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## Complete Summary

#### GUIDELINE TITLE

The role of trastuzumab (Herceptin®) in the treatment of women with
HER2/neu-overexpressing metastatic breast cancer.

#### BIBLIOGRAPHIC SOURCE(S)

Crump M, Trudeau M, Sinclair S, O\'Malley F, Breast Cancer Disease Site
Group. The role of trastuzumab (Herceptin®) in the treatment of women
with HER2/neu-overexpressing metastatic breast cancer. Toronto (ON):
Cancer Care Ontario (CCO); 2005 Nov 8. 28 p. (Practice guideline report;
no. 1-15). \[55 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

The Evidence-based Series report, initially the full original Guideline,
over time will expand to contain new information emerging from their
reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc1-15f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

On August 31, 2005, Genentech and the U.S. Food and Drug Administration
(FDA) notified healthcare professionals of updated cardiotoxicity
information related to the use of Herceptin (trastuzumab), obtained from
the National Surgical Adjuvant Breast and Bowel Project (NSABP) study
(B-31), a randomized, Phase III trial that was conducted in 2043 women
with operable, HER2 overexpressing breast cancer (IHC 3+ or FISH+). This
study demonstrated a significant increase in cardiotoxicity in patients
who were randomized to the Herceptin-containing arm as compared to
patients who received chemotherapy alone. See the [FDA Web
site](http://www.fda.gov/medwatch/safety/2005/safety05.htm#Herceptin)
for more information.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Human epidermal growth factor receptor 2 (HER2)/neu-overexpressing
metastatic breast cancer

#### GUIDELINE CATEGORY

Assessment of Therapeutic Effectiveness\
Treatment

#### CLINICAL SPECIALTY

Oncology

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

In women with human epidermal growth factor receptor 2
(HER2)/neu-overexpressing metastatic breast cancer:

-   To evaluate if trastuzumab in combination with chemotherapy can
    improve clinically meaningful outcomes (overall response rates,
    time-to-disease progression, overall survival, toxicity, or quality
    of life), compared with chemotherapy alone.

-   To evaluate if single-agent trastuzumab therapy can improve
    clinically meaningful outcomes compared with placebo or observation.

-   To evaluate the best way to identify women who will benefit from
    trastuzumab therapy

-   To evaluate the adverse events associated with trastuzumab therapy

-   To evaluate the optimal dose, schedule, and duration for trastuzumab
    therapy

#### TARGET POPULATION

Women with human epidermal growth factor receptor 2
(HER2)/neu-overexpressing metastatic breast cancer

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Trastuzumab alone

2.  Trastuzumab in combination with chemotherapy

3.  Monitor for adverse events

#### MAJOR OUTCOMES CONSIDERED

-   Overall response rates

-   Time-to-disease progression

-   Overall survival

-   Toxicity

-   Quality of life

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

**Literature Search Strategy**

MEDLINE was searched to August 2004 using disease-specific medical
subject heading terms (\"breast neoplasms\" and \"neoplasm metastasis\")
and an agent-specific MeSH term (\"antibodies, monoclonal\") or an
oncogene-specific MeSH term (\"receptor, erbB-2\"). The Excerpta Medica
database (EMBASE) was also searched up to August 2004 using a
disease-specific Excerpta Medica Tree (EMTREE) subject-heading term
(\"breast cancer\") and keywords (\"advanced\" or \"metastatic\" or
\"metastases\") as well as an agent-specific EMTREE subject heading term
(\"trastuzumab\") or an oncogene-specific EMTREE subject heading term
(\"oncogene c erb\"). The Cochrane Library, conference proceedings from
the American Society of Clinical Oncology, the European Society for
Medical Oncology, and the San Antonio Breast Cancer Symposium, article
bibliographies, and personal files were also searched up to August 2004
for relevant evidence.

**Inclusion Criteria**

Articles were selected for inclusion in this systematic review of the
evidence if they met the following criteria:

-   Trastuzumab, in combination or alone, was evaluated using a
    randomized controlled trial, meta-analysis, evidence-based clinical
    practice guideline, or non-randomized trial (for the non-randomized
    trials, only those with 25 or more patients evaluable for efficacy
    outcomes were included).

-   Reported outcomes included overall response rates, time to
    progression (TTP), overall survival, toxicity, or quality of life.

-   Clinical trial results were reported in either full papers or
    abstracts. Although data presented in meeting abstracts may not be
    as reliable and complete as that from papers published in
    peer-reviewed journals, abstracts can be a source of important
    evidence from randomized trials and add to the evidence available
    from fully published studies. Those data often appear first in
    meeting abstracts and may not be published for several years.

**Exclusion Criteria**

Papers published in languages other than English were not considered.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus (Committee)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

The data included in this review were not pooled because most of the
evidence was immature and clinically heterogeneous.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

**[Disease Site Group Consensus]{.underline}**

**Question #1: Compared with Chemotherapy Alone, Does Trastuzumab in
Combination with Chemotherapy Improve Clinically Meaningful Outcomes?**

Two randomized trials (one phase III, one phase II) detected improved
outcomes when trastuzumab was administered in combination with
chemotherapy compared to chemotherapy alone. Specifically, Slamon et al
detected improved overall response and time to progression (TTP) with
first-line weekly trastuzumab and six cycles of three-weekly
anthracycline-cyclophosphamide (doxorubicin at 60mg/m^2^ or epirubicin
at 75mg/m^2^, cyclophosphamide at 600mg/m^2^) in anthracycline-naïve
patients or paclitaxel (175mg/m^2^) in anthracycline-exposed patients.
Although survival was statistically significantly better in the
experimental arm as a whole, the difference in the subgroups (paclitaxel
and anthracycline-cyclophosphamide) was not statistically significant.
Extra et al detected improved overall response, TTP, and overall
survival with the addition of weekly trastuzumab to docetaxel 100mg/m^2^
given every three weeks. Based on that randomized evidence, the Breast
Cancer Disease Site Group (DSG) members felt it reasonable to recommend
first-line trastuzumab in combination with either six cycles of three
weekly paclitaxel (175mg/m^2^) or six cycles of three-weekly docetaxel
(100mg/m^2^). In combination with trastuzumab, there was no data to
suggest that one taxane is superior to the other in the first-line
setting.

Among the 13 non-randomized trastuzumab and taxane combination trials,
trastuzumab was always administered weekly in all but two. Schedule,
dose, and duration of paclitaxel or docetaxel treatment varied greatly.
Only two trials excluded women with prior therapy for metastatic
disease. Many of the women in the 11 trials that permitted previous
therapy for metastatic disease had received anthracycline or taxane
regimens. Overall response rates in women receiving either taxane ranged
from 49% to 69% where that outcome was reported. TTP ranged from 8.5
months to 12.4 months. Based on non-randomized evidence, the members
agreed that weekly trastuzumab in combination with a taxane could be
offered in the second-line or greater setting for women who have
received chemotherapy previously for metastatic breast cancer. In
combination with trastuzumab, there was no data to suggest that one
taxane is superior to the other in the second-line or greater setting.
Due to the lack of consistent evidence for one regimen, the members
agreed that the dose, schedule, and duration of taxane should be
individualized according to patient preference, local and institutional
standard patterns of practice, and best clinical judgement.

Several trials have evaluated the efficacy of trastuzumab in combination
with weekly vinorelbine at does of 25mg/m^2^ or 30mg/m^2^ until disease
progression or unacceptable toxicity. Overall response rates for
vinorelbine plus trastuzumab ranged from 52% to 86%, and TTP ranged from
four months to 17 months. Based on this non-randomized evidence, the
Breast Cancer DSG members felt it reasonable to offer trastuzumab in
combination with vinorelbine, particularly for those women whose disease
has progressed after previous therapy with anthracyclines and/or
taxanes, either in the adjuvant or metastatic setting.

The Breast Cancer DSG members agreed that the evidence for trastuzumab
in combination with gemcitabine, platinum salts, or liposomal pegylated
doxorubicin is insufficient to recommend their use outside clinical
trials at this time.

**Question #2: Compared with Placebo or Observation, Does Single-Agent
Trastuzumab Therapy Improve Clinically Meaningful Outcomes?**

Among five non-randomized single-agent trastuzumab trials and one
single-agent randomized trial of two trastuzumab doses, rates of overall
response in the two first-line trials ranged from 19% to 28% and 12% to
26% in the four second- or greater-line trials. TTP was 3.5 months or
3.8 months depending on trastuzumab dose in one first-line trial. TTP in
three second- or greater-line trials ranged from three to four months.
Based on this evidence, the Breast Cancer DSG agreed that trastuzumab is
effective as a single-agent for women with untreated metastatic breast
cancer. Therefore, the use of single-agent trastuzumab, which is
relatively non-toxic, could be an appropriate choice prior to initiating
any type of chemotherapy, for those women who would like to avoid the
side effects of chemotherapy (nausea and vomiting, alopecia and
myelosuppression) for as long as possible. As there were no randomized
trials identified comparing single-agent trastuzumab to chemotherapy,
there is no way to judge the effect on overall survival.

The Breast Cancer DSG also agreed that the evidence suggests that
trastuzumab has a unique mechanism of action, producing responses in
women whose cancer has progressed following treatment with
anthracyclines or taxanes, the most active chemotherapy agents in
metastatic breast cancer. Therefore, the members offered the opinion
that trastuzumab could be an appropriate second- or greater-line
single-agent therapy for women who wish to avoid the side effects of
further chemotherapy.

**Question #3: What is The Best Way to Identify Women Who Will Benefit
from Trastuzumab Therapy?**

In general, among trials where subgroup analysis of the level of human
epidermal growth factor receptor 2 (HER2)/neu overexpression was
available, the most benefit was seen with an immunohistochemical (IHC)
score of 3+ or fluorescence in situ hybridization (FISH) positivity. In
the experience of the Breast Cancer DSG members, tumour samples scoring
2+ (weak membrane staining) by IHC testing should undergo FISH analysis
and receive trastuzumab therapy if the FISH test is positive. Therefore,
the Breast Cancer DSG members felt it reasonable to include a qualifying
statement that trastuzumab combination therapy is appropriate for women
whose tumours show IHC 3+ staining (i.e., moderate to strong membrane
staining in at least 10% of tumour cells) or show HER2/neu gene
amplification by FISH analysis (defined as HER2/CEP ratio ≥ 2).

**Question #4: Adverse Events Associated with Trastuzumab**

The risk of cardiotoxicity from trastuzumab in combination with
anthracyclines led the Breast Cancer DSG members to conclude that this
combination could not be recommended. Furthermore, women with
significant pre-existing cardiac dysfunction should not receive
trastuzumab therapy. Women receiving trastuzumab should undergo a
thorough baseline cardiac assessment and continued monitoring for signs
and symptoms of congestive heart failure during treatment.

In addition to cardiac events, hypersensitivity reactions, infusion
reactions, exacerbation of chemotherapy-induced neutropenia, and
pulmonary events leading to death have been infrequently or rarely
reported with trastuzumab. While these events were not addressed in this
systematic review, the Breast Cancer DSG believed that women should be
monitored for hypersensitivity, infusion reactions, and neutropenia and
treated accordingly.

**Question #5: Trastuzumab Dose, Duration, and Schedule**

While the two randomized trials that showed a benefit with combination
therapy administered trastuzumab weekly, four non-randomized trials
administered a loading dose of 8mg/kg followed by a three-weekly 6mg/kg
maintenance dose. Pharmacokinetic and safety data suggest that the
increased dose and reduced frequency of trastuzumab administration are
feasible. The members of the Breast Cancer DSG agreed that until
randomized controlled data are available to confirm the efficacy of
three-weekly trastuzumab, weekly therapy should be considered standard.
The members felt that it might be reasonable to switch to three-weekly
maintenance trastuzumab (6mg/kg) at a later time in women who are
finding weekly treatments difficult. In the members\' experience, the
decision to switch from weekly to three-weekly therapy should be based
on concurrent chemotherapy scheduling and patient preference.

The two randomized trials that showed a benefit with combination therapy
administered a loading dose of 4mg/kg followed by 2mg/kg weekly doses.
There is little evidence to suggest that higher doses offer any added
benefit. Therefore the DSG members agreed that a loading dose of 4mg/kg
followed by weekly doses of 2mg/kg should be recommended.

There is little data available regarding trastuzumab therapy duration.
There are no prospective data to suggest that continuing trastuzumab
therapy beyond progression offers any benefit; thus, the Breast Cancer
DSG members recommend trastuzumab therapy only until disease
progression.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Practitioner feedback was obtained through a mailed survey of 102
practitioners in Ontario (76 medical oncologists and 26 hematologists).
The survey consisted of items evaluating the methods, results, and
interpretive summary used to inform the draft recommendations and
whether the draft recommendations should be approved as a practice
guideline. Written comments were invited. The practitioner feedback
survey was mailed out on October 14, 2004. Follow-up reminders were sent
at two weeks (post card) and four weeks (complete package mailed again).
The Breast Cancer Disease Site Group (DSG) reviewed the results of the
survey.

The final Practice Guideline report was reviewed and approved by one
member of the Program in Evidence-based Care (PEBC) Report Approval
Panel (RAP) with expertise in clinical and methodology issues.

The practice guideline report reflects the integration of the draft
recommendations with feedback obtained from the external review process.
The report has been approved by the Breast Cancer DSG.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**Question #1 \-- Compared with Chemotherapy Alone, Does Trastuzumab in
Combination with Chemotherapy Improve Clinically Meaningful Outcomes?**

-   Trastuzumab in combination with either six cycles of three-weekly
    paclitaxel (175mg/m^2^) or six cycles of three-weekly docetaxel
    (100mg/m^2^) is recommended as a first-line therapy for women with
    human epidermal growth factor receptor 2 (HER2)/neu-overexpressing
    metastatic breast cancer.

-   Due to concerns regarding cardiotoxicity, trastuzumab is not
    recommended in combination with doxorubicin.

-   Due to the lack of randomized trial data, no definitive
    recommendation regarding the use of trastuzumab with other
    combinations outside of clinical trials can be made at this time.

**Question #2 \-- Compared with Placebo or Observation, Does
Single-Agent Trastuzumab Therapy Improve Clinically Meaningful
Outcomes?**

-   Due to the lack of randomized trial data, no definitive
    recommendations regarding the use of single-agent trastuzumab
    therapy can be made at this time.

**Question #3 \-- What Is the Best Way to Identify Women Who Will
Benefit from Trastuzumab Therapy?**

-   Trastuzumab combination therapy is most likely to be effective in
    women with the highest level of HER2/neu protein overexpression, as
    indicated by an immunohistochemistry score of 3+ (moderate/strong
    membrane staining in at least 10% of tumour cells) or by HER2/neu
    gene amplification (defined as HER2/CEP17 [\>]{.underline}2 by
    fluorescence in situ hybridization).

**Question #4 \-- What Are the Adverse Events Associated with
Trastuzumab Therapy?**

-   Women should be monitored for signs and symptoms of congestive heart
    failure during treatment with trastuzumab.

**Question #5 \-- What Are the Optimal Dose, Schedule, and Duration for
Trastuzumab Therapy?**

-   Regardless of combination, trastuzumab should be initiated at 4mg/kg
    and continued at 2mg/kg weekly until disease progression or
    unacceptable toxicity.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are supported by randomized controlled trials and
non-randomized trials.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Two (one phase III \[N=469\], one phase II \[N=188\]) of three
    randomized trials in the first-line setting detected improved
    progression-free and overall survival when trastuzumab was
    administered in combination with chemotherapy versus chemotherapy
    alone. In the first trial, overall response (41% versus 17%;
    p\<0.001) and median time-to-disease progression (6.9 months versus
    3.0 months; p\<0.001) were significantly improved when trastuzumab
    was combined with paclitaxel in anthracycline-exposed patients.
    Median overall survival (22.1 months vs. 18.4 months, p=0.17) was
    not improved. In the second trial, overall response (61% versus 36%;
    p=0.001), time-to-disease progression (10.6 months versus 6.1
    months; p=0.0001), and overall survival (27.7 months versus 18.3
    months; p=0.0002) were improved when weekly trastuzumab was combined
    with docetaxel. An interim analysis of the third trial found no
    difference between the paclitaxel combined with trastuzumab versus
    paclitaxel but did find significant improvement when the analysis
    was limited to patients with human epidermal growth factor receptor
    2 (HER2)/neu immunohistochemical (IHC) 3+ disease. Of note, the two
    positive trials used every-three-week taxane therapy, while the
    negative trial used every-week taxane therapy.

-   Thirteen non-randomized phase II trials, 11 of which included women
    with previous chemotherapy for metastatic disease, also evaluated
    trastuzumab in combination with a taxane. Overall response rates
    (ORR) ranged from 49% to 69%, and time-to-disease progression ranged
    from 8.5 months to 12.4 months. The range of overall response rates
    in the two trials which included only patients receiving first line
    therapy was 51% to 69%.

-   Seven non-randomized trials, three of which included women with
    prior chemotherapy for metastatic disease, evaluated the efficacy of
    trastuzumab in combination with vinorelbine. Overall response rates
    ranged from 52% to 86%, and time-to-disease progression ranged from
    four months to 17 months. The range of overall response rate in the
    five trials which included only patients receiving first line
    therapy was 61% to 86%.

-   Among five non-randomized single-agent trastuzumab trials and one
    single-agent randomized trial of two trastuzumab doses, rates of
    overall response in the two first-line trials ranged from 19% to 28%
    and 12% to 26% in the four second- or greater-line trials.
    Time-to-disease progression was 3.5 months or 3.8 months for
    standard loading and weekly dose compared to double the loading and
    weekly dose of trastuzumab dose in one first-line trial.
    Time-to-disease progression in three second- or greater-line trials
    ranged from three to four months.

-   In the phase III randomized trial, human epidermal growth factor
    receptor 2/neu over-expression, documented by fluorescence in situ
    hybridization, was associated with a survival benefit in women
    treated with trastuzumab and chemotherapy (odds ratio, 0.71; 95% CI,
    0.54 to 0.92; p=0.009), while there was no survival benefit seen in
    women with fluorescence in situ hybridization (FISH)-negative
    tumours (odds ratio, 1.11; 95% CI, 0.70 to 1.77; p-value not
    significant).

-   Among several non-randomized combination and single-agent
    trastuzumab trials, immunohistochemical (IHC) 3+ or fluorescence in
    situ hybridization-positive assay results tended to be associated
    with improved overall response and time-to-disease progression
    compared with IHC 2+ results.

#### POTENTIAL HARMS

-   In one randomized trial, symptomatic or asymptomatic cardiac
    dysfunction was observed in 27% of patients receiving anthracycline,
    cyclophosphamide, and trastuzumab compared with 8% in those
    receiving anthracycline and cyclophosphamide alone. The incidence of
    symptomatic congestive heart failure was 2% in women receiving
    trastuzumab and paclitaxel versus 1% in those receiving paclitaxel
    alone.

-   In a second randomized trial, symptomatic heart failure in two
    patients receiving trastuzumab and docetaxel occurred compared with
    none in those receiving docetaxel alone.

-   The most common reported adverse reactions associated with
    trastuzumab use are mild and include fever, diarrhea, chills,
    increased cough, headache, rash, and insomnia. Trastuzumab can
    result in the development of ventricular dysfunction and congestive
    heart failure, especially when administered with doxorubicin or
    epirubicin.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

**Question #1 - Compared with Chemotherapy Alone, Does Trastuzumab in
Combination with Chemotherapy Improve Clinically Meaningful Outcomes?**

-   In combination with trastuzumab, there is no data to suggest that
    one taxane is superior to the other in any metastatic setting.

-   No randomized data evaluating the role of trastuzumab in combination
    with paclitaxel or docetaxel in the second-line or greater setting
    were identified; however, evidence from nonrandomized phase II
    trials suggests that, for women with human epidermal growth factor
    receptor 2 (HER2)/neu-overexpressing metastatic breast cancer who
    have received non-taxane-containing chemotherapy previously for
    metastatic breast cancer, trastuzumab in combination with paclitaxel
    or docetaxel (as above) may be an appropriate treatment.

-   No randomized data evaluating the role of trastuzumab in combination
    with vinorelbine in the treatment of metastatic breast cancer were
    identified; however, evidence from nonrandomized phase II trials
    suggests that, for women with HER2/neu-overexpressing metastatic
    breast cancer whose disease has progressed with anthracycline or
    taxane therapy (either in the adjuvant or metastatic setting),
    trastuzumab in combination with vinorelbine (25mg/m^2^ or 30mg/m^2^
    weekly until disease progression or unacceptable toxicity) may be an
    appropriate treatment.

-   Decisions about the dose, schedule, and duration for second-line or
    greater paclitaxel and docetaxel treatment in combination with
    trastuzumab should be individualized based on patient preference,
    local and institutional standard patterns of practice, and best
    clinical judgement.

**Question #2 \-- Compared with Placebo or Observation, Does
Single-Agent Trastuzumab Therapy Improve Clinically Meaningful
Outcomes?**

-   No randomized data evaluating the role of single-agent first-line
    trastuzumab were identified; however, evidence from phase II trials
    suggests that for women with HER2/neu-overexpressing metastatic
    breast cancer who wish to postpone the side effects of chemotherapy
    for as along as possible, trastuzumab may be a reasonable treatment
    prior to initiating any type of chemotherapy.

-   No randomized data evaluating the role of single-agent second-line
    or greater trastuzumab were identified; however, evidence from phase
    II trials suggests that, for women with HER2/neu-overexpressing
    metastatic breast cancer who wish to avoid the side effects of
    further chemotherapy, trastuzumab is a reasonable second-line or
    greater single-agent therapy.

-   There are no data supporting the addition of chemotherapy to
    trastuzumab if the use of the trastuzumab alone results in disease
    progression.

**Question #4 \-- What Are the Adverse Events Associated with
Trastuzumab Therapy?**

-   Although hypersensitivity and infusion reactions were not directly
    addressed by this systematic review, it is the opinion of the Breast
    Cancer Disease Site Group that patients receiving trastuzumab should
    also be monitored for hypersensitivity and infusion reactions, and
    that, when used in combination with chemotherapy, patients receiving
    trastuzumab should be monitored for neutropenia.

-   Trastuzumab should be administered with extreme caution in women
    with impaired cardiac function; such patients should be monitored
    frequently for symptoms and signs of congestive heart failure.

**Question #5 \-- What Are the Optimal Dose, Schedule, and Duration for
Trastuzumab Therapy?**

-   Trastuzumab given 6mg/kg every three weeks has been tested alone and
    combined with chemotherapy in non-randomized trials and appears to
    provide similar benefit to weekly trastuzumab. Therefore, it is the
    opinion of the Breast Cancer Disease Site Group that for women who
    prefer three-weekly treatment, a switch to three-weekly maintenance
    trastuzumab (6mg/kg) may be appropriate after a reasonable period of
    weekly therapy.

**Disclaimer**

-   Care has been taken in the preparation of the information contained
    in this document. Nonetheless, any person seeking to apply or
    consult the practice guideline 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.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Crump M, Trudeau M, Sinclair S, O\'Malley F, Breast Cancer Disease Site
Group. The role of trastuzumab (Herceptin®) in the treatment of women
with HER2/neu-overexpressing metastatic breast cancer. Toronto (ON):
Cancer Care Ontario (CCO); 2005 Nov 8. 28 p. (Practice guideline report;
no. 1-15). \[55 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2005 Nov 8

#### GUIDELINE DEVELOPER(S)

Program in Evidence-based Care - State/Local Government Agency
\[Non-U.S.\]

#### GUIDELINE DEVELOPER COMMENT

The Program in Evidence-based Care (PEBC), is a Province of Ontario
initiative sponsored by Cancer Care Ontario and the Ontario Ministry of
Health and Long-Term Care.

#### SOURCE(S) OF FUNDING

Cancer Care Ontario\
Ontario Ministry of Health and Long-Term Care

#### GUIDELINE COMMITTEE

Provincial Breast Cancer Disease Site Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

For a current list of past and present members, please see the [Cancer
Care Ontario Web
site](http://www.cancercare.on.ca/english/toolbox/qualityguidelines/diseasesite/breast-ebs/breastdsg/).

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

The members of the Breast Cancer Disease Site Group (DSG) disclosed
potential conflicts of interest relating to the topic of this practice
guideline. Two of the four lead authors reported related research
involvement and research funding. One author (MC) reported receiving
grant or research funding from Roche Canada, and one (MT) reported the
receipt of honoraria from that same company.

#### GUIDELINE STATUS

This is the current release of the guideline.

The Evidence-based Series report, initially the full original Guideline,
over time will expand to contain new information emerging from their
reviewing and updating activities.

Please visit the [Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc1-15f.pdf) for details on any
new evidence that has emerged and implications to the guidelines.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[Cancer Care Ontario Web
site](http://www.cancercare.on.ca/pdf/pebc1-15f.pdf).

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   The role of trastuzumab (Herceptin®) in the treatment of women with
    HER2/neu-overexpressing metastatic breast cancer. Summary. Toronto
    (ON): Cancer Care Ontario (CCO), 2005 Nov 8. Various p. (Practice
    guideline; no. 1-15 (Version 2.2004)). Electronic copies: Available
    in Portable Document Format (PDF) from the [Cancer Care Ontario Web
    site](http://www.cancercare.on.ca/pdf/pebc1-15s.pdf).

-   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.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on January 25, 2006. The information
was verified by the guideline developer on February 23, 2006.

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posted at the Program in Evidence-Based Care section of the Cancer Care
Ontario Web site.

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Date Modified: 11/3/2008