How to prevent and treat heart failure induced by trastuzumab treatment
The aforementioned pivotal study showed that the combination doxorubicin/cyclophosphamide and trastuzumab must not be used simultaneously
(2). According to the summary of product characteristics, if trastuzumab is administered first, anthracyclines should not be used until six months later, because the monoclonal antibodies have a long half-life in blood (13). However, this rule is gradually being relaxed.
Recommendations for regular monitoring of the heart function of patients who have been given trastuzumab were developed on the basis of several large studies
(14). An analogous algorithm is recommended by the Norwegian Breast Cancer Group (NBCG) (Fig. 1) (15). The check-ups include history of illness, clinical examination and echocardiography or nuclear medicine determination (GTSPECT or MUGA) of the ejection fraction. The nuclear medicine methods and echocardiography are regarded as more or less equivalent methods of examining the ejection fraction (14). Echocardiography can also provide information about other pathological conditions, for example whether the patient already has a reduced ejection fraction due to valve disease or previous infarction. In asymptomatic patients, the factor that determines whether treatment should be continued or discontinued is the ejection fraction. However, there are also descriptions in the literature of cases of clinically severe diastolic heart failure with a preserved ejection fraction (16).
Figure 1 Decision-making algorithm in connection with monitoring of the ejection fraction of patients who are being treated with trastuzumab. The figures indicate the decision-making criteria for the left ventricle’s ejection fraction (LVEF) as a percentage. Revised and reproduced with the permission of the NBCG ( 15).
Information is available on the risk of heart failure under many different treatment protocols
(16). In the HERA trial, surgery was followed by at least four chemotherapy courses, including anthracyclines and then trastuzumab for 12 months. This gave a 1.9 % risk of developing symptomatic heart failure, while 5.1 % had to discontinue trastuzumab therapy because of heart problems (17). The patient in question had not suffered myocardial infarction, valve defect or cardiomyopathy before.
In practice, risk profile and risk assessment will often be different in patients with recidivist or metastatic disease. Patients with recidivism are older and have been treated with cytostatics before. It has been documented that a high age, hypertension and a high body mass index (BMI) are risk factors predisposing subjects to develop heart failure under anthracycline treatment
(7). The risk of developing heart failure in connection with trastuzumab treatment is exacerbated by previous coronary disease, valve disease, diabetes or anthracycline treatment (18). Patients with metastases can have long-term treatment with trastuzumab. In one such cohort, a change in the ejection fraction was observed in 28 % of those studied. In the same study, trastuzumab treatment was temporarily stopped for 15 % of the patients, but could be resumed under close surveillance for most of them. Only 3 % of the patients had to terminate trastuzumab treatment (18).
The myocardial injury markers troponin T and troponin I show an early rise after each injection of trastuzumab in those patients who gradually develop heart failure
(19). Using troponins to monitor breast cancer patients is not recommended today, however.
If the injection fraction falls to less than 44 %, trastuzumab treatment must immediately be interrupted
(14, 18). Similarly, a break should be taken if the ejection fraction has fallen more than 10 %, and measurement shows 45 – 49 %. The ejection fraction of many patients will then gradually improve and heart failure symptoms will regress (14, 18, 20, 21). Long-term follow-up of the patients who developed heart failure shows that about 80 % regain their previous cardiac function (22, 23). The United Kingdom National Cancer Research Institute recommends administering betablockers and ACE inhibitors in response to signs of developing heart failure (14). There is no international consensus on this, however, unless the patients have symptoms of heart failure. Studies show that patients who are treated with betablocker or ACE inhibitor are less at risk of developing heart failure (24, 25). Prophylactic treatment is therefore assumed to be effective, but is not recommended for normotensive patients for fear of masking symptoms. It is recommended that ACE inhibitor form part of the treatment regime for hypertonics (14).