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Meta-Analysis
. 2014 Jun 12;2014(6):CD006242.
doi: 10.1002/14651858.CD006242.pub2.

Trastuzumab-containing regimens for metastatic breast cancer

Sara Balduzzi  1 , Stefania Mantarro, Valentina Guarneri, Ludovica Tagliabue, Vanna Pistotti, Lorenzo Moja, Roberto D'Amico
Affiliations
Meta-Analysis

Trastuzumab-containing regimens for metastatic breast cancer

Sara Balduzzi et al. Cochrane Database Syst Rev. .

Abstract

Background: Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system.

Objectives: To assess the evidence on the efficacy and safety of therapy with trastuzumab (overall) and in relation to the type of co-administered regimen and the line of treatment, i.e. first-line or beyond progression, in women with HER2-positive metastatic breast cancer.

Search methods: We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL (2013, Issue 1), MEDLINE, EMBASE, BIOSIS, the WHO International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (up to 17 January 2013).

Selection criteria: RCTs comparing the efficacy and safety of trastuzumab alone or in combination with chemotherapy, hormonal therapy or targeted agents in women with HER2-positive metastatic breast cancer.

Data collection and analysis: We collected data from published trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included type of regimen (taxane-containing, anthracycline-containing, aromatase inhibitor-containing or other) and treatment line (first-line, beyond progression).

Main results: The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths.

Authors' conclusions: Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab.Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.

PubMed Disclaimer

Conflict of interest statement

SB: nothing to declare.

SM: nothing to declare.

VG: she acted as speaker for GlaxoSmithkline, and as consultant for Novartis and AstraZeneca. VG institution received a grant from Roche to support a trial in which she is Principal Investigator.

LT: nothing to declare.

VP: nothing to declare.

LM: nothing to declare.

RD: nothing to declare.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Efficacy of trastuzumab, outcome: 1.1 Overall survival ‐ all studies.
4
4
Forest plot of comparison: 1 Efficacy of trastuzumab, outcome: 1.4 Overall survival ‐ stratified by treatment line.
5
5
Forest plot of comparison: 1 Efficacy of trastuzumab, outcome: 1.8 Progression‐free survival ‐ stratified by treatment line.
6
6
Forest plot of comparison: 2 Cardiac toxicity of trastuzumab, outcome: 2.1 Congestive heart failure ‐ all studies.
1.1
1.1. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 1: Overall survival ‐ all studies
1.2
1.2. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 2: Overall survival ‐ excluding Blackwell
1.3
1.3. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 3: Overall survival ‐ stratified by type of regimen
1.4
1.4. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 4: Overall survival ‐ stratified by treatment line
1.5
1.5. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 5: Progression‐free survival ‐ all studies
1.6
1.6. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 6: Progression‐free survival ‐ excluding Blackwell
1.7
1.7. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 7: Progression‐free survival ‐ stratified by type of regimen
1.8
1.8. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 8: Progression‐free survival ‐ stratified by treatment line
1.9
1.9. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 9: Overall response rate ‐ all studies
1.10
1.10. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 10: Overall response rate ‐ stratified by type of regimen
1.11
1.11. Analysis
Comparison 1: Efficacy of trastuzumab, Outcome 11: Overall response rate ‐ stratified by treatment line
2.1
2.1. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 1: Congestive heart failure ‐ all studies
2.2
2.2. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 2: Congestive heart failure ‐ stratified by type of regimen
2.3
2.3. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 3: Congestive heart failure ‐ stratified by treatment line
2.4
2.4. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 4: Left ventricular ejection fraction (LVEF) decline ‐ all studies
2.5
2.5. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 5: LVEF decline ‐ stratified by type of regimen
2.6
2.6. Analysis
Comparison 2: Cardiac toxicity of trastuzumab, Outcome 6: LVEF decline ‐ stratified by treatment line
3.1
3.1. Analysis
Comparison 3: Other toxicities, Outcome 1: Neutropenic fever ‐ all studies
3.2
3.2. Analysis
Comparison 3: Other toxicities, Outcome 2: Neutropenic fever ‐ stratified by type of regimen
3.3
3.3. Analysis
Comparison 3: Other toxicities, Outcome 3: Neutropenic fever ‐ stratified by treatment line
3.4
3.4. Analysis
Comparison 3: Other toxicities, Outcome 4: Anaemia ‐ all studies
3.5
3.5. Analysis
Comparison 3: Other toxicities, Outcome 5: Anaemia ‐ stratified by type of regimen
3.6
3.6. Analysis
Comparison 3: Other toxicities, Outcome 6: Anaemia ‐ stratified by treatment line
3.7
3.7. Analysis
Comparison 3: Other toxicities, Outcome 7: Neutropenia ‐ all studies
3.8
3.8. Analysis
Comparison 3: Other toxicities, Outcome 8: Neutropenia ‐ stratified by type of regimen
3.9
3.9. Analysis
Comparison 3: Other toxicities, Outcome 9: Neutropenia ‐ stratified by treatment line
4.1
4.1. Analysis
Comparison 4: Sensitivity analysis: progression‐free survival ‐ by allocation concealment, Outcome 1: Progression‐free survival ‐ by allocation concealment
See this image and copyright information in PMC

Comment in

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