed similar efficacy to the weekly
Vinorelbine and HER2 positive disease
Trastuzumab, a 95% humanized monoclonal antibody targeted against the extracellular domain of the
HER-2 receptor, is the standard of care for patients with
HER2 over-expressing tumors (about 20% of breast
carcinomas) in association with chemotherapy. In the
pivotal trials of single agent Trastuzumab, response
rates of 15% and 30% have been reported in previously treated125 and untreated126 patients.
Trastuzumab is frequently combined with a taxane,
however in patients who are not suitable for therapy
Table 5. Trials with combination of Trastuzumab and Vinorelbine.
Authors
Jahanzeb et al
N
Schedule
Setting
ORR
PFS months
OS months
40
30 mg/m /w
1st line
78%
72 w
NA
Bernardo et al132
48
25 mg/m2/w
1st line
86%
2
NA
Burstein et al
133
54
25 mg/m /w
1st line
68%
5.6
NA
Burstein et al
15
40
25 mg/m /w
1st line
75%
NA
NA
69
30 mg/m /w
1st line
62%
9.9
23.7
52
25 mg/m /w
1st line
58%
7
26
69
30 mg/m /w
NA
61%
10
NA
Chan et al
131
134
Bayo-Callero et al
Porta et al
135
136
Schilling et al
2
2
2
2
2
2
41
25 mg/m /w
NA
44%
7.8
NA
Franquesa et al138
18
25 mg/m2/w
1st and 2nd line
44%
11.9
NA
Brunello et al
19
20–30 mg/m /w
1st line
57%
NA
NA
35
25 mg/m /w
2nd line
51%
9
27
25
25 mg/m /w
up to 4th
72%
NA
NA
41
25 mg/m /w
1st line
51%
8.5
NA
139
Papaldo et al
Lal et al
137
140
141
Burstein et al 2007*
,130
2
2
2
2
2
*Phase III trial.
Clinical Medicine: Therapeutics 2009:1
1721
Brunello et al
taxanes-Trastuzumab combination, yet the trial was
prematurely closed due to slow accrual.
On the contrary of trials of combination taxanesTrastuzumab, the studies of combination VinorelbineTrastuzumab demonstrate a more favorable thera­peutic
index, with rates of cardiomiopathy not higher than
those reported with Trastuzumab single agent. Although
it would be inappropriate to consider the combination Trastuzumab-Vinorelbine as standard treatment
for patients with Her-2 overexpressing ABC in the
absence of controlled trials, this schedule may be
considered an acceptable option for patients willing
to avoid the side effects associated with taxanes (such
as alopecia), or for selected patients relapsing after
previous exposure to taxanes, a situation likely to be
more common with the increasing use of taxanes in the
(neo-)adjuvant setting.
Schedules with three-weekly Trastuzumab have
been studied as well,142 with manageable toxicity and
activity which falls in the range of expected response
rates for weekly schedules, though at the lower limits.
The oral formulation of Vinorelbine has also been
investigated in association with Trastuzumab for HER2
overexpressing tumors.
An observational study143 demonstrated that the
combination is an effective and safe treatment option
for HER2 positive ABC, with response rates and time
to progression depending mainly on line of treatment;
a schedule which consists of intravenous Vinorelbine
on day 1 and oral Vinorelbine on day 8 and Trastuzumab has also been studied144 and results showed
high antitumor efficacy, with overall response rate
62%, and excellent tolerability in 1st-line treatment
of HER2 overexpressing ABC.
Conclusions
The increasing evidence that anthracyclines and
taxanes improve the survival of patients with breast
cancer in the adjuvant setting has led to a restricted use
of these drugs in women with metastatic disease.145
Combination regimens of Vinorelbine with anthracyclines or taxanes have been demonstrated to have same
efficacy of the single agent (anthracycline or taxanes),
in some cases improving the overall response rate, but
usually at the price of increased toxicity that does not
justify the use of such combinations. On the contrary,
association with newer drugs such as Gemcitabine
or Capecitabine have shown increased efficacy over
1722
the single agent, with manageable toxicity profile.
Although Vinorelbine is clearly an active and well
tolerated agent in BC, its use is currently limited by the
lack of properly designed controlled trials. Generally,
Vinorelbine as a single agent is not recommended in
patients who are anthracycline naïve though it may
be considered a reasonable option for patients willing
to prioritize quality of life over maximum chance of
tumor response. Single agent Vinorelbine or combinations of Vinorelbine and Capecitabine can be
considered an alternative to the use of anthracyclines and taxanes in special populations of patients,
such as the elderly and/or frail patients or in those
willing to avoid alopecia and/or to prioritize other
aspects of quality of life. The new oral formulation of
Vinorelbine is particularly indicated for patients with
disease characterized by low aggressiveness with
or without visceral metastasis, or slowly progressing disease. In addition, recently Vinflunine, a novel
fluorinated Vinca alkaloid, has become available
and is currently under study for treatment of breast
cancer progressing after anthracycline- and taxanebased chemotherapy.
The availability of Vinorelbine and other novel,
well tolerated and effective treatments provides
greater potential to tailor treatment to meet individual
patient needs and, therefore, also provide the potential to improve patient outcomes.
Disclosures
The authors report no conflicts of interest.
References
1. Nicolini A, Giardino R, Carpi A, et al. Metastatic breast cancer: an updating.
Biomed Pharmacother. 2006;60:548–56.
2. Jassem J, Carroll C, Ward SE, et al. The clinical efficacy of cytotoxic agents
in locally advanced or metastatic breast cancer patients pretreated with an
anthracycline and a taxane: A systematic review. Eur J Cancer. 2009. [Epub
ahead of print].
3. Toso C, Lindley C. Vinorelbine a novel vinca alkaloid. Am J Health Syst
Pharm. 1995;52(12):1287–304.
4. Feigal EG, Christian M, Cheson B, et al. New chemotherapeutic agents
in non-small cell lung cancer. Semin Oncol. 1993;20:185–201.
5. Jehl F, Quoix E, Leveque D, et al. Pharmacokinetic and preliminary metabolic fate of Navelbine in humans as determined by high performance liquid
chromatography. Cancer Res. 1991;51:2073–6.
6. Marquet P, Lachatre G, Debord J, et al. Pharmacokinetics of vinorelbine in
man. Eur J Clin Pharmacol. 1992;42:545–7.
7. Sorio R, Robieux I, Galligioni E, et al. Pharmacokinetics and tolerance of
vinorelbine in elderly patients with metastatic breast cancer. Eur J Cancer.
1997;33(2):301–3.
8. Fazeny B, Zifko U, Meryn S, et al. Vinorelbine-induced neurotoxicity in
patients with advanced breast cancer pretreated with paclitaxel—a phase II
study. Cancer Chemother Pharmacol. 1996;39(1–2):150–6.
Clinical Medicine: Therapeutics 2009:1
Vinorelbine in ABC
9. Zelek L, Barthier S, Riofrio M, et al. Weekly vinorelbine is an effective
palliative regimen after failure with anthracyclines and taxanes in metastatic
breast carcinoma. Cancer. 2001;92(9):2267–72.
10. Udom DI, Vigushin DM, Linardou H, et al. Two weekly vinorelbine: administration in patients who have received at least two prior chemotherapy
regimes for advanced breast cancer. Eur J Cancer. 2000;36(2):177–82.
11. Keller AM, Mennel RG, Georgoulias V, et al. A randomized phase III trial of
Pegylated Liposomal Doxorubicin versus vinorelbine or mitomycin C plus
vinblastine in women with taxane-refractory advanced breast cancer. J Clin
Oncol. 2004;22(19):3893–901.
12. Gregory RK, Smith IE. Vinorelbine—a clinical review. Br J Cancer.
2000;82:1907–13.
13. Vogel C, O’Rourke M, Winer E, et al. Vinorelbine as first-line chemotherapy
for advanced breast cancer in women 60 years of age or older. Ann Oncol.
1999;10(4):397–402.
14. Addeo R, Faiola V, Guarrasi R, et al. Liposomal Pegylated Doxorubicin plus
vinorelbine combination as first-line chemotherapy for metastatic breast
cancer in elderly women /= 65 years of age. Cancer Chemother Pharmacol.
2008;62(2):285–92.
15. Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab
and vinorelbine in women with HER2-overexpressing metastatic breast
cancer. J Clin Oncol. 2001;19(10):2722–30.
16. Martin M, Ruiz A, Munoz M, et al. Gemcitabine plus vinorelbine versus
vinorelbine monotherapy in patients with metastatic breast cancer previously
treated with anthracyclines and taxanes: final results of the phase III Spanish
Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007;8:
219–25.
17. Jones S, Winer E, Vogel C, et al. Randomized comparison of vinorelbine
and melphalan in anthracycline-refractory advanced breast cancer. J Clin
Oncol. 1995;13(10):2567–74.
18. Fumoleau P, Delgado FM, Delozier T, et al. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin
Oncol. 1993;11(7):1245–52.
19. Garcia-Conde J, Lluch A, Martin M, et al. Phase II trial of weekly IV
vinorelbine in first-line advanced breast cancer chemotherapy. Ann Oncol.
1994;5(9):854–7.
20. Romero A, Rabinovich MG, Vallejo CT, et al. Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol. 1994;12(2):336–41.
21. Weber BL, Vogel C, Jones S, et al. Intravenous vinorelbine as first-line and
second-line therapy in advanced breast cancer. J Clin Oncol. 1995;13(11):
2722–30.
22. Bruno S, Puerto VL, Mickiewicz E, et al. Phase II trial of weekly i.v.
vinorelbine as a single agent in first-line advanced breast cancer chemotherapy. The Latin-American experience. Am J Clin Oncol. 1995;18(5):
392–6.
23. Terenziani M, Demicheli R, Brambilla C, et al. Vinorelbine: an active,
non-cross-resistant drug in advanced breast cancer. Results from a phase II
study. Breast Cancer Res Treat. 1996;39(3):285–91.
24. Twelves CJ, Dobbs NA, Curnow A, et al. A phase II, multicentre, UK study
of vinorelbine in advanced breast cancer. Br J Cancer. 1994;70(5):990–3.
25. Degardin M, Bonneterre J, Hecquet B, et al.Vinorelbine (navelbine) as a
salvage treatment for advanced breast cancer. Ann Oncol. 1994;5(5):423–6.
26. Langkjer ST, Ejlertsen B, Mouridsen H, et al. Danish Breast Cancer
Co-operative Group. Vinorelbine as first-line or second-line therapy for
advanced breast cancer: a Phase I–II trial by the Danish Breast Cancer
Co-operative Group. Acta Oncol. 2008;47(4):735–9.
27. Toi M, Saeki T, Aogi K, et al. Late phase II clinical study of vinorelbine
monotherapy in advanced or recurrent breast cancer previously treated with
anthracyclines and taxanes. Jpn J Clin Oncol. 2005;35(6):310–5.
28. Winer EP, Chu L, Spicer DV. Oral vinorelbine (Navelbine) in the treatment
of advanced breast cancer. Semin Oncol. 1995;22(2 Suppl 5):72–8.
29. Amadori D, Koralewsky P, Tekiela A. Efficacy and safety of navelbine
oral (NVBo) in first line metastatic breast cancer (MBC). Eur J Cancer.
2001;37:22. Abstr. 713
30. Romero AL, Langhi M, Perez J, et al. Vinorelbine and Paclitaxel as firstline chemotherapy in metastatic breast cancer. J Clin Oncol. 1999;17(1):
74–81.
Clinical Medicine: Therapeutics 2009:1
31. Martin M, Lluch A, Casado A, et al. Paclitaxel plus vinorelbine: an active
regimen in metastatic breast cancer patients with prior anthracycline
exposure. Ann Oncol. 2000;11(1):85–9.
32. Michelotti A, Gennari A, Salvadori B, et al. Paclitaxel in combination with
vinorelbine in pretreated advanced breast cancer patients. Semin Oncol. 1996;
23(5 Suppl 11):38–40.
33. Polyzos A, Tsavaris N, Kosmas C, et al. Full dose Paclitaxel plus vinorelbine as salvage chemotherapy in anthracycline-resistant advanced breast
cancer: a phase II study. J Chemother. 2003;15(6):607–12.
34. Cocconi G, Mambrini A, Quarta M, et al. Vinorelbine combined with
Paclitaxel infused over 96 hours (VI-TA-96) for patients with metastatic
breast carcinoma. Cancer. 2000;88(12):2731–8.
35. Vici P, Amodio A, Di Lauro L, et al. First-line chemotherapy with vinorelbine and Paclitaxel as simultaneous infusion in advanced breast cancer.
Oncology. 2000;58(1):3–7.
36. Bouillet T, Saintigny P, Levy E, et al. Weekly Paclitaxel (P) combined
with biweekly vinorelbine (V) in metastatic breast cancer (MBC):
final results of a clinical phase II study. ASCO annual meeting proceedings (post-meeting edition), J Clin Oncol. 2004;22(14S):783 [July 15
Supplement].
37. Ellis GK, Gralow JR, Pierce HI, et al. Infusional Paclitaxel and weekly
vinorelbine chemotherapy with concurrent filgrastim for metastatic breast
cancer: high complete response rate in a phase I–II study of Doxorubicintreated patients. J Clin Oncol. 1999;17(5):1407–12.
38. Kornek GV, Ulrich-Pur H, Penz M, et al. Treatment of advanced breast
cancer with vinorelbine and Docetaxel with or without human granulocyte
colony-stimulating factor. J Clin Oncol. 2001;19(3):621–7.
39. Paz LDA, Lluch A, Martin M, et al. A phase II study of Docetaxel (D)
and vinorelbine (V) in metastatic breast cancer (MBC). Proc Am Soc Clin
Oncol. 1999; [abstract 452].
40. Vassilomanolakis M, Koumakis G, Drufakou S, et al. Vinorelbine and
Docetaxel as first-line chemotherapy in metastatic breast cancer. Cancer
Chemother Pharmacol. 2003;51(2):179–83. [Epub 2000].
41. Marti JL, Bueso P, Mayordomo JI, et al. Combination chemotherapy with
Docetaxel plus vinorelbine in metastatic breast cancer patients with prior
exposure to anthracyclines. Ann Oncol. 2001;12(8):1061–5.
42. Pectasides D, Dimopoulos MA, Aravantinos G, et al. First line combination
chemotherapy with Docetaxel and vinorelbine in advanced breast cancer.
A phase II study. Anticancer Res. 2001;21(5):3575–80.
43. Mayordomo JI, Milla A, Morales S, et al. Biweekly Docetaxel and vinorelbine as first-line chemotherapy in metastatic breast cancer. Clin Breast
Cancer. 2004;5(2):131–5.
44. Gomez-Bernal A, Cruz JJ, Garcia-Palomo A, et al. Biweekly Docetaxel and
vinorelbine in anthracycline-resistant metastatic breast cancer: a multicenter
phase II study. Am J Clin Oncol. 2003;26(2):127–31.
45. Airoldi M, Cattel L, Pedani F, et al. Clinical data and pharmacokinetics
of a Docetaxel-vinorelbine combination in anthracycline resistant/relapsed
metastatic breast cancer. Acta Oncol. 2003;42(3):186–94.
46. Rodriguez J, Calvo E, Cortes J, et al. Docetaxel plus vinorelbine as salvage
chemotherapy in advanced breast cancer: a phase II study. Breast Cancer
Res Treat. 2002;76(1):47–56.
47. Spielmann M, Dorval T, Turpin F, et al. Phase II trial of vinorelbine/
Doxorubicin as first-line therapy of advanced breast cancer. J Clin Oncol.
1994;12(9):1764–70.
48. Alvarez A, Balbiani L, Block J, et al. Phase II study: navelbine (NVB) +
adriamycin as first line chemotherapy in advanced breast cancer (ABC).
Ann Oncol. 1994;5(Suppl 8). [Abstract 161].
49. Hochster HS, Vogel CL, Burman SL, White R. Activity and safety of
vinorelbine combined with Doxorubicin or fluorouracil as first-line therapy
in advanced breast cancer: a stratified phase II study. Oncologist. 2010;6(3):
269–77.
50. Pawlicki M, Rolski J, Zaluski J, et al. A phase II study of intravenous navelbine and Doxorubicin combination in previously untreated advanced breast
carcinoma. Oncologist. 2002;7(3):205–9.
51. Hegg R, Costa MA, Perdicaris M, et al. A phase II trial of fractionated
vinorelbine/Doxorubicin as first-line therapy for advanced breast cancer.
Curr Med Res Opin. 2001;16(4):225–34.
1723
Brunello et al
52. Baldini E, Tibaldi C, Chiavacci F, et al. Epirubicin/vinorelbine as first line
therapy in metastatic breast cancer. Breast Cancer Res Treat. 1998;49(2):
129–34.
53. Vici P, Colucci G, Gebbia V, et al. First-line treatment with Epirubicin and
vinorelbine in metastatic breast cancer. J Clin Oncol. 2002;20(11):2689–94.
54. Frontini L, Ardizzoia A, Giordano M, et al. Epirubicine-vinorelbine (EV)
intravenous combination followed by oral vinorelbine (VNR) as first-line
treatment in advanced breast cancer (ABC) patients: A POLONORD Group
study, Proc Am Soc Clin Oncol. 2005;23. [Abstract 770].
55. Llombart-Cussac A, Pivot X, Rhor-Alvarado A, et al. First-line vinorelbineMitoxantrone combination in metastatic breast cancer patients relapsing
after an adjuvant anthracycline regimen: results of a phase II study. Oncology.
1998;55(5):384–90.
56. Adenis A, Vanlemmens L, Fournier C, et al. Does induction chemotherapy
with a Mitoxantrone/vinorelbine regimen allow a breast-conservative treatment
in patients with operable locoregional breast cancer? A French Northern
Oncology Group trial in 105 patients. French Northern Oncology Group.
Breast Cancer Res Treat. 1996;40(2):161–9.
57. Onyenadum A, Gogas H, Markopoulos C, et al. Mitoxantrone plus vinorelbine in pretreated patients with advanced breast cancer. Proc Am Soc Clin
Oncol. 2005;23(16):93S. [Abstract 863].
58. Rimassa L, Carnaghi C, Garassino I, et al. Unexpected low efficacy of
stealth liposomal Doxorubicin (Caelyx) and vinorelbine in metastatic breast
cancer. Breast Cancer Res Treat. 2003;77(2):185–8.
59. Martin M, Garcia-Donas J, Casado A, et al. Phase II study of Pegylated
Liposomal Doxorubicin plus vinorelbine in breast cancer with previous
anthracycline exposure. Clin Breast Cancer. 2004;5(5):353–7.
60. Gebbia V, Mauceri G, Fallica G, et al. Pegylated liposomal Doxorubicin
with vinorelbine in metastatic breast carcinoma. A phase I–II clinical investigation. Oncology. 2002;63(1):23–30.
61. Mlineritsch B, Schabel-Moser R, Andel J, et al. Multicenter phase II study
of Pegylated Liposomal Doxorubicin in combination with vinorelbine
as first-line treatment in elderly patients with metastatic breast cancer.
Onkologie. 2009;32(1–2):18–24.
62. Hortobagyi GN. Gemcitabine in combination with vinorelbine for treatment
of advanced breast cancer. Clin Breast Cancer. 2002;3(Suppl 1):34–8.
63. Donadio M, Ardine M, Berruti A, et al. Gemcitabine and vinorelbine as
second-line treatment in patients with metastatic breast cancer: a phase II
study. Cancer Chemother Pharmacol. 2003;52(2):147–52.
64. Rossi E, Perrone F, Labonia V, et al. Is Gemcitabine plus vinorelbine active
in second-line chemotherapy of metastatic breast cancer? a single-center
phase 2 study. Oncology. 2003;64(4):479–80.
65. Morabito, Filippelli G, Palmeri S, et al. The combination of Gemcitabine
and vinorelbine is an active regimen as second-line therapy in patients with
metastatic breast cancer pretreated with taxanes and/or anthracyclines: a
phase I–II study. Breast Cancer Res Treat. 2003;78(1):29–36.
66. Lobo F, Virizuela JA, Dorta FJ, et al. Spanish Group for Research in Breast
Cancer. Gemcitabine/vinorelbine in metastatic breast cancer patients previously treated with anthracyclines: results of a phase II trial. Clin Breast
Cancer. 2003;4(1):46–50.
67. Nicolaides A, Dimopoulos MA, Samantas E, et al. Gemcitabine and vinorelbine as second-line treatment in patients with metastatic breast cancer
progressing after first-line taxane-based chemotherapy: a phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2000;11(7):
873–875.
68. Stathopoulos GP, Rigatos SK, Pergantas N, et al. Phase II trial of biweekly
administration of vinorelbine and Gemcitabine in pretreated advanced
breast cancer. J Clin Oncol. 2002;20(1):37–41.
69. Haider K, Kornek GV, Kwasny W, et al. Treatment of advanced breast
cancer with Gemcitabine and vinorelbine plus human granulocyte colonystimulating factor. Breast Cancer Res Treat. 1999;55(3):203–11.
70. Sanal SM, Gokmen E, Karabulut B, Sezgin C. Gemcitabine and vinorelbine combination in patients with metastatic breast cancer. Breast J. 2002;
8(3):171–6.
71. Gennatas A, Mouratidou D, Tsavaris N, et al. Gemcitabine in combination
with vinorelbine for heavily pretreated advanced breast cancer. Proc Am
Soc Clin Oncol. 2005;23(16):63S. [Abstract 741].
1724
72. Gokmen AC, Sezgin CB, Karabulut B, et al. Gemcitabine plus vinorelbine
as first-line treatment of metastatic breast cancer. Proc Am Soc Clin Oncol.
2005;23(16):85S. [Abstract 830].
73. Basso U, Fratino L, Brunello A, et al. Which benefit from adding Gemcitabine
to vinorelbine in elderly ( or = 70 years) women with metastatic breast
cancer? Early interruption of a phase II study. Ann Oncol. 2007;18(1):
58–63.
74. Lombardi A, Magri MD, Crivellari D, et al. Combination chemotherapy
with navelbine and continuous infusion of 5-Fluorouracil in metastatic,
chemotherapy refractory breast cancer. Ann Oncol. 2000;11(8):1041–3.
75. Berruti A, Sperone P, Bottini A, et al. Phase II study of vinorelbine with
protracted fluorouracil infusion as a second- or third-line approach for
advanced breast cancer patients previously treated with anthracyclines.
J Clin Oncol. 2000;18(19):3370–7.
76. Zambetti M, Mariani G, Demicheli R, et al. Five-day infusion fluorouracil
plus vinorelbine in women with breast cancer previously treated with
anthracyclines and paclitaxel. Breast Cancer Res Treat. 2000;62(2):135–9.
77. Zambelli A, Robustelli della Cuna FS, Ponchio L, et al. Four-day infusion
of fluorouracil plus vinorelbine as salvage treatment of heavily pretreated
metastatic breast cancer. Breast Cancer Res Treat. 2000;61(3):241–7.
78. Dieras V, Extra JM, Bellissant E, et al. Efficacy and tolerance of vinorelbine
and fluorouracil combination as first-line chemotherapy of advanced breast
cancer: results of a phase II study using a sequential group method. J Clin
Oncol. 1996;14(12):3097–104.
79. Pienkowski T, Jagiello-Gruszfeld A. Five-day infusion of fluorouracil and
vinorelbine for advanced breast cancer patients treated previously with
anthracyclines. Int J Clin Pharmacol Res. 2001;21(3–4):111–7.
80. Vassilomanolakis M, Koumakis G, Barbounis V, et al. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000;11(9):1155–60.
81. Chehal A, Taher A, Khalil M, Shamseddine A. Cisplatin plus vinorelbine (PVn) as a salvage regimen for refractory breast cancer. Breast.
2004;13(5):421–4.
82. Shamseddine AI, Taher A, Dabaja B, et al. Combination cisplatin-vinorelbine
for relapsed and chemotherapy-pretreated metastatic breast cancer. Am J
Clin Oncol. 1999;22(3):298–302.
83. Mustacchi A, Muggia M, Milani S, et al. A phase II study of cisplatin and vinorelbine in patients with metastatic breast cancer. Ann Oncol.
2002;13(11):1730–6.
84. Estevez LG, Batista N, Sánchez-Rovira P, et al. Phase II study with the
combination of Capecitabine (C) and vinorelbine (V) in metastatic breast
cancer (MBC) previously treated with anthracyclines and taxanes. J Clin
Oncol. 2004;22(14S):748
85. Ghosn M, Kattan J, Farhat F, et al. Phase II trial of Capecitabine and
vinorelbine as first-line chemotherapy for metastatic breast cancer patients.
Anticancer Res. 2006;26(3B):2451–6.
86. Nolè F, Crivellari D, Mattioli R, et al. Phase II study of an all-oral combination of vinorelbine with Capecitabine in patients with metastatic breast
cancer. Cancer Chemother Pharmacol. 2009;64(4):673–80.
87. Delcambre C, Veyret C, Levy C, et al. A phase I/II study of Capecitabine
combined with oral vinorelbine as first or second line therapy in locally
advanced or metastatic breast cancer. Breast Cancer Res Treat. 2005;94:S67.
(Abstract 1061).
88. Stuart N, Bishop JL, Johnson SRD, et al. Vinorelbine and Capecitabine
(VX) for advanced breast cancer—a phase II study showing good activity
and potential for further development. Proc Am Soc Clin Oncol. 2003;22.
[Abstract 183]
89. Garrone O, Principe E, Occelli M, et al. A phase II study of Epirubicin,
vinorelbine and cisplatin in advanced breast cancer. Anticancer Drugs.
2004;15(1):23–7.
90. Frasci A, D’Aiuto G, Comella P, et al. Cisplatin–Epirubicin–Paclitaxel weekly
administration in advanced breast cancer: a phase I study of the Southern
Italy Cooperative Oncology Group. Breast Cancer Res Treat. 1999;56(3):
239–52.
91. Nole F, Munzone E, Mandala M, et al. Vinorelbine, cisplatin and continuous
infusion of 5-Fluorouracil (ViFuP) in metastatic breast cancer patients:
a phase II study. Ann Oncol. 2001;12(1):95–100.
Clinical Medicine: Therapeutics 2009:1
Vinorelbine in ABC
92. Esteban E, de Sande G, Puertas J, et al. A phase II trial of cyclophosphamide,
Epirubicin and vinorelbine in the treatment of advanced breast cancer.
Breast Cancer Res Treat. 2000;62(2):127–33.
93. Bonneterre J, Roché H, Monnier A, et al. Docetaxel vs. 5-Fluorouracil plus
vinorelbine in metastatic breast cancer after anthracycline therapy failure.
Br J Cancer. 2002;87(11):1210–5.
94. Namer M, Soler-Michel P, Turpin F, et al. Results of a phase III prospective, randomised trial, comparing Mitoxantrone and vinorelbine (MV) in
combination with standard FAC/FEC in front-line therapy of metastatic
breast cancer. Eur J Cancer. 2001;37(9):1132–40.
95. Blajman C, Balbiani L, Block J, et al. A prospective, randomized Phase III
trial comparing combination chemotherapy with cyclophosphamide, Doxorubicin, and 5-Fluorouracil with vinorelbine plus Doxorubicin in the treatment of advanced breast carcinoma. Cancer. 1999;85(5):1091–7
96. Norris A, Pritchard KI, James K, et al. A phase III comparative study of
vinorelbine combined with Doxorubicin versus Doxorubicin alone in
disseminated metastatic/recurrent breast cancer: National Cancer Institute
of Canada Clinical Trials Group Study MA8. J Clin Oncol. 2000;18(12):
2385–94.
97. Ejlertsen A, Mouridsen HT, Langkjer ST, et al. Phase III study of intravenous vinorelbine in combination with Epirubicin versus Epirubicin alone
in patients with advanced breast cancer: a Scandinavian Breast Group Trial
(SBG9403). J Clin Oncol. 2004;22(12):2313–20.
98. Pajk B, Cufer T, Canney P, et al. Anti-tumor activity of Capecitabine and
vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II
trial. Breast. 2008;17(2):180–5.
99. Debled M, Madranges M, Mertens C, et al. Retrospective analysis of
chemotherapy choices and overall survival according to treatment in
96 patients 75 years old with metastatic breast cancer, Eur J Cancer.
2008;6:174. [Abst. 415].
100. Verma S, Wong NS, Trudeau M, et al. Survival differences observed in
metastatic breast cancer patients treated with Capecitabine when compared
with vinorelbine after pretreatment with anthracycline and taxanes. Am J
Clin Oncol. 2007;30:297–302.
101. Lee M, Wei W, Morandi N, Harris L. Capecitabine is associated with lower
chemotherapy-related expenditures than those associated with vinorelbine
in women with metastatic breast cancer. Cancer Res. 2009;69(Suppl):391s.
[Abstract 6107].
102. Sawada N, Fujimoto-Ouchi K, Ishikawa T, et al. Antitumour activity of
combination therapy with Capecitabine plus vinorelbine, and Capecitabine
plus Gemcitabine in human tumor xenograft models. Proc Am Assoc
Cancer Res. 2002;43:1088a. [Abstr 5388].
103. Elghazaly A, Tawfik H, Mahrous M, et al. Vinorelbine and Capecitabine
combination as first-line treatment in patients with metastatic breast cancer:
final results of a multicentric trial in Egypt. J Clin Oncol. 2008;26(15S):72s.
[Abstract 1125].
104. Ghosn M, Kattan J, Farhat F, et al. For the Cancer Research Group/
Collaborative Group (CRG/CG), Beirut–Lebanon. Sequential vinorelbineCapecitabine followed by Docetaxel in advanced breast cancer: longterm results of a pilot phase II trial. Cancer Chemother Pharmacol.
2008;62:11–8.
105. Köhler U, Luhn B, Kleine-TebbeA, et al. Capecitabine (C) and vinorelbine
(V) in elderly patients (pts) with metastatic breast cancer (MBC) as 1st line
treatment: a prospective multicentre phase II study of the NOGGO breast
cancer study group, Breast Cancer Res Treat. 2006;100(Suppl 1):S285.
[Abst 6089].
106. Hess A, Koberle D, Thurlimann B, et al. Swiss Group for Clinical Cancer
Research. Capecitabine and vinorelbine as first-line treatment in elderly
patients (or =65 years) with metastatic breast cancer. A phase II trial
(SAKK 25/99). Oncology. 2007;73:228–37.
107. Iodice GD, Aiuto G, Costanzo R, et al. Dose-escalated Capecitabine/
vinorelbine for elderly patients with metastatic breast cancer (MBC).
A SICOG phase II study. Ann Oncol. 2006;17(Suppl 9):p. ix73. [Abstract 155P].
108. Palumbo R, Bernardo A, Strada MR, et al. Activity and safety of vinorelbine
and Capecitabine as first-line treatment in patients with metastatic breast
cancer—a phase II trial, Eur J Cancer Suppl. 2008;6:177. [Abstract 425].
Clinical Medicine: Therapeutics 2009:1
109. Davis AJ, Brew S, Gebski VJ, et al. Multicenter phase II study of
combination chemotherapy with Capecitabine and intravenous vinorelbine
in patients with pretreated metastatic breast cancer. Asia–Pacific J Clin
Oncol. 2007;3:37–43.
110. Orphanos G, Alexopoulos A, Ioannidis G, et al. High efficacy and low
toxicity of the combination of vinorelbine and Capecitabine as second
line treatment in metastatic breast cancer previously treated with taxanes and/or anthracyclines. Proc Am Soc Clin Oncol. 2006;24(18S):
10719.
111. Estévez LG, Batista N, Sánchez-Rovira P, et al. A phase II study of
Capecitabine and vinorelbine in patients with metastatic breast cancer
pretreated with anthracyclines and taxanes. Clin Breast Cancer. 2008;8:
149–54.
112. Lorusso V, Forcignano R, Leo S, et al. Vinorelbine plus Capecitabine in
salvage therapy of breast cancer. Comparison of intravenous vs. oral administration of Vinorelbine. J Clin Oncol. 2008;26(15S):69s. [Abstract 1114].
113. Xu B, Wu Q, Zhou M, et al. Capecitabine plus vinorelbine as secondline therapy in Chinese patients with metastatic breast cancer (MBC).
Ann Oncol. 2006;17(Suppl 9):ix75. [Abstract 163P].
114. Ahn JH, Kim SB, Kim TW, et al. Capecitabine and vinorelbine in patients
with metastatic breast cancer previously treated with anthracycline and
taxanes. J Korean Med Sci. 2004;19:547–53.
115. Jassem J, Kosmidis P, Ramlau R, et al. Oral vinorelbine in combination
with cisplatin: a novel active regimen in advanced non-small-cell lung
cancer. Ann Oncol. 2003;14(11):1634–9.
116. Marty M, Fumoleau P, Adenis A, et al. Oral vinorelbine pharmacokinetics
and absolute bioavailability study in patients with solid tumors. Ann Oncol.
2001;12(11):1643–9.
117. Lush RM, McCune JS, Tetteh L, et al. The absolute bioavailability of oral
vinorelbine in patients with solid tumors. Cancer Chemother Pharmacol.
2005;56:578–84.
118. Depierre A, Freyer G, Jassem J, et al. Oral vinorelbine: feasibility and
safety profile. Ann Oncol. 2001;12(12):1677–81.
119. Freyer G, Delozier T, Lichinister M, et al. Phase II study of oral vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol. 2003;
21(1):35–40.
120. Baweja M, Suman VJ, Fitch TR, et al. Phase II trial of oral vinorelbine for
the treatment of metastatic breast cancer in patients 65 years of age an
NCCTG study. Ann Oncol. 2006;17:623–9.
121. Lotz A, Husseini F, Finck M, et al. French experience of patient management when receiving oral vinorelbine chemotherapy (NVBO) for metastatic breast cancer: Final results of a prospective observational survey on
practices. J Clin Oncol. 2009;(Suppl 27). [Abstr e12013].
122. Gil-Delgado M, Rocher M, Boostandoost E, Khayat D. First step of oral
vinorelbine and Capecitabine combination in advanced breast cancer
patients: Feasibility study. J Clin Oncol. 2008;26:1135(15S).
123. Tubiana-Mathieu N, Bougnoux P, Becquart D, et al. All-oral combination
of oral vinorelbine and Capecitabine as first-line chemotherapy in HER2negative metastatic breast cancer: an International Phase II Trial. Br J
Cancer. 2009;101(2):232–7.
124. Addeo R, Faiola V, Cennamo G, et al. A novel metronomic schedule of oral
vinorelbine for the treatment of metastatic breast cancer in elderly patients:
A phase II trial. J Clin Oncol. 2009;27:15s. [Abstr 1085].
125. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the
efficacy and safety of humanized anti-HER2 monoclonal antibody in
women who have HER2-overexpressing metastatic breast cancer that
has progressed after chemotherapy for metastatic disease. J Clin Oncol.
1999;17(9):2639–48.
126. Vogel CL, Cobleigh MA, Tripathy D, 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(3):719–26.
127. Pegram MD, Konecny GE, O’Callaghan C, et al. Rational combinations of
trastuzumab with chemotherapeutic drugs used in the treatment of breast
cancer. J Natl Cancer Inst. 2004;96:739–49.
128. Slamon DJ, Leyland-Jones B, Shak S, 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.
1725
Brunello et al
129. Kaufman PA, Schwartz G, Dragnev K, et al. Phase I trial of Herceptin
and Navelbine for patients with HER-2/neu (+) advanced breast cancer. In:
Poster 431 presented at the 25th San Antonio Breast Cancer Symposium
San Antonio TX U S A. 2002 December. 11–14.
130. Burstein HJ, Keshaviah A, Baron A, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast
cancer:the trastuzumab and vinorelbine or taxane study. Cancer. 2007;
110(5):965–72.
131. Jahanzeb M, Mortimer JE, Yunus F, et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer. Oncologist. 2002;7:410–7.
132. Bernardo G, Palumbo R, Bernardo A, et al. Final results of phase II study
of weekly trastuzumab and vinorelbine in chemonaive patients with
HER2-overexpressing metastatic breast cancer. Proc Am Soc Clin Oncol.
2004;23:59. [Abstr 731].
133. Burstein HJ, Harris LN, Marcom PK, 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 predictive factors, and cardiac surveillance algorithm. J Clin
Oncol. 2003;21:2889–95.
134. Chan A, Martin M, Untch M, et al. Vinorelbine plus trastuzumab combination
as first-line therapy for HER2-positive metastatic breast cancer patients:
an international phase II trial. Br J Cancer. 2006;95:788–93.
135. Bayo-Callero JL, Mayordomo JI, Sanchez-Rovira P, et al. A phase II study
of weekly vinorelbine and trastuzumab in patients with HER2-positive
metastatic breast cancer. Clin Breast Cancer. 2008;8(3):264–8.
136. Porta VG, Martin M, Gil M, et al. Evaluation of Vinorelbine (N) and
trastuzumab (H) as first-line therapy for patients (pts) with HER2-positive
metastatic breast cancer (HER2 + MBC): impact on clinical response
and cardiac function. ASCO annual meeting proceedings (post-meeting
edition). J Clin Oncol. 2004;22(14S):636.
137. Schilling G, Bruweleit M, Harbeck N, 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.
Invest New Drugs. 2009;27(2):166–72.
138. Franquesa RM, Centelles M, Villadiego K, et al. A multicenter study of
trastuzumab (H) and vinorelbine (N) as first and second line therapy for
patients (pts) with HER2-positive metastatic breast cancer (HER2 + MBC).
J Clin Oncol. 2005;23:94s. [Abstr 868].
139. Brunello A, Monfardini S, Crivellari D, et al. Multicenter analysis of activity and safety of trastuzumab plus chemotherapy in advanced breast cancer
in elderly women (70 years). J Clin Oncol. 2008;26 (Suppl). [Abstr 1096].
140. Papaldo P, Fabi A, Ferretti G, 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 Oncol. 2006;17:630–6.
141. Lal A, Alidina A. Interim analysis of a phase II study of biochemotherapy
in metastatic breast cancer (MBC). Eur J Cancer. 2005;3(Suppl):131.
[Abstr 470].
142. De Maio E, Pacilio C, Gravina A, et al. A single-centre phase 2 study of
vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer. Ann
Oncol. 2004;15(Suppl 3):37. [Abstr 139P].
143. Bartsch R, Wenzel C, Altorjai G, et al. Results from an observational trial
with oral vinorelbine and trastuzumab in advanced breast cancer. Breast
Cancer Res Treat. 2007;102(3):375–81.
144. Laessig D, Vehling-Kaiser U, Harich HD, et al. Oral and intravenous
vinorelbine plus trastuzumab for 1st-line treatment of HER2-overexpressing
metastatic breast cancer (MBC). A trial of the german AIO breast cancer
group. J Clin Oncol. 2008;26(May 20 Suppl). [Abstr 1061].
145. Estevez LG, Tusquets I, Munoz M, et al. Advanced breast cancer:
Chemotherapy phase III trials that change a standard. Anti Cancer Drugs.
2007;18:843–59
Publish with Libertas Academica and
every scientist working in your field can
read your article
“I would like to say that this is the most author-friendly
editing process I have experienced in over 150
publications. Thank you most sincerely.”
“The communication between your staff and me has
been terrific. Whenever progress is made with the
manuscript, I receive notice. Quite honestly, I’ve
never had such complete communication with a
journal.”
“LA is different, and hopefully represents a kind of
scientific publication machinery that removes the
hurdles from free flow of scientific thought.”
Your paper will be:
•
Available to your entire community
free of charge
•
Fairly and quickly peer reviewed
•
Yours! You retain copyright
http://www.la-press.com
1726
Clinical Medicine: Therapeutics 2009:1