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Guideline Summary
Guideline Title
The continued use of trastuzumab beyond disease progression in patients with metastatic breast cancer.
Bibliographic Source(s)
Madarnas Y, Haynes AE, Eisen A. The continued use of trastuzumab beyond disease progression in patients with metastatic breast cancer. Toronto (ON): Cancer Care Ontario (CCO); 2009 Aug 17. 26 p. (CED-CCO special advice report; no. 13).  [21 references]
Guideline Status

This is the current release of the guideline.

Please visit the Cancer Care Ontario Web site External Web Site Policy for details on any new evidence that has emerged and implications to the guidelines.

Scope

Disease/Condition(s)

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

Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Clinical Specialty
Oncology
Intended Users
Physicians
Guideline Objective(s)

To evaluate whether the continued use of trastuzumab (alone or in combination with other systemic therapies) after disease progression improves outcomes in women with metastatic breast cancer compared to best supportive care or systemic therapy without trastuzumab

Target Population

Adult women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer (MBC) whose disease has progressed following prior treatment with trastuzumab

Interventions and Practices Considered
  1. Trastuzumab in combination with capecitabine
  2. Trastuzumab with other systemic agents
Major Outcomes Considered
  • Overall survival
  • Progression-free survival
  • Objective response rate
  • Quality of life
  • Adverse events

Methodology

Methods Used to Collect/Select the 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 (Ovid) (1990 through June Week 3 [June 26] 2009), EMBASE (Ovid) (1990 through Week 25 [June 26] 2009), and the Cochrane Library (2009, Issue 2) databases were searched. The search strategies for MEDLINE and EMBASE are shown in Appendix 1 in the original guideline document. Search strategies in other databases were similar.

In addition, conference proceedings of the American Society of Clinical Oncology (ASCO) 2004 to 2009, the San Antonio Breast Cancer Symposium (SABCS) 2003 to 2008, the European Breast Cancer Conference (EBCC) 2004 to 2008, and the Congresses of the European Society for Medical Oncology (ESMO) and the European Cancer Organization (ECCO) 2003 to 2008 were searched for abstracts of relevant trials. The Canadian Medical Association Infobase (http://mdm.ca/cpgsnew/cpgs/index.asp External Web Site Policy), the National Guideline Clearinghouse (http://www.guideline.gov/ External Web Site Policy), and the National Institute for Health and Clinical Excellence (http://www.nice.org.uk/ External Web Site Policy) were also searched for existing evidence-based practice guidelines.

Relevant articles and abstracts were selected and reviewed by two reviewers, and the reference lists from these sources were searched for additional trials. Personal files were also searched.

Study Selection Criteria

Inclusion Criteria

Articles were selected for inclusion in this systematic review of the evidence if they were published full-report articles or published meeting abstracts of:

  1. Randomized trials that compared systemic therapy with trastuzumab to either best supportive care or systemic therapy without trastuzumab in adult women with metastatic breast cancer (MBC) who had progressive disease following previous treatment with trastuzumab.
  2. Single-arm phase II trials of trastuzumab, alone or in combination with other systemic therapies, in adult women with MBC who had progressive disease following previous treatment with trastuzumab.
  3. Systematic reviews, meta-analyses, or clinical practice guidelines of trastuzumab in adult women with MBC who had progressive disease following previous treatment with trastuzumab.
  4. Publications of single-arm trials, randomized trials, systematic reviews, or meta-analyses that have reported data on one or more of the following outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), quality of life (QOL), or adverse events.

Exclusion Criteria

Studies were excluded if they were:

  1. Single-arm trials reported in abstract form only.
  2. Letters, comments, books, notes, or editorial publications.
  3. Articles published in a language other than English, due to financial considerations for translation.
Number of Source Documents

Two randomized trials, five single-arm trials, and one systematic review were identified.

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

Data appropriate for pooling or meta-analysis were not expected but were investigated when possible. For planned analyses, the primary outcome of interest was progression-free survival (PFS), secondary outcomes of interest were response rate and overall survival (OS), and subset analyses were conducted by histology.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The recommendations reflect the opinions of the authors of this special advice report.

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
Peer Review
Description of Method of Guideline Validation

Not stated

Recommendations

Major Recommendations

The following recommendations reflect the opinions of the authors of this special advice report.

  1. For women with metastatic breast cancer (MBC) whose disease has progressed on trastuzumab, continued use of trastuzumab in combination with capecitabine confers a clinically meaningful gain in progression-free survival and is a valid treatment option.
  2. Until more data becomes available, the continued use of trastuzumab with other agents is not supported.
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The recommendations are supported by randomized trials, single-arm trials, and a systematic review.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits
  • One group of investigators randomized patients to either capecitabine plus trastuzumab or to capecitabine alone. The authors reported a significant difference in progression-free survival in favour of capecitabine plus trastuzumab (median 8.2 months versus [vs.] 5.6 months, respectively; hazard ratio [HR]=0.69; 95% confidence interval [CI], 0.48 to 0.97; p=0.0338).
  • Another group of investigators randomized patients to either lapatinib plus trastuzumab to lapatinib alone. The authors reported a significant difference in progression-free survival in favour of lapatinib plus trastuzumab (median 12.0 weeks vs. 8.4 weeks, respectively; HR=0.77; 95% CI 0, 0.6 to 1.0; p=0.029).
Potential Harms
  • One group of investigators reported that the rate of grade 1 or 2 diarrhea was 53% vs. 41% for patients receiving lapatinib plus trastuzumab compared to lapatinib alone, respectively. The authors did not report whether that difference was statistically significant. One patient in the lapatinib plus trastuzumab arm died due to cardiac toxicity. No further data on adverse events were reported.
  • Another group of investigators reported the rates of several grade 3 or 4 adverse events, which can be found in Table 5 in the original guideline document. The authors reported no statistically significant differences in grade 3 or 4 adverse events. Grade 1 to 4 anemia was significantly more common in the capecitabine plus trastuzumab arm compared to the capecitabine-alone arm (64.0% vs. 44.4%; p=0.0208). No other significant differences in any grade of adverse events were reported.
  • Each of the single-arm trials reported different grade 3 or 4 adverse events (see Table 8 in the original guideline document). The only adverse event that was reported in more than one trial was grade 3 or 4 neutropenia: 11.5% of 26 patients in one trial and 20.7% of 29 patients in another. Of note, one group of investigators reported that no patient experienced grade 3 or 4 neutropenia. Grade 1 or 2 adverse events were reported in all four trials and included, but were not limited to, rash, fatigue, mucositis, diarrhea, neutropenia, thrombocytopenia, anemia, nausea, and vomiting.

Qualifying Statements

Qualifying Statements
  • Two randomized controlled trials (RCTs) reported non-significant trends to improved overall survival (OS), ranging from 2.9 months for lapatinib in combination with trastuzumab to 5.1 months for capecitabine in combination with trastuzumab. However, the O'Shaughnessy study has yet to be published in full, and given the lack of toxicity reporting and one death ascribed to cardiac toxicity, the observation of a 3.6 week difference in progression-free survival (PFS) is of questionable clinical significance.
  • The published data only supports continued use of trastuzumab with either capecitabine or lapatinib and should only be used in this manner until such time as data regarding the continued use of trastuzumab with other agents is published.
  • While the published data supports the continued administration of trastuzumab in combination with lapatinib, the current Health Canada approved indication for lapatinib limits the applicability of this data in the Canadian context.
  • Dose and schedule: trastuzumab 6 mg/kg intravenously (IV) every 21 days can be continued in combination with capecitabine 2500 mg/m2 orally (PO) in divided doses daily x 14 days every 21 days. Trastuzumab 2 mg/kg IV weekly after a 4 mg/kg loading dose can be continued in combination with lapatinib 1000 mg PO daily continuously. However, the 21-day trastuzumab schedule of 6 mg/kg that is considered equivalent to the weekly schedule and is more commonly used in Ontario is an acceptable alternative to the weekly schedule.
  • Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report 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 guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its 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
Getting Better
Living with Illness
Staying Healthy
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Madarnas Y, Haynes AE, Eisen A. The continued use of trastuzumab beyond disease progression in patients with metastatic breast cancer. Toronto (ON): Cancer Care Ontario (CCO); 2009 Aug 17. 26 p. (CED-CCO special advice report; no. 13).  [21 references]
Adaptation

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

Date Released
2009 Aug 17
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

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 External Web Site Policy.

Financial Disclosures/Conflicts of Interest

The authors of this special advice report were asked to disclose potential conflicts of interest related to the topic of this special advice report and reported no conflicts of interest.

Guideline Status

This is the current release of the guideline.

Please visit the Cancer Care Ontario Web site External Web Site Policy 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 External Web Site Policy.

Availability of Companion Documents

The following is available:

  • 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 Institute on November 4, 2010.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions. Please refer to the Copyright and Disclaimer Statements External Web Site Policy posted at the Program in Evidence-based Care section of the Cancer Care Ontario Web site.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouseâ„¢ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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