(cardiac) risk/benefit analysis of adjuvant perception use outlined

[Lani]

Balancing Trastuzumab's Survival Benefits and Heart Risks for Women with Breast Cancer
Wiley

Adding trastuzumab (trade name Herceptin) to the treatment offered to women who have HER2-positive breast cancer, significantly increases the chance of life being prolonged, and reduces the chance of tumours reappearing once therapy stops. This is important, because about one-fifth of women who develop early breast cancer have HER2-positive tumours that, if untreated, are associated with a worse outlook than HER2-negative tumours. At the same time, however, women given trastuzumab have a higher risk of experiencing problems with their heart. These findings are the key conclusions of a systematic review published in The Cochrane Library.

Breast cancer is the most common diagnosed cancer in women. There are different types of breast cancer cells, but one feature is whether the tumour's cells produce excess quantities of a particular protein called the human epidermal growth factor receptor 2 (HER2). Cells which do are known as HER2-positive, while those with normal production are referred to as HER2-negative. Trastuzumab is a new-generation antibody based medicine that blocks the receptor and stops it triggering the excessive cell growth that causes tumours.

To provide clinicians and patients with accurate evidence of trastuzumab's harms and benefits, a team of researchers based in Milan and Modena, Italy, were keen to study available clinical trial data. They identified eight trials that involved 11,991 women with HER2-positive operable breast cancer who had been assigned randomly either to receive trastuzumab or not, in addition to other treatments. Women were followed by clinicians for several years (three on average).

The overall finding was that breast cancer mortality was reduced by one-third, but the risk of heart toxicity went up five times for women receiving trastuzumab compared with women receiving standard therapy alone.

If 1000 women were given standard therapy with no trastuzumab then after three years about 900 would survive, but if 1000 women were treated with standard chemotherapy and trastuzumab for one year, about 933 would survive.

"This means that for every 1000 women treated with trastuzumab, 33 more women will have their lives prolonged," says lead researcher Lorenzo Moja who works in the Department of Public Health at the University of Milan. In addition, about 95 more women will remain disease-free once therapy has stopped.

However, the study showed that the treatment isn't free of problems. About 26 in 1000 women taking trastuzumab experienced serious heart toxicity. This is 21 more than the chemotherapy alone group.

"These heart toxicities are often reversible if the treatment is stopped straight away," says Moja.

The researchers conclude that 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 is less clear and must be carefully evaluated in women at lower risk of recurrence, for example if they only have a small tumour, or those who are at increased risk for cardiac complications. "The oncologist should share the decision with the patient, after careful consideration of the risks and benefits," says Roberto D'Amico, senior scientist at the Clinical Trial Unit of the Department of Oncology of the University of Modena.
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ABSTRACT: Efficacy and safety of trastuzumab in early breast cancer[The Cochrane Library

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 strategy: 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.