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Trastuzumab containing regimens for early breast cancer

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Background

Approximately one‐fifth of women who develop early breast cancer have HER2‐positive tumours, which if untreated, have a worse prognosis than HER2‐negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk.

Objectives

To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2‐positive early breast cancer.

Search methods

We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010).

Selection criteria

RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2‐positive early breast cancer including women with locally advanced breast cancer.

Data collection and analysis

We collected data from published and unpublished trials. We used hazard ratios (HRs) for time‐to‐event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration.

Main results

We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease‐free survival (DFS) significantly favoured the trastuzumab‐containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies. 

Authors' conclusions

Trastuzumab significantly improves OS and DFS in HER2‐positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Efficacy and safety of trastuzumab in early breast cancer

Patients with early breast cancer may have HER2‐positive or ‐negative tumours. HER2‐positive cancers tend to be more aggressive. Knowing whether a cancer has high levels of the HER2 protein (about one in five breast cancers) influences the choice of treatment. Trastuzumab (brand name Herceptin) is a drug specifically available for these patients. The aim of the cancer treatment is to eliminate micrometastases at an early stage (i.e. adjuvant) so that more women survive without recurrence of the disease.

The review includes eight trials that involved 11,991 women with HER2‐positive operable breast cancer who were assigned by chance to receive trastuzumab or not. Trastuzumab is always paired with a standard chemotherapy as starting treatment but it can also be continued alone or with hormone‐blocking medications, such as an aromatase inhibitor or tamoxifen. Women were followed by clinicians for several years (three on average). The review found that trastuzumab significantly reduced recurrence and mortality. Some patients in treatment develop severe heart toxicity (i.e. congestive heart failure (CHF)). Breast cancer mortality is reduced by one‐third but the risk of heart toxicity is five times more likely for women receiving trastuzumab than women receiving standard therapy alone. If 1000 women were given standard therapy alone (with no trastuzumab) then about 900 would survive and five would have experienced heart toxicities. If 1000 women were treated with standard chemotherapy and trastuzumab for one year, about 933 would survive (33 more women will have their lives prolonged), about 740 would be free of disease recurrence (95 more women will not experience the disease return), and 26 would have serious heart toxicity (21 more than the chemotherapy alone group) due to the drug. These heart toxicities are often reversible if the treatment is stopped straight away.

Longer treatment (one year) might involve a greater risk of severe heart toxicities than shorter treatment (six months or less), although these results are based on only two studies and few patients. In women at higher risk of recurrence and with no signs of a weak heart, trastuzumab offers far more benefits than risks. The balance of risks to benefits in patients at lower risk of recurrence (e.g. a small rather than a large tumour) must be carefully evaluated. The oncologist should share the decision with the patient concerning whether and how to start the treatment.