Cardiac Rehabilitation Program on the Prevention of Cardiotoxicity in Breast Cancer Patients Undergoing Treatment With Anthracyclines and/or Trastuzumab

Official title

Rationale and Design of a Cardiac Rehabilitation Program on the Prevention of Cardiotoxicity in Breast Cancer Patients Undergoing Treatment With Anthracyclines and/or Trastuzumab: A Randomized, Active Control Group, Open-Label Trial

Overview

This study aims to evaluate the effectiveness of a cardiac rehabilitation protocol, incorporating aerobic and resistance exercise, in reducing the incidence of cardiotoxicity in breast cancer patients receiving treatment with anthracyclines and/or trastuzumab through a randomized, active control group, open-label clinical trial.

Detailed description

This is a randomized, open-label, with an active control group trial. This study adopts the main evaluation indicator being the incidence of cardiac dysfunction or heart failure as a manifestation of cardiovascular toxicity, assessed following the 2022 European Society of Cardiology (ESC) definitions for cancer-related therapy cardiac dysfunction (CTRCD).

Participants who pass the inclusion criteria through research will provide written informed consent to take part in the study. Once consent is obtained, participants will be randomly assigned to one of two study groups using a simple randomization process. This will be accomplished through a computer-generated random number sequence list, which will be managed by a designated investigator from the research team. The intervention group will receive standard oncological treatment combined with an aerobic and resistance exercise program, following the FITT principle (Frequency, Intensity, Type, and Time) for exercise prescription. Three out of five weekly sessions will be conducted per week. The control group will continue standard oncological treatment in addition to general recommendations regarding diet and physical activity but without a structured exercise protocol. During the treatment process, both branches of the trial will be followed over a 12 months period, with scheduled outpatient evaluations to assess biochemical parameters, a 12-lead electrocardiogram (ECG), a transthoracic echocardiogram (TTE), and a cardiopulmonary exercise test (CPET). Both the intervention and control groups will undergo these assessments at four key time points: baseline (defined as the time before the start of the chemotherapy regime and after the study enrollment), 3 months, 6 months, and 12 months post-initiation of chemotherapy. The main outcome of this clinical trial is a composite of incident cardiotoxicity, defined according to the ESC guidelines. Other cardiac function related indicators such as symptomatic congestive heart failure or asymptomatic but decreased left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and changes in cardiac biomarkers will be evaluated to determine the occurrence of cardiac toxicity. Secondary outcomes assessed the impact on echocardiographic parameters of cardiac function, fluctuations in biomarkers and blood tests, cardiorespiratory performance, the impact of quality of life and explore the role of traditional cardiovascular risk factors.

Interventions

• Other Rehabilitation Program
  Three of the five weekly sessions will take place at the gym in the Functional Unit of Breast Tumors at INCAN, under the supervision of Physical and Sports Medicine specialists and three physical therapists. These sessions allow for personalized feedback, enabling participants to confidently perform prescribed aerobic exercises at home on the remaining two days. Each session starts with a 10- to 15-minute warm-up focused on joint mobility. Aerobic training is conducted at moderate intensity (40
• Other No Rehabilitation Program
  The control group will continue standard oncological treatment in addition to general recommendations regarding diet and physical activity, but without a structured exercise protocol.

Primary outcome measures

• Incidence of cardiac dysfunction or heart failure as a manifestation of cardiovascular toxicity in the intervention group and control group [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]

Secondary outcome measures (5)

• Impact on echocardiographic parameters [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]
• Modification in series of circulating cardiac biomarkers [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]
• Evaluation of cardiorespiratory performance [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]
• Quality of Life Questionnaire: FACT-B [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]
• Explore the role of traditional cardiovascular risk factors [Time frame: From 1 week before starting oncological treatment to 1 year after the start of the chemotherapy regimen]

Eligibility criteria

Inclusion criteria

• Women aged between 18 and 70 years will be considered eligible.
• Active residents of any municipality within Mexico City and the surrounding metropolitan area will qualify, conditioned that their maximum travel time from their residence to our recruitment center does not exceed three hours using private or public transportation. This criterion is established to ensure adherence to the protocol and availability for participation in the required interventions and assessments throughout the study.
• Patients diagnosed with early-stage or locally advanced breast cancer (stages I, II, or III, according to the TNM classification-Tumor, Node, Metastasis) who will undergo treatment with anthracyclines and/or adjuvant/neoadjuvant anti-HER2 therapy will be included. Participants must be scheduled to receive pharmacological treatment, ensuring that the study focuses on a population undergoing specific therapies for breast cancer management.
• Candidates must have the capacity, availability, and willingness to participate in an aerobic and resistance exercise program. Participants are required to possess both the physical ability and the willingness to actively engage in a structured exercise program, which includes aerobic and resistance activities essential to the study's objectives.
• Patients will provide informed written consent to participate in the study. To uphold ethical research principles and ensure the protection of participants' rights, all patients must voluntarily give their informed consent after receiving comprehensive information regarding the study's objectives, procedures, benefits, and potential risks.

Exclusion criteria

• Metastatic disease: Individuals with medical or imaging evidence of metastasis to any peripheral organ.
• Cardiovascular disease: Patients with a self-reported history of cardiovascular conditions, such as heart failure or uncontrolled hypertension, that may limit their ability to safely engage in physical activity. Additionally, those with peripheral arterial disease or valvular heart disease will not be eligible.
• Ischemic heart disease: Patients with a history of ischemic heart disease.
• Neurological disorders: Individuals with self-reported neurological diseases that significantly impair coordination, balance, or motor control, such as advanced Parkinson's disease, late-stage multiple sclerosis, or paralysis, making physical activity unsafe.
• Musculoskeletal conditions: Patients with self-reported musculoskeletal injuries or disorders that hinder physical activity, including fractures within the last five years, moderate to severe sprains, tendinitis, or severe arthritis.
• Uncontrolled systemic comorbidities: Individuals with decompensated systemic conditions, including heart failure, chronic kidney disease, or poorly controlled diabetes, will be excluded.
• Severe respiratory diseases: Patients with severe respiratory conditions that prevent physical exercise participation.
• Physical limitations: Individuals with mobility impairments or conditions requiring constant assistance for basic physical activities, such as those using assistive devices (e.g., wheelchairs, walkers) or with limb amputations, will not be eligible for participation.
• Severe psychiatric disorders: Patients with uncontrolled psychiatric conditions, including schizophrenia, severe bipolar disorder, or major depressive disorder, that may interfere with their ability to actively participate in a supervised exercise program.

Elimination Criteria:

• Voluntary withdrawal from the protocol.
• Development of severe cardiotoxicity requiring pharmacological treatment.
• Adverse reactions to chemotherapeutic agents.
• Disease progression according to the TNM classification during treatment.
• Failure to complete at least 80% of the prescribed adjuvant or neoadjuvant oncological treatment.
• Occurrence of adverse events during the study, such as falls or injuries.
• Death during the study period.
• Any accident related to the exercise protocol, including falls, sprains, or fractures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

Mexico · 2 centers

• Instituto Nacional de Cancerología (INCAN) — Mexico City
• National Institute of Cancerology (INCAN) — Mexico City

Publications

• Kerrigan DJ, Reddy M, Walker EM, Cook B, McCord J, Loutfi R, Saval MA, Baxter J, Brawner CA, Keteyian SJ. Cardiac Rehabilitation Improves Fitness in Patients With Subclinical Markers of Cardiotoxicity While Receiving Chemotherapy: A RANDOMIZED CONTROLLED STUDY. J Cardiopulm Rehabil Prev. 2023 Mar 1;43(2):129-134. doi: 10.1097/HCR.0000000000000719. Epub 2022 Aug 4. PMID 35940850
• Viamonte SG, Joaquim AV, Alves AJ, Vilela E, Capela A, Ferreira C, Duarte BF, Rato ND, Teixeira MP, Tavares A, Santos M, Ribeiro F. Cardio-Oncology Rehabilitation for Cancer Survivors With High Cardiovascular Risk: A Randomized Clinical Trial. JAMA Cardiol. 2023 Dec 1;8(12):1119-1128. doi: 10.1001/jamacardio.2023.3558. PMID 37819656
• Diaz-Balboa E, Pena-Gil C, Rodriguez-Romero B, Cuesta-Vargas AI, Lado-Baleato O, Martinez-Monzonis A, Pedreira-Perez M, Palacios-Ozores P, Lopez-Lopez R, Gonzalez-Juanatey JR, Gonzalez-Salvado V. Exercise-based cardio-oncology rehabilitation for cardiotoxicity prevention during breast cancer chemotherapy: The ONCORE randomized controlled trial. Prog Cardiovasc Dis. 2024 Jul-Aug;85:74-81. doi: 10.1 PMID 38395212
• Yang HL, Hsieh PL, Hung CH, Cheng HC, Chou WC, Chu PM, Chang YC, Tsai KL. Early Moderate Intensity Aerobic Exercise Intervention Prevents Doxorubicin-Caused Cardiac Dysfunction Through Inhibition of Cardiac Fibrosis and Inflammation. Cancers (Basel). 2020 Apr 28;12(5):1102. doi: 10.3390/cancers12051102. PMID 32354131
• Kouzi SA, Uddin MN. Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity. J Pharm Pharm Sci. 2016 Jul-Sep;19(3):399-410. doi: 10.18433/J3JS5R. PMID 27806245
• Yu AF, Jones LW. Breast cancer treatment-associated cardiovascular toxicity and effects of exercise countermeasures. Cardiooncology. 2016;2:1. doi: 10.1186/s40959-016-0011-5. Epub 2016 Feb 25. PMID 28133540
• Xie S, Sun Y, Zhao X, Xiao Y, Zhou F, Lin L, Wang W, Lin B, Wang Z, Fang Z, Wang L, Zhang Y. An update of the molecular mechanisms underlying anthracycline induced cardiotoxicity. Front Pharmacol. 2024 Jun 26;15:1406247. doi: 10.3389/fphar.2024.1406247. eCollection 2024. PMID 38989148
• Nebigil CG, Desaubry L. Updates in Anthracycline-Mediated Cardiotoxicity. Front Pharmacol. 2018 Nov 12;9:1262. doi: 10.3389/fphar.2018.01262. eCollection 2018. PMID 30483123

Identifiers

NCT: NCT06881940 · 24-1488

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗