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Guideline Summary
Guideline Title
The use of bevacizumab in metastatic breast cancer.
Bibliographic Source(s)
Dent R, Haynes AE, Enright K, Hamm C, Trudeau M, Eisen A. The use of bevacizumab in metastatic breast cancer. Toronto (ON): Cancer Care Ontario (CCO); 2009 Apr 17. 24 p. (CED-CCO special advice report; no. 12).  [24 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)

Locally-advanced (stage IIIb) or metastatic (stage IV) breast cancer

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

To evaluate whether bevacizumab (alone or in combination with other systemic therapies) improves outcomes in women with locally-advanced or metastatic breast cancer compared with the same therapy without bevacizumab

Target Population

Adult women with locally-advanced (stage IIIb) or metastatic (stage IV) breast cancer

Interventions and Practices Considered
  1. Bevacizumab with weekly paclitaxel chemotherapy
  2. Bevacizumab with docetaxel chemotherapy
  3. Bevacizumab with capecitabine chemotherapy
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) (2001 through February Week 3 [February 26] 2009), EMBASE (Ovid) (2001 through Week 08 [February 26] 2009), and the Cochrane Library (2009, Issue 1) 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) 2001 to 2008 and the San Antonio Breast Cancer Symposium (SABCS) 2001 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 bevacizumab to the same therapy without bevacizumab in adult women with locally advanced or metastatic breast cancer.
  2. Randomized trials including adult women with locally advanced or metastatic breast cancer evaluating bevacizumab alone or in combination with other systemic therapies.
  3. Systematic reviews, meta-analyses, or clinical practice guidelines of bevacizumab in adult women with locally advanced or metastatic breast cancer.
  4. Publications of randomized trials, systematic reviews, or meta-analyses must have reported comparative data on one or more of the following outcomes: overall survival, progression-free survival, objective response rate, quality of life, or adverse events.

Exclusion Criteria

Studies were excluded if they were:

  1. Letters, comments, books, notes, or editorial publication types.
  2. Articles published in a language other than English, due to financial considerations for translation.
Number of Source Documents

Two full publications met eligibility criteria and were included. Eight abstracts met the eligibility criteria and were included. In total, three unique trials 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
Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

An aggregate data meta-analysis was performed by pooling results of published studies using Review Manager 5.0 statistical software, available through the Cochrane Collaboration. Outcomes considered for pooling included overall survival, progression-free survival, and adverse events. A random effects model was used for all pooling.

As hazard ratios (HR), rather than the number of events at a certain time point, are the preferred statistic for pooling time-to-event outcomes, those were extracted directly from the most recently reported trial results. The variances of the HR estimates were calculated from the reported confidence intervals (CI), using the methods described by Parmar et al.*

Statistical heterogeneity was calculated using the X2 test for heterogeneity and the I2 percentage. A probability level for the X2 statistic less than or equal to 10% (p≤0.10) indicates significant statistical heterogeneity. An I2 value of 25%, 50%, or 75% was considered low, moderate, or high heterogeneity, respectively. The measures of treatment effect were expressed as HRs for overall survival and progression-free survival (PFS), with 95% CI. An HR >1.0 indicates that patients receiving bevacizumab had worse PFS or overall survival (OS); conversely, an HR <1.0 suggests that patients receiving the control experienced a higher probability of an event.

An a priori decision was made to split the trials of first-line therapy and second-line or greater therapy into different subgroups in the meta-analysis as bevacizumab may have a greater effect when given earlier in the disease course. In addition, the trials of first-line therapy both gave patients bevacizumab in combination with a taxane, whereas the second-line trial gave bevacizumab in combination with capecitabine.

*Parmar MKB, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815-34.

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

The current evidence for bevacizumab in metastatic breast cancer consists of three randomized controlled trials (RCTs). Two trials investigated the use of bevacizumab as part of first-line therapy with taxane-based regimens while the remaining trial investigated its use as part of second-line or later therapy in combination with capecitabine. None of the RCTs reported a significant difference in overall survival (OS); however, data are still being accumulated for OS in the AVADO first-line trial. There was a significant improvement in progression-free survival (PFS) in patients receiving bevacizumab and weekly paclitaxel, but the study was an open label trial, and the assessment of outcome was not blinded. There was, however, a retrospective independent review of blinded radiological and clinical data prior to Food and Drug Administration (FDA) approval confirming the results. After controlling for an imbalance at baseline in presence of measurable disease and visceral metastatic sites between the control and bevacizumab groups, the results remained significant. The improvement in PFS with the combination of bevacizumab and docetaxel in the AVADO trial was much less impressive. These studies would likely be strengthened by the ability to identify patients most likely to benefit from vascular endothelial growth factor (VEGF)-directed therapies, analogous to human epidermal growth factor receptor 2 (HER2) directed therapy with trastuzumab.

A meta-analysis of PFS produced conflicting results. There was no significant difference in PFS when the data from the AVADO 7.5 mg/kg arm compared to control were used (hazard ratio [HR]=0.77; 95% confidence interval [CI], 0.57 to 1.02). When the 15 mg/kg comparison was used instead, there was a significant difference in PFS (HR=0.74; 95% CI, 0.56 to 0.99). The two first-line taxane-based RCTs, through three comparisons of bevacizumab to control, independently and consistently demonstrated a significant improvement in PFS (Table 4 in the original guideline document), although the clinical significance of the improvement in the AVADO trial is minimal.

The second-line or greater RCT of bevacizumab in combination with capecitabine compared to capecitabine alone demonstrated no significant difference in PFS (HR=0.98; 95% CI, 0.77 to 1.25). These results may reflect the late-disease stage and poor prognostic factors of the patient population in the study, such as the inclusion of 23.4% of women with HER2-positive breast cancer. Patients in this trial had also received more chemotherapy than those in the RCT of paclitaxel and bevacizumab that targeted first-line treatment of metastatic breast cancer. In comparison, more than 80% of patients in capecitabine trial had received prior treatment for metastatic breast cancer, and 40% had received two or more prior regimens. As a result, patients in that trial likely had more chemotherapeutic resistance. It has also been suggested that as breast cancers progress the proportion and type of angiogenic mediators change.

Commonly observed adverse events in the RCTs of bevacizumab included grade 3 or 4 bleeding, thrombosis, hypertension, neutropenia, and proteinuria. Hypertension seen in clinical trials has been manageable with oral anti-hypertensive medications. Reported and ongoing phase III trials have excluded patients with cerebral metastases, proteinuria, or bleeding diathesis; thus, those conditions should be considered contraindications to the use of bevacizumab.

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.

  • For women with metastatic or locally advanced breast cancer receiving taxane-based chemotherapy as first-line therapy, the addition of bevacizumab could be offered to improve progression-free survival.
  • The addition of bevacizumab to chemotherapy is not recommended for patients with metastatic breast cancer receiving second-line therapy or greater.
Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The recommendations are supported by two full publications and eight abstracts detailing three unique randomized controlled trials (RCTs).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Bevacizumab with Weekly Paclitaxel Chemotherapy

One group of investigators randomized patients to receive weekly paclitaxel and 10 mg/kg of bevacizumab every two weeks or to weekly paclitaxel alone. Patients receiving weekly paclitaxel with bevacizumab did not have a statistically significant improvement in overall survival (26.7 versus [vs.] 25.2 months; hazard ratio [HR]=0.88, p=0.16) compared to weekly paclitaxel alone. There was a statistically significant increase in median progression-free survival (11.8 vs. 5.9 months; HR=0.60, p<0.001) and overall response rate (36.9% vs. 21.2%; p<0.001) in the cohort receiving bevacizumab with paclitaxel vs. paclitaxel alone.

Bevacizumab with Docetaxel Chemotherapy

A phase III randomized controlled trial (RCT) by another group of investigators randomized patients to one of three arms of docetaxel combined with either bevacizumab 15 mg/kg or 7.5 mg/kg, or placebo given every three weeks. The median overall survival has not yet been reached in any arm. Patients receiving docetaxel in combination with bevacizumab 15 mg/kg and 7.5 mg/kg had a small but statistically significant increase in median progression-free survival compared to docetaxel alone (8.8 vs. 8.0 months; HR=0.72, p=0.0099) and (8.7 vs. 8.0 months; HR=0.79, p=0.0318). There was a significant increase in overall response rate in patients receiving bevacizumab 15 mg/kg (63.1% vs. 44.4%, p=0.0001) and 7.5 mg/kg (55.2% vs. 44.4%, p=0.0295) compared to docetaxel alone.

Meta-Analysis

A meta-analysis of reported hazard ratios for progression-free survival from the two RCTs with first-line taxane-based therapy indicated a significant benefit in progression-free survival for the addition of bevacizumab to taxane-based chemotherapy compared to taxane-based therapy alone (HR=0.64; 95% confidence interval, 0.54 to 0.77, p<0.00001).

Potential Harms

Bevacizumab with Weekly Paclitaxel Chemotherapy

One group of investigators randomized patients to receive weekly paclitaxel and 10 mg/kg of bevacizumab every two weeks or to weekly paclitaxel alone. The predominant grade 3/4 toxicities observed in the combination arm vs. standard arm included hypertension (14.8% vs. 0%, p<0.001), proteinuria (3.6% vs. 0%, p<0.001), headache (2.2% vs. 0.0%, p=0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, p=0.02).

Bevacizumab with Docetaxel Chemotherapy

A phase III randomized controlled trial (RCT) by another group of investigators randomized patients to one of three arms of docetaxel combined with either bevacizumab 15 mg/kg or 7.5 mg/kg, or placebo given every three weeks. Grade 3/4 toxicities seen in earlier studies were observed less frequently than in previous studies. For example, there did not appear to be a significant increase in the rate of grade 3/4 hypertension in patients receiving bevacizumab 15 mg/kg (3.2% vs. 1.3%, p=not reported) and 7.5 mg/kg (0.4% vs. 1.3%, p=not reported). Further details of toxicity are expected in the final publication of the study.

Contraindications

Contraindications

Reported and ongoing phase III trials have excluded patients with cerebral metastases, proteinuria, or bleeding diathesis; thus, those conditions should be considered contraindications to the use of bevacizumab.

Qualifying Statements

Qualifying Statements
  • Bevacizumab should not be administered to patients with cerebral metastases, uncontrolled hypertension, severe proteinuria, advanced atherosclerotic disease, bleeding diatheses, or with non-healing wounds, recent surgery, or trauma (i.e., within the previous 28 days), as those patients were excluded from enrollment in clinical trials using bevacizumab.
  • The addition of bevacizumab to paclitaxel chemotherapy is associated with significant but manageable toxicity, specifically hypertension, proteinuria, neuropathy, fatigue, and infection. In the most recent randomized study of bevacizumab and docetaxel chemotherapy, the toxicities were much less frequent than in the study of bevacizumab and paclitaxel.
  • 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
IOM Domain
Effectiveness
Safety

Identifying Information and Availability

Bibliographic Source(s)
Dent R, Haynes AE, Enright K, Hamm C, Trudeau M, Eisen A. The use of bevacizumab in metastatic breast cancer. Toronto (ON): Cancer Care Ontario (CCO); 2009 Apr 17. 24 p. (CED-CCO special advice report; no. 12).  [24 references]
Adaptation

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

Date Released
2009 Apr 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 disclosed potential conflicts of interest relating to the topic of this special advice report. One author (RD) received honoraria from the manufacturer of bevacizumab for conducting presentations and as an advisory board participant. One author has received research support from the manufacturer of bevacizumab (MT). The remaining authors (AEH, CH, AE) 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 5, 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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