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Evidence-based Series 1-4 EDUCATION AND INFORMATION 2011
Vinorelbine in Stage IV Breast Cancer
A Quality Initiative of the
Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO)
A review conducted in September 2011 put Evidence-based Series (EBS) 1-4 in
the Education and Information Section. This means that the recommendations will
no longer be maintained but may still be useful for academic or other information
purposes. The PEBC has a formal and standardize process to ensure the
currency of each document (PEBC Assessment & Review Protocol)
It is available on the CCO website
(http://www.cancercare.on.ca)
PEBC Breast Cancer Disease Site Group page at
https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs/
and consists of a Guideline Report Overview, Summary, and Full Report.
Release Date: September 6, 2012
For information about the PEBC and the most current version of all reports,
please visit the CCO website at http://www.cancercare.on.ca/
or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: [email protected]
Citation (Vancouver Style): Program in Evidence-based Care. Vinorelbine in stage IV breast cancer.
Toronto (ON): Cancer Care Ontario; 2012 Sep 06 [Education and Information 2011 Sep]. Program in
Evidence-based Care Evidence-based Series Guideline No.: 1-4 EDUCATION AND INFORMATION 2011.
EBS 1-4 EDUCATION AND INFORMATION 2011
Evidence-based Series 1-4 EDUCATION AND INFORMATION 2011
Vinorelbine in Stage IV Breast Cancer
Guideline Report History
GUIDELINE VERSION
SYSTEMATIC REVIEW
PUBLICATIONS
NOTES AND KEY CHANGES
Full Report
Web publication
Not applicable (NA)
N/A
Updated web publication
NA
Search Dates
Data
Original version
November 1998
1992 to 1996
Updated Version
January 2002
1996 to 2001
Document Assessment
July 2012
NA
Web publication
Guideline
ARCHIVED
EBS 1-4 EDUCATION AND INFORMATION 2011
Evidence-based Series 1-4 ARCHIVED 2011
Vinorelbine in Stage IV Breast Cancer
Guideline Review Summary
Review Date: September 2011
The 2002 guideline recommendations are
ARCHIVED
This means that the recommendations will no longer be
maintained but may still be useful for academic or other
information purposes.
OVERVIEW
Evidence-based Series History
This guidance document was originally released by the Program in Evidence-based
Care (PEBC), Cancer Care Ontario (CCO) as an evidence summary in 1998, and its first update
was released in 2002. In July 2012, the PEBC guideline update strategy was applied, and the
recommendations were archived. The Summary and Full Report in this version are the same as
in the January 2002 version.
Update Strategy
The PEBC update strategy includes an annual screening of our guidelines. If necessary,
an updated search of the literature is completed, with the review and interpretation of new
eligible evidence by the clinical experts from the authoring panel and consideration of the
guideline. The recommendations are then based on the new available evidence.
Impact on Guidelines and Its Recommendations
During the annual screening process, it was agreed that this document will no longer
be maintained by PEBC; therefore, no update search was conducted. The 2002 guideline and
its recommendations on Vinorelbine in Stage IV Breast Cancer have been ARCHIVED.
EBS 1-4 EDUCATION AND INFORMATION 2011
Document Assessment and Review Outcomes
1. ARCHIVED – An archived document is a document that will no longer be tracked or updated
but may still be useful for academic or other informational purposes. The document is
moved to a separate section of the Web site and each page is watermarked with the
phrase “ARCHIVED”.
2. ENDORSED – An endorsed document is a document that the DSG/GDG has reviewed for
currency and relevance and determined to be still useful as guidance for clinical decision
making.
A document may be endorsed because the DSG/GDG feels the current
recommendations and evidence are sufficient, or it may be endorsed after a literature
search uncovers no evidence that would alter the recommendations in any important way.
3. DEFERRAL – A Deferral means that the clinical reviewers feel that the document is still
useful and the decision has been made to postpone further action for a number of reasons.
The reasons for the deferral are in the Document Assessment and Review Tool in the
document.
4. UPDATE – An Update means that the DSG/GDG recognizes that there is new evidence that
makes changes to the existing recommendations in the guideline necessary but these
changes are more involved and significant than can be accomplished through the Document
Assessment and Review process. The DSG/GDG will rewrite the guideline at the earliest
opportunity to reflect this new evidence. Until that time, the document will still be
available as its existing recommendations are still of some use in clinical decision making.
EBS 1-4 EDUCATION AND INFORMATION 2011
Cancer Care Ontario Practice Guidelines Initiative
Sponsored by: Cancer Care Ontario
Ontario Ministry of Health and Long-term Care
Vinorelbine in Stage IV Breast Cancer
Evidence Summary #1-4
ORIGINAL EVIDENCE SUMMARY: November 11, 1998
UPDATE: January 2002
This summary integrates the original evidence summary with the most current information
(labelled NEW).
SUMMARY
Question
What is the evidence for vinorelbine as second-line chemotherapy in stage IV (metastatic)
breast cancer?
Target Population
Women with stage IV breast cancer who have failed first-line chemotherapy for metastatic
disease.
Methods
Entries to the MEDLINE (to December 2001) and Cochrane Library (Issue 4, 2001) databases
and abstracts published in the proceedings of the annual meeting of the American Society of
Clinical Oncology have been searched for evidence relevant to this practice guideline. The most
recent literature search was performed in January 2002.
Evidence was selected and reviewed by one member of the Cancer Care Ontario Practice
Guidelines Initiative’s (CCOPGI) Breast Cancer Disease Site Group (DSG) and methodologists.
This evidence summary has been reviewed and approved by the Breast Cancer DSG, which
comprises surgeons, medical oncologists, radiation oncologists, epidemiologists, a pathologist,
a medical sociologist and community representatives.
Final approval of the original evidence summary was obtained from the Practice Guidelines
Coordinating Committee. The CCOPGI has a formal standardized process to ensure the
currency of each guideline report. This consists of periodic review and evaluation of the
scientific literature, and where appropriate, integration of this literature with the original guideline
information.
Key Evidence
• One randomized controlled trial detected a significant difference in survival between
vinorelbine and melphalan (median survival, 35 weeks with vinorelbine versus 31 weeks
with melphalan; p=0.034). Better physical functioning was observed in vinorelbine-treated
patients than in melphalan-treated patients, with no differences in symptom status, role
function, and global quality of life.
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EBS 1-4 EDUCATION AND INFORMATION 2011
•
•
•
A randomized trial of vinorelbine plus doxorubicin versus doxorubicin alone detected no
significant difference in response rate, duration of response, survival or quality of life.
The pooled objective response rate from phase II trials of vinorelbine as second-line or
greater therapy was 24% (95% confidence interval, 20 to 28%); in anthracycline-resistant
disease, the pooled response rate was 19% (95% confidence interval, 14 to 24%). One
phase II trial showed a decline in physical and role functions, with a corresponding increase
in symptom distress during the first cycle of treatment.
The majority of adverse events observed were hematologic: neutropenia (96% of patients in
three studies), febrile neutropenia (9%) and anemia (87%). Other adverse events included
nausea (50%), vomiting (23%), diarrhea (20%), constipation (38%), and alopecia (12%).
Peripheral neuropathy was observed in 31% of patients, but it was usually grade 1 or 2 and
reversible. Approximately 20% of patients reported pain at the site of infusion.
Prepared by the Breast Cancer Disease Site Group
For further information about this practice guideline, please contact:
Dr. Wendy Shelley; Co-chair, Breast Cancer Disease Site Group; Kingston Regional Cancer
Centre, 25 King St W, Kingston ON, K7L 5P9; Telephone: 613-544-2631 x4502; Fax: 613-5468209; E-mail: [email protected]
or
Maureen Trudeau; Co-chair, Breast Cancer Disease Site Group; Toronto-Sunnybrook Regional
Cancer Centre, 2075 Bayview Ave, Toronto ON, M4N 3M5; Telephone 416-480-5145; FAX 416217-1338; E-mail: [email protected].
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EBS 1-4 EDUCATION AND INFORMATION 2011
PREAMBLE: About Our Evidence Summary Reports
The Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) is a project supported by
Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care, as part of the
Program in Evidence-based Care. The purpose of the Program is to improve outcomes for
cancer patients, to assist practitioners to apply the best available research evidence to clinical
decisions, and to promote responsible use of health care resources. The core activity of the
Program is the development of practice guidelines by Disease Site Groups of the CCOPGI
using the methodology of the Practice Guidelines Development Cycle.1
An evidence summary report is a systematic overview of the best evidence available on a
specific clinical question when there is insufficient high-quality evidence on which to base a
practice guideline. The report is intended as information for individuals and groups to use in
making decisions and policies where the evidence is uncertain. For example, the evidence
comes from uncontrolled studies, from studies with control groups that are not relevant to
current practice in Ontario, or from subgroup analyses, or the evidence consists solely of
preliminary results from ongoing trials. The Program in Evidence-based Care will monitor the
scientific literature and will develop a practice guideline on this topic when more evidence
becomes available.
This evidence summary report has been formally approved by the Practice Guidelines
Coordinating Committee, whose membership includes oncologists, other health providers,
community representatives, and Cancer Care Ontario executives. Formal approval of an
evidence summary by the Coordinating Committee does not necessarily mean that the evidence
summary has been adopted as a practice policy of CCO. The decision to adopt an evidence
summary as a practice policy rests with each regional cancer network that is expected to
consult with relevant stakeholders, including CCO.
Reference:
1
Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni A, et al. The practice
guidelines development cycle: a conceptual tool for practice guidelines development and
implementation. J Clin Oncol 1995;13(2):502-12.
For information about the PEBC and the most current version of all reports,
please visit the CCO website at http://www.cancercare.on.ca/
or contact the PEBC office at:
Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: [email protected]
Copyright
This evidence summary is copyrighted by Cancer Care Ontario; the evidence summary
and the illustrations herein may not be reproduced without the express written permission of
Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole
discretion, to change or revoke this authorization.
Disclaimer
Care has been taken in the preparation of the information contained in this document.
Nonetheless, any person seeking to apply or consult the evidence summary is expected to use
independent medical judgment in the context of individual clinical circumstances or seek out the
supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties
of any kind whatsoever regarding their content or use or application and disclaims any
responsibility for their application or use in any way.
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EBS 1-4 EDUCATION AND INFORMATION 2011
FULL REPORT
Original evidence summary information and new information that has emerged from
review and updating activities is labelled ORIGINAL and UPDATE, respectively.
I. QUESTION
What is the evidence for vinorelbine as second-line chemotherapy in stage IV (metastatic)
breast cancer?
II. CHOICE OF TOPIC AND RATIONALE
Vinorelbine is a new and relatively expensive drug that has been approved by the Health
Protection Branch for use in Canada for the treatment of patients with metastatic breast cancer
who have failed standard first-line chemotherapy for metastatic disease, as well as for patients
with metastatic breast cancer who have relapsed within six months of anthracycline-based
adjuvant therapy. A critical examination of the clinical evidence is required to help inform
decisions by clinicians and policy makers in Ontario.
In June 1998, the Provincial Breast Cancer Disease Site Group completed an evidencebased recommendation (EBR) report and sent this report to 71 clinicians in Ontario for feedback
on the evidence-based recommendation and whether it should serve as a practice guideline.
Clinicians responding to the survey echoed the DSG members’ concerns about formulating
practice guidelines in situations where there is no clinically relevant high quality evidence. As a
consequence, the Breast Cancer DSG reformatted the EBR report as an evidence summary,
i.e., as a systematic overview of the evidence without treatment recommendations.
III. METHODS
Evidence Summary Development
This evidence summary report was developed by the Cancer Care Ontario Practice Guidelines
Initiative (CCOPGI), using the methodology of the Practice Guidelines Development Cycle 1.
Evidence was selected and reviewed by one member of the CCOPGI’s Breast Cancer Disease
Site Group (DSG) and methodologists. The guideline is a convenient and up-to-date source of
the best available evidence on vinorelbine as second-line chemotherapy in stage IV breast
cancer, developed through systematic reviews, evidence synthesis and input from practitioners
in Ontario. It is intended to enable evidence-based practice. The Practice Guidelines Initiative is
editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Longterm Care.
Final approval of the original guideline report was obtained from the Practice Guidelines
Coordinating Committee. The CCOPGI has a formal standardized process to ensure the
currency of each guideline report. This consists of periodic review and evaluation of the
scientific literature, and where appropriate, integration of this literature with the original guideline
information.
Evidence Summary History
This evidence summary report was originally completed on November 11, 1998 and published
in Current Oncology 2000;7(1): 24-8. The evidence summary was reviewed monthly in 1999,
and quarterly beginning in 2000 with the most recent being January 2002. Original evidence
1
Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni A, et al. The practice
guidelines development cycle: a conceptual tool for practice guidelines development and
implementation. J Clin Oncol 1995;13(2):502-12.
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EBS 1-4 EDUCATION AND INFORMATION 2011
summary information and new information that has emerged from review and updating activities
is labelled ORIGINAL and UPDATE, respectively, in this report.
Literature Search Strategy
Original: November 1998
The MEDLINE and CANCERLIT databases were searched for the time period from January
1992 to February 1996 to find relevant practice guidelines, meta-analyses and clinical trials.
Search terms used were "breast neoplasms/ (as a MeSH term), and "vinorelbine" and
"Navelbine" (as text words). Articles identified by the searches, recently published reviews and
articles cited in these papers were retrieved and reviewed. The proceedings of meetings of the
American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were
also reviewed. Unpublished information was provided by Glaxo-Wellcome. The search was
updated in June and November 1998, at which time the Cochrane Library (1998, Issues 2 and
3) and the Physician Data Query database were also searched.
Update: January 2002
The literature search used for updating the evidence combined disease-specific text words and
subject headings (breast, mammary, cancer, carcinoma, neoplasm[s], advanced, metastatic,
stage IV), treatment-specific terms (vinorelbine, navelbine), and design-specific terms (metaanalysis, clinical trial[s], phase II, phase III, randomized controlled trials, multicenter studies).
The literature search has been updated using MEDLINE (through December 2001), the
Cochrane Library (Issue 4, 2001), and the proceedings of the annual meeting of the American
Society of Clinical Oncology (1999-2001).
Inclusion Criteria
Articles were selected for inclusion in this systematic review of the evidence if they met the
following criteria:
1. Included patients with stage IV breast cancer and evaluated vinorelbine as second-line
treatment.
2. Randomized controlled trials (RCTs) of vinorelbine, either alone or in combination with other
chemotherapeutic agents, were of primary interest but reports of prospective case series
(phase II studies) where vinorelbine was used as a single-agent were also retrieved.
Synthesizing the Evidence
Original: November 1998
In order to get overall precise estimates of response rates, results were pooled across studies.
Study results were classified according to the type of chemotherapy used prior to administering
vinorelbine. For each group of studies, the response rates were pooled by dividing the total
number of responses by the total number of patients in the group of studies; the 95%
confidence intervals (CI) were calculated for the pooled response rates. Results from all the
studies were pooled to produce an estimate of the overall response rate.
Update: January 2002
Trials described in the update sections below have not been included in the pooled estimate of
response rate calculated for the original evidence summary.
IV. RESULTS
Literature Search Results
Original: November 1998
At present, there is only one report of a randomized trial which evaluated vinorelbine, as a
single agent, in stage IV breast cancer (1). There are also two abstracts which report
randomized trials (2,3) of vinorelbine in combination with other chemotherapeutic agents. Eight
prospective case series (phase II studies) evaluated vinorelbine as second- to fifth-line
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EBS 1-4 EDUCATION AND INFORMATION 2011
chemotherapy (4-11). While response rates are given for all of these studies, data on survival,
functional status and quality of life are minimal at present.
Update: January 2002
A published report of randomized trial data available only in abstract form for the original
evidence summary (1u), five phase II studies (2u-4u,6u,7u) and a cost-utility analysis (5u) were
identified by update searches and reviewed by the Breast Cancer DSG.
Comparison of Vinorelbine, as a Single Agent, with Other Second-line Therapies
Original: November 1998
One randomized controlled trial (1) compared vinorelbine with melphalan in 179 patients who
failed to respond to anthracycline-containing chemotherapy. A survival benefit for vinorelbine
was found (p=0.034). The median survival time for patients treated with vinorelbine was 35
weeks compared with 31 weeks for those treated with melphalan; the one-year survival rate was
35.7% for the vinorelbine group compared with 21.7% for melphalan. Quality of life was
measured in this trial and results are presented on the next page of this report.
Update: January 2002
A phase II randomized controlled trial by Venturino et al (2u) compared vinorelbine (arm A)
versus 5-flourouracil (5-FU) plus leucovorin (arm B) versus mitoxantrone, 5-FU and leucovorin
(arm C). Ninety-nine eligible patients were randomized to one of the three treatment arms and
all but one patient were assessable for response and toxicity. All patients had previous
chemotherapy for metastatic disease, and approximately three-quarters had previous
anthracyclines as adjuvant treatment or for metastatic disease. The objective response rates
and survival times were equivalent in all three groups; objective response rate 24%, 30%, 21%,
and survival time 9.5, 9, and 9 months for patients in the vinorelbine, 5-FU+leucorvorin, or
mitoxantrone+5-FU+leucovorin arms respectively.
Randomized Trials of Combination Therapy with Vinorelbine
Original: November 1998
Numerous phase II studies of vinorelbine in combination with various chemotherapeutic agents
have been conducted and summarized by Hortobagyi (12). In general, response rates vary from
11% to 74% when vinorelbine is used in combination with 5-fluorouracil, doxorubicin, epirubicin,
mitoxantrone or ifosphamide. These response rates are higher than those seen with singleagent vinorelbine, and these promising results stimulated the development of two randomized
trials comparing vinorelbine combinations with standard therapy (2,3).
Blajman and colleagues compared vinorelbine plus doxorubicin with 5-fluorouracil plus
doxorubicin plus cyclophosphamide (FAC) (2). Preliminary results showed response rates of
76% for vinorelbine plus doxorubicin and 85% for FAC. Median durations of response were 12
weeks and 16 weeks respectively. Follow-up was too short for survival analysis.
The National Cancer Institute of Canada Clinical Trials Group recently completed a
randomized comparison of vinorelbine plus doxorubicin with doxorubicin alone (3). Response
rates were similar for both groups: 35% for the combination therapy and 30% for doxorubicin
alone. Median duration of response was also equivalent (6.9 months with
vinorelbine/doxorubicin versus 6.4 months with doxorubicin). Follow-up was too short for
survival analysis.
Update: January 2002
The published results of the randomized trial by the National Cancer Institute of Canada (NCIC)
Clinical Trials Group (1u) update the information obtained from an abstract for the original
evidence summary (6). Of 303 patients randomized to receive vinorelbine plus doxorubicin or
doxorubicin alone, 289 were assessable for response. No significant differences between
treatment groups were detected in response rate (38% versus 30%, p=0.2), duration of
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response (median, 7.2 months versus 6.8 months; p=0.6) or survival (median, 13.8 months
versus 14.4 months; p=0.4).
Phase II Studies
Original: November 1998
With the exceptions noted above (1-3), published studies of vinorelbine for breast cancer are
prospective case series (phase II studies). The patient populations studied have included
patients with metastatic breast cancer with no previous chemotherapy (13-17), as well as
patients who have failed first- to fifth-line chemotherapy (4-11). The major outcomes described
are response rate and median duration of response. Survival times are not generally given, and
data on the impact of therapy on quality of life and functional improvement are sparse (18).
Results from phase II studies of vinorelbine as second-line or greater therapy are presented
in Table 1 according to the type of chemotherapy used prior to administering vinorelbine. Seven
of these studies used weekly intravenous (I.V.) treatments. Doses ranged from 20 to 30
mg/m2/week and the most frequently used dose was 30 mg/m2/week. One study examined
escalating doses of vinorelbine given as a 96-hour infusion, with no clear benefit over the
weekly I.V. schedule (11). A study of vinorelbine given every two weeks to 14 women with
advanced breast cancer was not included because it was reported in Chinese and translation
was not feasible (19).
When vinorelbine was used alone as second-line or greater therapy, the pooled objective
response rate (complete responses + partial responses), from eight phase II studies (4-11) and
the vinorelbine group from the RCT of vinorelbine versus melphalan (1), was 24% (95% CI, 20
to 28%). There was no clear difference in response rate according to prior anthracycline
treatment or number of previous treatments for metastatic disease.
One additional phase II study was presented at the 1998 meeting of the American Society of
Clinical Oncology after the pooled analysis described above had been completed. Ibrahim et al
reported a 17% response rate in 44 women who received vinorelbine by 96-hour continuous
infusion as second-line or greater therapy for metastatic breast cancer (20).
Update: January 2002
Four recent phase II trials have used schedules other than the standard 21-day cycle
(3u,4u,6u,7u).
Udom et al (3u) reported on 20 patients who had received at least two prior chemotherapy
regimens. Nineteen of 20 patients had prior anthracycline exposure and a similar number had
prior taxane exposure. Vinorelbine was administered at 25 mg/m2 twice weekly for 6 months,
until disease progression or undue toxicity. Seven (35%) partial responses were observed. The
median response duration was 4 months and the median time to progression was 2.75 months.
Gasco (4u) et al administered one of two different schedules of vinorelbine to 30 patients
with metastatic breast cancer. Fourteen patients received a weekly bolus of 30 mg/m 2 and 16
patients received a continuous infusion schedule of 8 mg/m2 on day 1, and 8 mg/m2 continuous
infusion on days 1 to 4. Twenty patients had prior chemotherapy for metastatic disease, and 17
of these had prior anthracycline exposure. Two patients (7%) achieved a complete response
and 8 (27%) patients had a partial response.
Two phase II trials evaluated weekly vinorelbine at a dose of 25 mg/m2 as treatment for
metastatic breast cancer (6u,7u). Both trials enrolled 40 patients and assessed tumour
response in all 40. Zelek et al reported a response rate of 25% (no complete responses and 10
partial responses) (6u), in contrast to the 52.5% response rate detected by Nistico et al (5
complete responses and 16 partial responses) (7u). There were important differences in the
patients enrolled in the two trials. All participants in the trial by Zelek et al had received prior
anthracycline and taxane treatment; 65% were anthracycline refractory or resistant and 59%
were taxane refractory or resistant. All patients had received at least one course of
chemotherapy for metastatic disease and 70% were receiving vinorelbine as third-line therapy.
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Only 5% of participants in the trial by Nistico et al were anthracycline refractory or resistant (7u).
Sixty-three percent of patients were receiving vinorelbine as second-line therapy and 15% as
first-line.
Toxicity of Vinorelbine
Original: November 1998
Smith reported on adverse effects associated with vinorelbine in an overview of data from three
North American studies involving 222 women with metastatic breast cancer (20). The majority of
adverse events were hematologic. Neutropenia was the most common toxic effect, with 96% of
women having an absolute neutrophil count (ANC) less than 2 x 109/l, and 41% having an ANC
less than 0.5 x 109/l. Febrile neutropenia was observed in 9% of patients. Anemia (< 11 g/l)
developed in 87%, but severe anemia (<80 g/l) was seen in only 14%. Thrombocytopenia was
uncommon, with platelet counts of less than 100 x 109/l in 6% of patients. Nonhematologic
toxicity was modest. Mild asymptomatic elevation of liver enzymes occurred in 74% of patients,
but clinical symptoms of hepatic toxicity have not been reported. Nausea was reported by 50%
of patients but vomiting occurred in only 23% and did not usually require potent antiserotonin
antiemetics. Other gastrointestinal adverse effects included constipation (38%) and diarrhea
(20%). Approximately 20% of patients reported pain at the infusion site or local reactions
including phlebitis. Peripheral neuropathy occurred in 31% of patients but was virtually always
grade 1 or 2, and was reversible. Alopecia occurred in 12% of women. Dyspnea was reported in
9% within hours of administration and may represent a mild allergic reaction.
Update: January 2002
In the NCIC phase III randomized trial, grade 3 or 4 adverse events were reported for 100
patients in the doxorubicin plus vinorelbine group and 103 patients in the vinorelbine alone
group (1u). Venturino et al observed grade 3 or 4 adverse events in 11 patients on vinorelbine,
10 patients on 5-FU plus leucovorin, and 6 patients on mitoxantrone, 5-FU and leucovorin in
their phase II randomized trial (2u).
Additional toxicity data were available from four phase II trials. Udom et al reported no grade
4 adverse events with twice weekly vinorelbine (3u), but seven patients (35%) experienced
neutropenic effects, ranging from grade 1 to 3 in severity (3u). Gasco (4u) et al observed more
grade 3 or 4 adverse events in patients treated with the bolus IV schedule than those treated
with continuous infusion (17 episodes vs. 6 episodes) (4u). Grade 3 or 4 neutropenia was
observed in 23-25% of patients treated with weekly vinorelbine (6u,7u).
Quality of Life during Vinorelbine Treatment
Original: November 1998
Results from two studies which evaluated quality of life during vinorelbine treatment were
reported by Bertsch and Donaldson (18). In both studies, role functioning and physical
functioning were measured using the Medical Outcomes Study Short Form-20 and -26
questionnaires, symptom status was evaluated using the Symptom Distress Scale, and patients
reported global quality of life on a five-point scale.
Quality of life measurements from the only published randomized trial (1,18) demonstrated
that vinorelbine-treated patients had better physical functioning than those treated with
melphalan throughout most of the study (p=0.03 on an analysis of linear time trends). Other
dimensions including symptom distress, role functioning and global quality of life were similar for
vinorelbine and melphalan.
During cycle one of treatment in a phase II study, a decrease in physical functioning and
role functioning was observed, with a corresponding increase in symptom distress (18). Women
who received vinorelbine as first-line therapy had greater declines in these dimensions than
women receiving the drug as second-line therapy. The meaning of these observations is not
clear, given the lack of a control group for comparison.
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Update: January 2002
Quality of life data were provided by 191 participants in the NCIC randomized trial of vinorelbine
plus doxorubicin versus doxorubicin alone (1u). These patients had completed at least six
cycles of treatment and completed from two to five questionnaires. No significant differences
between the two treatment groups were noted.
V. INTERPRETIVE SUMMARY
Original: November 1998
A randomized trial of vinorelbine versus melphalan found vinorelbine to be superior to
melphalan with respect to survival rate and physical functioning. Preliminary results, which do
not include survival data, from two additional RCTs show similar response rates for vinorelbine
plus doxorubicin and FAC or doxorubicin alone.
Numerous phase II trials of vinorelbine as second-line or greater therapy for metastatic
breast cancer have demonstrated acceptable response rates (pooled response rate, 24%; 95%
CI, 20 to 28%).
Vinorelbine has an acceptable toxicity profile and limited quality of life data are favourable.
Update: January 2002
The published results of the randomized trial by the NCIC Clinical Trials Group showed no
benefit in combining vinorelbine with doxorubicin as part of first-line chemotherapy for
metastatic disease.
As a single agent in pretreated populations, the randomized phase II trial by Venturino
showed similar rates of objective response, overall survival, and toxicity in patients treated with
vinorelbine versus those treated with two types of combination chemotherapy. The results of
this trial are in keeping with other trials in this patient population, with 24% of patients in the
vinorelbine arm achieving an objective response. Results from the recent non-randomized
phase II trials are also consistent with those from previously reported trials.
Overall, for patients considering second- or greater-line chemotherapy for metastatic
disease, vinorelbine remains an acceptable treatment option with a reasonable toxicity profile.
VI. ONGOING TRIALS
Original: November 1998
The Breast Cancer Disease Site Group (DSG) is aware of no ongoing randomized trials of
vinorelbine as second-line or greater chemotherapy for stage IV breast cancer. Randomized
trials that compare vinorelbine with standard regimens for metastatic breast cancer, such as
CAF (cyclophosphamide, doxorubicin, 5-fluorouracil), CEF (cyclophosphamide, epirubicin,
fluorouracil), CMF, mitomycin-c/vinblastine, 5-fluorouracil/folinic acid, or the taxanes are
essential to determine the role of vinorelbine in the treatment of metastatic breast cancer.
Update: January 2002
The information above remains current.
VII. OPINIONS OF THE PROVINCIAL BREAST CANCER DISEASE SITE GROUP
Original: November 1998
The Breast Cancer DSG has previously considered the value of using response rate as a
primary outcome measure for stage IV breast cancer. The group concluded that there is
evidence to suggest that objective response is a surrogate for improvement in quality of life and
symptomatology (21,22). Since the major objective of treatment of stage IV breast cancer is to
maintain quality of life and performance status, it was agreed that response rates could be
considered as surrogate outcomes for these more important functional outcomes. Members of
the DSG felt that the phase II studies indicate that vinorelbine does produce response rates
which may be in the same range as paclitaxel, and these response rates are likely to control
6
EBS 1-4 EDUCATION AND INFORMATION 2011
breast cancer and improve quality of life. Vinorelbine has a reasonable toxicity profile, with
modest nausea and little alopecia.
The Breast Cancer DSG's advice on the administration of vinorelbine is discussed below.
Update: January 2002
The information above remains current.
VIII. DOSE AND SCHEDULE OF ADMINISTRATION OF VINORELBINE
Original: November 1998
Although a variety of schedules of administration have been studied, currently vinorelbine is
most commonly given in 21-day cycles. Vinorelbine 25 to 30 mg/m2 I.V. is generally given on
days 1 and 8 of each cycle. The same dose may be given on day 15 if blood counts permit.
Approximately 20% of patients in clinical trials reported pain at the infusion site or local
reactions including phlebitis, in keeping with the mild vesicant property of vinorelbine. This
problem may be overcome by a shorter infusion time, but central venous access is suggested
for patient comfort and ease of administration.
Update: January 2002
The information above remains current.
IX. IMPLICATIONS FOR POLICY
Update: April 2001
A Canadian cost-utility analysis was conducted at the Princess Margaret Hospital in Toronto,
Ontario (5u). Eighty-eight patients with anthracycline resistant metastatic breast cancer were
identified and evaluated for total resource consumption using the drugs paclitaxel, docetaxel or
vinorelbine. Resource consumption was defined as any costs relating to chemotherapy,
supportive care, laboratory testing, adverse effects management, and health provider fees.
While there was no reported difference in overall survival between the comparison drugs and in
terms of cost, vinorelbine was the least costly alternative ($3,259 per patient followed by
paclitaxel $6,039, and docetaxel $10,090), it should be noted that there are no published
studies directly comparing the three drugs, and any comparisons must be interpreted with
caution.
X. JOURNAL REFERENCE
Sawka C, and the Breast Cancer Disease Site Group. Use of vinorelbine in stage IV breast
cancer: An evidence summary. Current Oncology 2000;7(1): 24-8.
XI. ACKNOWLEDGMENTS
The Breast Cancer Disease Site Group would like to thank Dr. C. Sawka for taking the lead in
drafting, revising and updating this evidence summary. For a full list of members of the Cancer
Care Ontario Breast Cancer Disease Site Group please visit the website of the Program in
Evidence-based Care at http://www.cancercare.on.ca/copgi.
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EBS 1-4 EDUCATION AND INFORMATION 2011
REFERENCES
Original: November 1998
1. Jones S, Winer E, Vogel C, et al. Randomized comparison of vinorelbine and melphalan in
anthracycline-refractory advanced breast cancer. J Clin Oncol 1995;13:2567-74.
2. Blajman C, Balbiani L, Block J, et al. Navelbine plus adriamycin vs FAC in advanced breast
cancer [abstract]. Proc Am Soc Clin Oncol 1993;12:92.
3. Norris B, Pritchard K, James K, et al. A. phase III comparative study of vinorelbine combined
with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: a National
Cancer Institute of Canada study [abstract]. Proc Am Soc Clin Oncol 1996;15:98.
4. Degardin M, Bonneterre J, Hecquet B, et al. Vinorelbine (Navelbine) as a salvage treatment
for advanced breast cancer. Ann Oncol 1994;5:423-6.
5. Barni S, Ardizzola A, Bernardo G, et al. Vinorelbine as single agent in pretreated patients
with advanced breast cancer. Tumori 1994; 80:280-2.
6. Marty M, Leandri S, Extra JM, Espie M, Besenval M. A phase II study of vinorelbine in
patients with advanced breast cancer [abstract]. Proc Am Assoc Cancer Res 1989;30:256.
7. Weber BL, Vogel C, Jones S, Harvey H, et al. Intravenous vinorelbine as first-line and
second-line therapy in advanced breast cancer. J Clin Oncol 1995;13:2722-32.
8. Gasparini G, Caffo O, Barni S, et al. Vinorelbine is an active antiproliferative agent in
pretreated advanced breast cancer patients: a phase II study. J Clin Oncol 1994;12:2094101.
9. Tresca P, Fumoleau P, Roche H, et al. Vinorelbine, a new active drug in breast carcinoma:
results of an ARTAC phase II trial [abstract]. Breast Cancer Res Treat 1990;16:161.
10. Canobbio L, Boccardo F, Pastorino G, et al. Phase-II study of Navelbine in advanced breast
cancer. Semin Oncol 1989;16(Suppl. 4):33-6.
11. Toussaint C, Izzo J, Spielmann M, et al. Phase I/II trial of continuous infusion vinorelbine for
advanced breast cancer. J Clin Oncol 1994;12:2102-12.
12. Hortobagyi GN. Future directions for vinorelbine (Navelbine). Semin Oncol 1995; 22(Suppl
5):80-7.
13. Romero A, Rabinovich MG, Vallejo CT, et al. Vinorelbine as first-line chemotherapy for
metastatic breast carcinoma. J Clin Oncol 1994;12:336-41.
14. 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;11:1245-52.
15. Bruno S, Lira-Puerto V, Texeira L, et al. Phase II trial with vinorelbine (Navelbine) in the
treatment of advanced breast cancer [abstract]. Ann Oncol 1992;3(Suppl 1):268A.
16. 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;5:854-7.
17. Twelves CJ, Dobbs NA, Curnow A, et al. A phase II, multicenter, UK study of vinorelbine in
advanced breast cancer. Br J Cancer 1994;70:990-3.
18. Bertsch LA, Donaldson G. Quality of life analyses from vinorelbine (Navelbine) clinical trials
of women with metastatic breast cancer. Semin Oncol 1995;22(Suppl. 5):45-54.
19. Jiang A, Song S, Xu J. Navelbine as a single agent to treat advanced breast cancer. Chung
Hua Chung Liu Tsa Chih 1996;18:208-10.
20. Ibrahim NK, Willey J, Raham Z, Valero V, Hortobagyi GN. Phase II study of vinorelbine by
96hour continuous infusion for patients with metastatic breast cancer [abstract]. Proc Am
Soc Clin Oncol 1998;17:A436.
21. Smith GA. Current status of vinorelbine for breast cancer. Oncology 1995; 9:767-79.
22. Denefrio JM, East DR, Troner MB, Vogel CL. Phase II study of mitomycin C and vinblastine
in women with advanced breast cancer refractory to standard cytotoxic therapy. Cancer
Treat Rep 1978;62:2113-5.
23. Arbuck SG. Paclitaxel: what schedule? What dose? [editorial]. J Clin Oncol 1994;12:233-6.
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EBS 1-4 EDUCATION AND INFORMATION 2011
Update: January 2002
This section includes all references from the review and updating activities.
1u. Norris B, Pritchard KI, James K, et al. 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;18:2385-94.
2u. Venturino A, Comandini D, Simoni C, et al. Is salvage chemotherapy for metastatic breast
cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus
5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus
leucovorin. Breast Cancer Res Treat 2000;60:195-200.
3u. Udom DI, Vigushin DM, Linardou H, Graham H, Palmieri C, Coombes RC. Two weekly
vinorelbine: administration in patients who have received at least two prior chemotherapy
regimes for advanced breast cancer. Eur J Cancer. 2000;36:177-82.
4u. Gasco M, Gardin G, Repetto L, Campora E, Rosso R. Vinorelbine as palliative therapy in
advanced breast cancer. Anticancer Res 1997;17:1431-3.
5u. Leung PP, Tannock IF, Oza AM, Puodziunas A, Dranitsaris G. Cost-utility analysis of
chemotherapy using paclitaxel, docetaxel, or vinorelbine for patients with anthracyclineresistant breast cancer. J Clin Oncol 1999;17:3082-90.
6u. 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;92:2267-72.
7u. Nistico C, Garufi C, Milella M, et al. Weekly schedule of vinorelbine in pretreated breast
cancer patients. Breast Cancer Res Treat 2000;59:223-9.
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EBS 1-4 EDUCATION AND INFORMATION 2011
Table 1. Tumour response with single-agent vinorelbine for metastatic breast cancer.
Reference/
year
Treatment
Dose
N
N
CR
(%)
N
PR
(%)
N
OR
(%)
MRD
a. Prior anthracycline/mitoxantrone for metastases
Jones
1995 (1)
2nd-3rd line
30 mg/m
2
95*
4
(5)
9 (11)
13
(16)
32 wk.
Degardin
1994 (4)
2nd-4th line
30 mg/m
2
100
1
(1)
15 (15)
16
(16)
5 mo.
Barni
1994 (5)
2nd-4th line
20 mg/m
2
30
1
(3)
10 (33)
11
(37)
5 mo.
Marty
1989 (6)
2nd-4th line
30 mg/m
2
13
0
(0)
5 (38)
5
(38)
range:
3,10+mo.
238
6
(3)
39 (16)
45
(19)
Pooled data for group a studies
(95% confidence interval on response rate)
(1.5, 4.5)
(11.7, 21.1)
(13.9, 23.9)
12
(25)
15
(32)
34 wk.
b. No prior anthracyclines for metastases
Weber
1995 (7)
2nd line
30 mg/m
2
47
3
(6)
c. Prior chemotherapy for metastases - variable use of anthracyclines
Gasparini
1994 (8)
2nd-5th line
20 mg/m
2
70
3
(5)
21
(31)
24
(36)
29 wk.
Tresca
1990 (9)
2nd line
30 mg/m
2
38
2
(5)
7
(18)
9
(24)
14 wk.
Canobbio
1989 (10)
2nd line
30 mg/m
2
5
NR
1
(20)
NR
Toussaint
1994 (11)
2nd line
96 hour
continuous
I.V. infusion
30
0
12
(40)
6 mo.
Pooled data for group c studies
(0)
12
(40)
st
nd
(1 & 2
line
combined)
143
5
(95% confidence interval on response rate)
Data pooled across all studies
NR
(4)
(0.5, 6.7)
436
14
(95% confidence interval on response rate)
(3)
(1.5, 4.9)
40
(29)
46
(32)
(21.4, 36.6)
(24.5, 39.9)
91
106 (24)
(21)
(17.2, 25.0)
(20.3, 28.3)
Note: N=number of patients, CR=complete response, PR=partial response, OR=objective
response (complete response + partial response), MRD=median response duration,
NR=not reported
* Results are given for vinorelbine treatment arm in a randomized trial of vinorelbine
versus melphalan
10