Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab

Study Overview
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Brief Summary
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The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab.

Detailed Description
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Over the years, due to the use of new generation therapeutic regimens, as well as the use of advanced radiation techniques, the curability of breast cancer reached an overall 10-year survival rate of approximately 80%. Anthracyclines have a key role in the treatment of breast cancer. Many published studies showed a benefit of disease-free survival in patients with positive lymph nodes treated with anthracyclines-based regimens. Many anthracyclines and taxanes-based regimens are currently used in clinical practice in the treatment of breast cancer. Numerous randomized trials have confirmed the benefit of the addition of taxanes to anthracyclines. Trastuzumab is a recombinant humanized monoclonal antibody with specificity for the extracellular domain of human epidermal growth factor receptor 2 (HER2). The use of trastuzumab administered sequentially or concurrently with adjuvant chemotherapy compared to chemotherapy in patients with HER2 positive was evaluated in several randomized trials. Many data concerning the incidence of adverse cardiovascular events acute, subacute and late are now available. The cardiac toxicity of anthracyclines may be acute, subacute and chronic. The acute toxicity occurs during or shortly after the infusion of the drug with arrhythmias, which in some cases leads to heart failure, pericarditis-myocarditis and electrocardiographic abnormalities. The acute toxicity is usually reversible in a dose-dependent manner. The acute and subacute toxicity are rare (1-4%). Data are available concerning clinically relevant cardiac toxicity with a chronic progressive deterioration of ventricular function up to heart failure. Beside the cumulative dose risk factor, other unfavourable features such as advanced age, female sex, and the combination of anthracyclines and trastuzumab should be evaluated. In most cases, the late toxicity occurs within the first year following completion of chemotherapy but nevertheless the clinical manifestations can occur even after 10-20 years. This fact suggests that in women treated in (neo)adjuvant setting is strongly necessary an echocardiographic monitoring even after a longer time. The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab, using myocardial strain imaging monitoring.

Official Title
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Role of ACE Inhibitors and Beta Blockers as Cardiotoxicity Prevention in Breast Cancer Patients Treated With (Neo)Adjuvant Anthracyclines and/or Trastuzumab: a Four Arm, Placebo Control, Randomized Trial

Conditions
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Breast Cancer, Cardiotoxicity

Intervention / Treatment
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* Drug: Bisoprolol
* Drug: Ramipril
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female Age >18 years Non-metastatic histologically confirmed primary invasive breast cancer Scheduled to receive neoadjuvant and/or adjuvant anthracyclines with or without anti-HER2 therapy Provided informed consent Able to swallow capsules LVEF > 50% Exclusion Criteria: Pregnant or lactating women Treatment with ACE-inhibitors or beta blockers at diagnosis History of NCI Common Toxicity Criteria for Adverse Effects (CTCAE) (version 4.0) Grade >2 symptomatic congestive heart failure (CHF), previous myocardial infarction, significant symptoms (Grade>2) relating to LVEF dysfunction, valvular disease, cardiac arrhythmia (Grade>3)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>bisoprolol plus ramipril | Drug: Bisoprolol<br>* 5 mg daily<br>Drug: Ramipril<br>* 5 mg daily<br>|
| Active Comparator: Arm 2<br>Bisoprolol plus placebo | Drug: Bisoprolol<br>* 5 mg daily<br>Drug: Placebo<br>* 1 capsule daily<br>|
| Active Comparator: Arm 3<br>Ramipril plus placebo | Drug: Ramipril<br>* 5 mg daily<br>Drug: Placebo<br>* 1 capsule daily<br>|
| Placebo Comparator: Arm 4<br>Placebo | Drug: Placebo<br>* 1 capsule daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) | Change in LVEF (3-dimensional and 2-dimensional) at time-frame | at months 6,9,12,24 | 
| Global longitudinal strain (GLS) | Change in GLS at time-frame | at months 6,9,12,24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Indexed left ventricular end diastolic volume (EDVI) | Change in EDVI at time-frame | at months 6,9,12,24 | 
| Indexed left ventricular end systolic volume (ESVI) | Change in ESVI at time-frame | at months 6,9,12,24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adjuvant chemotherapy, Neoadjuvant chemotherapy, Cardioprotection, Anthracyclines, Breast cancer