Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Heart and Blood Diseases

Symptoms and General Pathology

Substance Related Disorders

Wounds and Injuries

Breast Neoplasms

Cardiotoxicity

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Breast Diseases

Skin Diseases

Participants will receive standard of care treatment for their breast cancer.

Participants will receive standard of care treatment for their breast cancer plus be given a 12-week home based aerobic exercise program.

All participants will receive standard of care for their cancer as well as given a 12-week, home-based progressive aerobic exercise (AE) program. A nonlinear progressive training approach will be used whereby each participant will perform two AE sessions (e.g. walking), on non-consecutive days, per week. AE sessions will vary between low (35-45% heart rate reserve (HRR)), low-moderate (46-55% HRR), high-moderate (56-70% HRR) and high (71-85% HRR) intensity.

Aerobic exercise

Scott A Grandy, PhD

Melanie R Keats, PhD

Davinder S Jassal, MD

Thang Nguyen, MD

Tallal Younis, MD

Nicholas Giacomantonio, MD

Although great progress has been made in treating breast cancer, long-term health may be impaired by cancer therapy. For example, some chemotherapy drugs (e.g., anthracyclines) are known to cause declines in heart health. While the impact can vary, some will experience substantial heart damage that may lead to heart failure and death. As these treatments are highly effective, there is a need to find ways to reduce the damaging effects while not interfering with its anticancer potential. As it is well-known that regular exercise can improve heart health, the purpose of this study is to explore the role of exercise as a heart protective therapy for breast cancer patients receiving heart damaging chemotherapy.

As a result of advances in cancer treatment, the number of breast cancer (BC) survivors is increasing in Canada. Unfortunately, the drugs used to treat BC can have a negative impact on the long term health and welfare of the BC survivors (BCS). For example, commonly used cancer therapies, such as anthracyclines (AC) are known to cause declines in heart health. While the impact can vary, some individuals treated with these medications will experience substantial heart damage that may lead to heart failure and death. As a result, risk of cardiovascular morbidity/mortality has become a major concern for BCS that received AC treatment. As a result, there is an immediate need to find therapies that can be used to prevent damage to the heart without limiting the anticancer potential of AC.

A growing body of evidence suggests that aerobic exercise training may help protect the heart against the damaging effects of AC therapy. These studies, which were conducted using animal models, have shown that performing aerobic exercise before or while undergoing AC therapy helps to maintain heart function and prevent structural changes in the heart. However, to the author's knowledge similar studies have not been conducted in BCS undergoing treatment, thus it remains unclear whether exercise has the same cardioprotective effect in BCS. As a first step in answering this question, our research group conducted a pilot study that showed a 12-week aerobic exercise program is safe and feasible for BCS undergoing chemotherapy. The next step in our research is to determine whether aerobic exercise decreases or prevents cardiotoxicity in BCS receiving AC treatment. Therefore, the purpose of this study is to determine whether a 12-week home based aerobic exercise program mitigates AC-mediated cardiotoxicity in BCS on active treatment. The specific objectives of the study are to determine whether the aerobic exercise program: 1) prevents structural and functional changes in the heart; 2) maintains peak aerobic capacity throughout the treatment process; and 3) decreases biological markers associated with heart damage.

This is a randomized control trial with repeated measures. BCSs will be randomly assigned to either the wait-list control (CTL) group (standard of care (SOC) or the aerobic exercise (AEX; SOC + 12-week home-based aerobic exercise program). One hundred BCS (18-65 years of age) on AC treatment will be recruited from two sites, Halifax, NS (n=50) and Winnipeg, MB (n=50). Patients in the AEX group will perform two exercise sessions per week that will range from low intensity (\~45 min) to vigorous intensity (\~20 min). BCS will monitor their exercise intensity with Polar A370 HR monitors, which they will be given for the duration of the study.The primary outcome measure for the study is cardiac function as determined by echocardiography and a cardiac stress test. Secondary outcome measures include serum biomarkers associated with cardiotoxicity (e.g. c-reactive protein, hsTNT, NT-proBNP). Patient-reported outcomes including levels of fatigue and quality of life will also be assessed. The study outcome measures will be assessed prior to the participants starting AC therapy (week-0), post-exercise intervention (week-12) and 6 months after the completion of the AEX. Of note, upon completion of the 6 month follow-up testing participants in the CTL group, if interested, will be given the home-based AEX as well the necessary support to complete the program.

This research will provide the first direct evidence that aerobic exercise protects the heart from AC-mediated damage in BCS undergoing cancer treatment. Both the medical and research communities will benefit from this research as it could lead to the improvement of long term health of cancer survivorship as well as improve the understanding of how the heart health can be maintained during cancer therapy. Given the significant impact of AC therapy on improving BC prognosis, and the potential protective effects of exercise training, this study will be important in improving BC care via the improvement of the quality of life and increased survivorship.

Participants will be randomly allocated to either the standard of care group (control) or the intervention group (standard of care + 12-weeks aerobic exercise).

Clinicians interpreting the echocardiograms and stress test results will not know whether the participant is in the control group or the exercise intervention.

Exercise to Prevent AnthraCycline-based Cardio-Toxicity Study 2.0 (EXACT2)

EXercise to Prevent AnthraCycline-based Cardio-Toxicity 2.0 (EXACT2) in Individuals With Breast Cancer

LV function will be assessed using serial transthoracic echocardiography (TTE) as well as tissue velocity imaging (TVI) and strain imaging (SI.) For 2-dimensional (2D) LV cavity dimensions and LVEF will be determined from the acquired 2D images according to established criteria. Tissue Doppler-derived indexes will be recorded at the base of the lateral mitral annuli to determine longitudinal endocardial velocities. The indexes that will be assessed are systolic (S'), early diastolic (e') and late diastolic (a') velocities. Doppler-independent strain will be assessed offline using semi-automated speckle tracking techniques. These will be performed using parasternal and apical views to determine both global longitudinal and radial strain.

Cardiac electrocardiogram at rest will be assessed using a 12 lead ECG (General Electric Case System). Specifically, the duration (ms) of the PR interval, RR interval, QRS interval and QT interval will be determined.

Cardiac Stress Tests results will be used to predict peak oxygen consumption (ml/kg/min). In brief, participants will perform a graded exercise test until they reach volitional fatigue or the test is terminated due to adverse physiological changes. Predictive equations will then be used to predict the participant's peak oxygen uptake based on the total duration (seconds) of the treadmill test.

Venipuncture will be performed by a nurse/phlebotomist to collect blood samples which will be used to quantify systemic levels of c-reactive protein (CRP), high sensitivity troponin (hs-TNT) and NTproBNP levels. Upon collection, blood samples will be processed, and the serum will be extracted and stored at -20°C until it is required for analysis. CRP, hs-TNT and N-terminal pro b-type natriuretic peptide (NTproBNP) levels will be assessed using commercially available ELISA kits. All biomarkers will be measured in pg/ml.

The Functional Assessment for Cancer Therapy survey for patients with breast cancer (FACT-B) will be used to assess quality of life. The FACT-B includes sub-scales for assessing physical, social/family, emotional, and functional well-being. FACT-B total score ranges from 0-148.

The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) is a 13 item questionnaire (maximum score =160) that will be used to assess cancer-related fatigue. Higher scores are indicative of higher levels of fatigue.

Canadian Cancer Society (CCS)

Canadian Institutes of Health Research (CIHR)

Nova Scotia Health Authority

Affiliate Scientist Cardiology

Rare Diseases

Chronic Graft Versus Host Disease

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Vasodilator Agents

Respiratory System Agents

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Superoxide Dismutase

Nitric Oxide

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

The patients will be assessed before and after chemotherapy treatment.

Body weight, height and waist circumference

Physical Characteristics

Muscular Sympathetic Nervous Activity

Cardiac Function

Heart rate

Blood pressure

Serum and Plasma will be extracted by centrifugation. Endothelial microparticles by flow cytometry Interleukin-6 and tumor necrosis factor α by ELISA, High-sensitive reactive serum C-reactive protein by immunoturbidimetric assay, NT- ProBNP According to Central Laboratory, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo. Endothelin-1 by immunoenzymatic method Nitric oxide by gas chemiluminescence Lipoperoxidation by fluorimetry Carbonyl by spectrophotometer, and Superoxide Dismutase (SOD) by colorimetry.

Blood Assessments

Muscle blood flow

Endothelium-dependent vascular function

Vascular intima-media thickness

Physical Capacity

Four session of intravenous (in bolus) infusion of doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 with an interval of 21 days between sessions.

Anthracycline & Cyclophosphamide treatment scheme

Raphaela VR Groehs, PhD

Ursula Urias, PhD

Carlos Eduardo Negrao, PHD

Carlos E Negrao, PhD

The present study aims to investigate the chronic effect of treatment with doxorubicin and cyclophosphamide on neurovascular control and blood pressure in women undergoing adjuvant treatment for breast cancer.

The development of new drugs and different adjuvant therapeutic regimens, based on the combination of anthracycline (A) and cyclophosphamide (C), have contributed greatly to improve survival rate in breast cancer patients. Despite the clinical benefits of this therapy, AC treatment can cause cardiovascular acute and chronic changes. In a recent investigation, we observed that an acute AC chemotherapy session increases sympathetic nervous activity and blood pressure in patients with breast cancer.

The present study aims to investigate the chronic effects of AC regimen on sympathetic nervous activity, peripheral vasoconstriction, endothelial microparticles and blood pressure, in women with breast cancer.

Effect of Anthracyclines and Cyclophosphamide on Cardiovascular Responses

Chronic Effect of Doxorubicin and Cyclophosphamide on Neurovascular Control and Blood Pressure in Women in Adjuvant Treatment for Breast Neoplasia

Change in muscular sympathetic nerve activity measured by microneurography

Change in muscle blood flow measured by venous oclusion plethysmography

Change in blood pressure measured by finometer

Change in physical capacity measured by cardiopulmonary exercise test

Change in cardiac function measured by echocardiography

Universidade Federal Fluminense

Hospital Israelita Albert Einstein

University of Sao Paulo General Hospital

Cardiotonic Agents

Natriuretic Agents

Dobutamine

Natriuretic Peptide, Brain

Cardiac MRI has increased use in evaluating structural and functional cardiac pathologies. For detection of coronary artery disease, MRI outperforms SPECT and dobutamine stress echocardiography for the detection of ischemia. MRI also can detect wall-motion abnormalities and other dysfunction. Dynamic contrast-enhanced MRI (DCE-MRI) can evaluate microvascular parameters such as vessel permeability and fluid volume fraction as an assessment of tissue perfusion. Cardiac MRI holds promise for early detection of subclinical cardiac abnormalities after radiotherapy and could potentially identify patients for intervention to prevent cardiac events. All patients will follow the protocol calendar requiring research MRIs, but will receive standard radiation treatment determined by their physician. Treatment will not be altered based on MRI.

Research Cardiac MRI

We have identified potential candidates based on other processes affecting heart function in a way similar to probable mechanisms of RT-related injury. For fibrosis and left ventricular dysfunction, these include galectin-3 and N-terminal-Pro brain natriuretic peptide. For myocyte destruction, troponin; for inflammation and oxidative stress, C-reactive protein, myeloperoxidase, and growth differentiation factor 15. Additional blood will be collected and stored for future assessment of other candidate biomarkers.

All patients will follow the calendar of protocol required research blood draws for biomarker collection, but will receive standard radiation treatment as clinically indicated by their physician. Treatment will not be altered based upon the data collected from these samples.

Biomarkers

Radiotherapy plays an integral role in breast cancer therapy. Multiple randomized studies have demonstrated decreased local-regional recurrence rates and decreased breast-cancer mortality. However, balanced with this survival benefit is the potential toxicity of the treatment itself. In particular, cardiac effects of radiotherapy have been a concern and an area of research for the past 20 years. From long-term follow up of patients with lymphoma, it is known that radiotherapy can lead to increased risk of myocardial infarction, valvular dysfunction, systolic and diastolic function abnormalities, and heart failure among cancer-survivors. Patients with breast cancer receive lower doses to smaller volumes of the heart, but they also have an excellent long-term survival, so it is crucial to study the effects of low dose radiotherapy. Indeed, a recent study suggests that these effects can be seen within the first 5 years after treatment, and that there is no dose threshold. This study aims to develop imaging and blood biomarkers of cardiac exposure, as a first step to identifying patients at increased risk for cardiac effects, so they can be targeted for close monitoring and early intervention, potentially with statins or ACE inhibitors. Additionally, by characterizing a time-course and radiation dose-volume relationship, potentially real-time modifications can be made to RT field design for patients sensitive to RT effects. Finally, this information can be incorporated into better designs of treatment plans for future patients.

Radiotherapy plays an integral role in breast cancer therapy. Multiple randomized studies have demonstrated decreased local-regional recurrence rates and decreased breast-cancer mortality. However, balanced with this survival benefit is the potential toxicity of the treatment itself. In particular, cardiac effects of radiotherapy have been a concern and an area of research for the past 20 years. From long-term follow up of patients with lymphoma, it is known that radiotherapy can lead to increased risk of myocardial infarction, valvular dysfunction, systolic and diastolic function abnormalities, and heart failure among cancer-survivors. Patients with breast cancer receive lower doses to smaller volumes of the heart, but they also have an excellent long-term survival, so it is crucial to study the effects of low dose radiotherapy. Indeed, a recent study suggests that these effects can be seen within the first 5 years after treatment, and that there is no dose threshold. The investigators hypothesize that they can develop imaging and blood biomarkers of cardiac exposure, as a first step to identifying patients at increased risk for cardiac effects. These patients can then be targeted for close monitoring and early intervention, potentially with statins or ACE inhibitors. Additionally, by characterizing a time-course and radiation dose-volume relationship, potentially real-time modifications can be made to RT field design for patients sensitive to RT effects. Finally, this information can be incorporated into better designs of treatment plans for future patients.

Collection of approximately 20 ml of blood will be performed by venipuncture at the specified time points. When possible, blood collection will be coordinated with other routine blood studies. These blood samples will be drawn at the clinical blood drawing station in the Radiation Oncology department.

For fibrosis and left ventricular dysfunction, biomarkers include galectin-3 and NT-Pro brain natriuretic peptide. For myocyte destruction, troponin; for inflammation and oxidative stress, C-reactive protein, myeloperoxidase, and growth differentiation factor. Additional blood will be collected and stored for future assessment of other candidate biomarkers.

Biomarkers and Cardiac MRI as Early Indicators of Cardiac Exposure Following Breast Radiotherapy

Biomarkers and Cardiac MRI as Early Indicators of Cardiac Exposure

The study aims to characterize longitudinal changes in imaging characteristics of cardiac damage. Cardiac MRI endpoints will include myocardial edema, microvascular dysfunction, myocardial fibrosis, and subclinical impairment of systolic and diastolic function.

The study aims to characterize longitudinal changes in potential early biomarkers of cardiac damage. Biomarker endpoints derived from blood or its components include measuring levels of galectin-3, NT-Pro brain natriuretic peptide, troponin, C-reactive protein, myeloperoxidase, and growth differentiation factor 15.

Biomarker endpoints derived from blood or its components include measuring levels of galectin-3, NT-Pro brain natriuretic peptide, troponin, C-reactive protein, myeloperoxidase, and growth differentiation factor 15. Additional biomarkers may be included as the research in those fields progresses during the conduct of this clinical trial.

University of Michigan Rogel Cancer Center

Henry Ford Health System

Senior Staff Physician

adult survivors of childhood malignancies

Yiu-fai Cheung, MD

Anthracyclines have been used commonly to treat children with solid tumours and haematological malignancies and have led to their increased survival. Nonetheless, anthracycline has the side effect of cardiotoxicity. The purpose of this study is to assess the impact of anthracycline therapy on heart deformation and fibrosis, heart-vessel interaction, usefulness of circulating biomarkers in the assessment of heart function and potential genetic predisposition to heart failure in adult survivors of childhood cancers.

Incorporation of anthracyclines into chemotherapy protocols has improved the survival of children with solid tumours and haematological malignancies. Nonetheless, longitudinal studies have implicated the absence of a safe anthracycline dose that is free of cardiotoxicity. Substantial risk for cardiovascular disease has been shown recently in large cohorts of adult survivors of childhood and adolescent survivors. Serial monitoring of cardiac function is hence of paramount importance in childhood cancer survivors for early detection of myocardial damage and timely institution of interventions. The optimal monitoring of cardiac function in the long term in these at-risk patients remains to be established. Novel noninvasive imaging modalities including echocardiography and cardiac magnetic resonance allow interrogation of myocardial deformation and fibrosis, while circulating biomarkers are increasingly used to monitor the cardiac status in heart failure patients. Additionally, genetics of heart failure are increasingly unveiled.

Cardiovascular Function in Adult Survivors of Childhood Malignancies

Novel Imaging and Circulation Biomarkers for Comprehensive Evaluation of Cardiovascular Function in Adult Survivors of Childhood Malignancies

The University of Hong Kong

Professor

Trastuzumab

Pertuzumab

Eligible participants will be women aged 18 years or over who have the following main characteristics:

* Early invasive breast cancer (stage I-III)
* Due to start SAT (adjuvant or neoadjuvant chemotherapy +/- trastuzumab +/- pertuzumab)
* WHO performance status 0-2.

Professor Lewis

This study will investigate the influence of systemic adjuvant/neoadjuvant therapy (SAT: chemotherapy +/- anti-HER2 antibodies (trastuzumab +/- pertuzumab) on heart function/rhythm and cardio-respiratory fitness in recently diagnosed breast cancer patients. In some patients, SAT damages the heart (so-called 'cardiotoxicity') and this can have a serious impact on the patient's quality of life and overall survival. It has also been suggested that anticancer therapies may lead to repolarization abnormalities, QT prolongation and autonomic dysfunction, clinically reflected by an increase in HR and a reduction in heart rate variability (HRV). There is a lack of information in the literature regarding the extent and time-course of changes in cardiac function, cardiac rhythm and cardio-respiratory performance ('fitness') in these patients. Moreover, the differential influences of specific treatment regimes (e.g. SAT or SAT plus radiotherapy) and different chemotherapy drugs on cardio-respiratory performance remain unclear. A better understanding of these issues is the primary aim of this study.

This study will focus on the following:

1. Cardiac function assessment: The conventional method for assessing heart function (in terms of 'ejection fraction') in patients being treated for cancer uses nuclear medicine (MUGA scan). MRI can also provide this information but it is not typically used for cardiac function assessment in these patients. MUGA scans are typically performed before chemotherapy in selected patients at higher risk of cardiotoxicity and in all cases before starting anti-HER2 antibody treatment (trastuzumab, pertuzumab). Patients receiving anti-HER2 antibody treatment receive repeat cardiac assessments at 3-4 month intervals until the completion of treatment - it is not practical or cost-effective to scan more frequently. This study will determine whether an alternative and inexpensive method for monitoring heart function (Impedance Cardiography, ICG) can adequately quantify changes in ejection fraction during treatment. If it can, then this technique could be used more frequently during and following treatment, with the aim of determining the treatment stages during which the heart is most at risk of damage. The ability of ICG to dynamically characterise a relatively rapid decline in cardiac function in breast cancer patients has not been established. Neither has its performance been compared with MRI or MUGA in this population. This study will investigate whether ICG is a sufficiently accurate and reliable alternative to MRI/MUGA for determining cardiac dysfunction during and following cancer treatment.
2. Cardiac rhythm and autonomic function assessment: Heart rate variability (HRV) reflects the modulation of the heart by the autonomic nervous system, and it can be quantified using several different methods based on analysis of the temporal changes between successive heartbeats. The development of autonomic dysfunction in breast cancer patients has been shown in a few small clinical studies, but the majority of these studies have considered HR rather than HRV, which is a much less robust measure of autonomic function. The few studies that have used HRV analysis have demonstrated significant reductions in HRV following the completion of anthracycline-based therapy. Previous research on other ECG markers (e.g. QT and QRS duration) in breast cancer patients has mainly focused on anthracycline-based regimes; the influence of trastuzumab treatment on ECG makers has been evaluated in only two studies to date. It is still not clear whether these changes can predict subsequent LV dysfunction although QT variability is a possible marker of myocardial contractility and has been shown to increase as a result of anthracycline therapy in breast cancer patients. This study aims to characterise the impact of different treatment regimes on the temporal properties of the ECG and will compare beat-to-beat QT variability and beat-to-beat T wave variability in breast cancer patients receiving a range of treatment regimes.
3. Body composition and cardiorespiratory fitness assessment: This study also aims to characterise the patterns of change in body composition, physical activity and cardiorespiratory fitness in breast cancer patients. The study will examine whether these modifiable factors might influence a patient's susceptibility to cardiac changes during treatment and, in turn, how these factors are affected by treatment. Of particular interest, it has been suggested that cardiorespiratory fitness (measured by the rate of oxygen uptake) is impaired in breast cancer patients compared to healthy controls, even seven years following the completion of treatment. Oxygen-uptake analysis will be performed in this study to explore possible compensatory mechanisms for abnormal pathology- or treatment-induced cardiac function in breast cancer patients. Fitness, physical activity and body composition will be assessed quantitatively using a range of objective techniques, including cardiopulmonary exercise testing on a cycle ergometer (fitness) with breath-by-breath gas analysis (cardiorespiratory function), accelerometery (activity levels) and DEXA radiography scans (body composition).

The main research questions in this study are:

1. Is the CARE-B protocol practically feasible and tolerable to early-stage breast cancer patients?
2. What is the level of agreement between cardiac (ventricular) function determined using cardiac MRI, MUGA and Impedance Cardiography in breast cancer patients receiving SAT?
3. Is cardiac rhythm (heart rate and QT variability) altered in breast cancer patients receiving SAT?
4. Is oxygen transport and oxygen uptake into tissue altered in breast cancer patients receiving SAT?
5. Does a patient's baseline physical activity, fitness and body composition affect their susceptibilities to treatment-induced cardio-respiratory problems?
6. Does a patient's physical activity, physical fitness and body composition change appreciably during SAT in these patients?

CARdiac Function Evaluation in Breast Cancer Patients

Longitudinal Characterisation of Cardiac Function in Recently-diagnosed Breast Cancer Patients

Cardiac function during/following treatment in breast cancer patients.

Cardiac rhythm during/following treatment in breast cancer patients.

Physical activity level during/following treatment in breast cancer patients.

Cardiorespiratory function during/following treatment in breast cancer patients.

Body fat mass and fat-free mass, and bone mineral density

Abertawe Bro Morgannwg University Health Board

Swansea University

The intervention group will follow a physical exercise and lifestyle counselling program.

the intervention group will follow a physical exercise and health counselling intervention--see below.

The exercise program will be performed in the hospital gymnasium (3 supervised sessions/week of aerobic and muscle strength exercises) or in the patients' room (during phases of treatment-induced immunodepression, where isolation is needed to prevent infections). It will also include specific training of the respiratory ('inspiratory') muscles (e.g., diaphragm) on 5 days/week. The counselling program will include psychological (once weekly), nutritional (twice monthly), support (with survivors of adolescent cancer, twice/month) and educational (for relatives/caregivers, once monthly) sessions.

lifestyle and physical exercise

Alejandro Lucia

The investigators will study the effects of an inhospital exercise intervention combined with lifestyle--including diet--counselling along the duration of treatment (neoadjuvant \[solid tumours\]/intense chemotherapy \[leukemias\], expected median duration 5-6 months) on several health-related variables. Participants will be recruited from 3 hospitals in Madrid (Spain). Inclusion criteria: male/female aged 12-19 years, newly diagnosed with a malignant extracranial tumour; not having received any type of therapy--except surgery--at the time of diagnosis; adequate health status (Karnofsky/Eastern Cooperative Oncology Group scale score ≥50/2); to understand Spanish language and to provide written informed consent. The investigators will recruit ≥136 participants and conduct a randomised controlled trial. In addition to usual care, the control group will be informed of the benefits of a healthy lifestyle. The intervention group will follow a physical exercise and lifestyle counselling program. The exercise intervention will be performed in the hospital gymnasium, except for neutropenic phases--during which time sessions will be performed in the patients' ward--and will also include inspiratory muscle training). Health counselling will include a psychological intervention based on motivational interviewing techniques, guidance by a nutritionist, and support sessions with survivors who will share their experiences with the study participants. The following outcomes will be assessed at baseline (diagnosis), end of treatment, and at 3-month follow-up in all participants: echocardiography-determined left ventricular function (primary outcome); and blood pressure, blood lipids, body composition, physical activity levels, energy intake, cardiorespiratory fitness, muscle strength, functional mobility, health-related quality of life, cancer-related fatigue, stress coping, anxiety, depression, clinical variables, and potential biological underpinnings of exercise multisystemic benefits (metabolic and inflammatory \[cytokine panel\] markers, plasma proteome, gut microbiome, and immune function).

Background. Health promotion interventions are needed during adolescent cancer treatment to facilitate the acquisition of good health practices as patients transition to survivorship. Although meta-analytical evidence supports the health benefits of exercise in the context of childhood cancer, there is scant data focusing solely on adolescents.

Hypothesis and objectives. The investigators hypothesise that an inhospital exercise intervention combined with lifestyle counselling during treatment for adolescent cancer will provide several health benefits, particularly related to the cardiometabolic profile. Thus, the investigators will study the effects of an inhospital exercise intervention combined with lifestyle--including diet--counselling along the duration of treatment (neoadjuvant \[solid tumours\]/intense chemotherapy \[leukaemias\], expected median duration 5-6 months) on several health-related variables.

Setting and Methods. Participants will be recruited from 3 hospitals in Madrid (Spain). Inclusion criteria: male/female aged 12-19 years, newly diagnosed with a malignant extracranial tumour; not having received any type of therapy--except surgery--at the time of diagnosis; adequate health status (Karnofsky/Eastern Cooperative Oncology Group scale score ≥50/2); to understand Spanish language and to provide written informed consent. The investigators will recruit ≥136 participants and conduct a randomised controlled trial (1:1 ratio randomisation with a block on gender and tumour type \[leukaemias/lymphomas\]). In addition to usual care, the control group will be informed of the benefits of a healthy lifestyle. The intervention group will follow a physical exercise and lifestyle counselling program. The exercise intervention will be performed in the hospital gymnasium (3 sessions/week of aerobic and resistance exercises), except for neutropenic phases--during which time sessions will be performed in the patients' ward--and will also include inspiratory muscle training (5 days/week). Health counselling will include a psychological intervention (1 session/week) based on motivational interviewing techniques, guidance by a nutritionist (2 sessions/month), and support sessions (1/month) with survivors (≥5-year survivorship) who will share their experiences with the study participants. The following outcomes will be assessed at baseline (diagnosis), end of treatment, and at 3-month follow-up in all participants: echocardiographydetermined left ventricular function (primary outcome); and blood pressure, blood lipids, dual-energy X-ray absorptiometry-determined body composition (fat \[including visceral adipose tissue\]/lean mass, bone mineral content/density), accelerometry-determined physical activity, dietary recall determined energy intake, cardiorespiratory fitness, muscle strength, functional mobility, health-related quality of life, cancer-related fatigue, stress coping, anxiety, depression, clinical variables (survival, treatment tolerability, hospitalisation length, infections), and potential biological underpinnings of exercise multisystemic benefits (metabolic \[glucose homeostasis indicators, high-sensitivity C-reactive protein\] and inflammatory \[cytokine panel\] markers, plasma proteome, gut microbiome, and immune function \[lymphocyte subpopulations, natural killer cell cytotoxicity\]) (secondary outcomes).

The investigators will apply a two-arm RCT design, following the Consolidated Standards of Reporting Trials recommendations (1:1 randomisation ratio using a computer-generated random allocation sequence with a block on gender and main tumour type \[leukaemias/solid tumours\])

Assessment staff will be blinded to participant randomisation assignment. Yet, because of the nature of the study, it will not be possible to conceal the group assignment from the staff (i.e., fitness specialists, psycho-oncologists and nutritionists) involved in the different intervention (physical exercise and health counselling) sessions. Participants will be explicitly informed on the group to which they will be assigned as well as on the study hypotheses and will be reminded not to discuss their randomisation assignments with assessment staff and/or other patient.

Exercise and Lifestyle in Adolescent Cancer (HEALTHYADOL)

Exercise and Lifestyle Intervention for Patients With Adolescent Cancer: a Randomised Controlled Trial (HEALTHY ADOL)

Echocardiography-determined LV ejection fraction (unit = %)

Echocardiography-determined LV fractional shortening (unit = %)

Arterial blood pressure (BP) (ausculatory method) (units = mmHg)

Total/HDL/LDL-cholesterol will be quantified with an automated chemistry analyser (units = mg/dL).

Tiglycerides will be quantified with an automated chemistry analyser (units = mg/dL).

DXA-determined total lean and fat mass (grams)

DXA-determined bone mineral density (unit = g/m2)

PA levels (moderate/vigorous PA) determined using triaxial accelerometry (units =minutes/week)

PA levels (moderate/vigorous PA) determined using triaxial accelerometry (units = minutes/week)

3-day 24 h-dietary recalls to record the participants' energy intake by either themselves or parents/caregivers.

3-day, 24 h-dietary recalls will be used to record the participants' energy intake by either themselves or parents/caregivers. The investigators will provide participants with instructions on how to obtain a correct food record. Dietary recall data will be analysed using Dietsource 3.0 (Novartis) to determine total energy intake (kcal)

3-day 24 h-dietary recalls to record the participants' energy intake by either themselves or parents/caregivers.

3-day, 24 h-dietary recalls will be used to record the participants' energy intake by either themselves or parents/caregivers. The participants will provide participants with instructions on how to obtain a correct food record. Dietary recall data will be analysed using Dietsource 3.0 (Novartis) to determine protein, fat, carbohydrate, and fiber intake (g/day)

VO2peak will be determined with 'breath-by breath' analysis of expired gases on a metabolic cart using a ramp-like treadmill--or arm-crank ergometer--test (units = mL/kg/min)

The 5-repetition maximum (commonly abbreviated as 5RM), which is the maximum strength capacity to perform 5 repetitions until momentary muscular exhaustion, will be measured for leg press and bench press (units = kg).

PImax (units = cmH20) will be determined using a mouth pressure meter with the best result from 3 attempts (interspersed with rest periods of ≥1 min-duration) taken.

Health-related QoL (HRQoL) (Paediatric Quality of Life Inventory \[PedsQL\] 3.0 Cancer Module, designed to measure paediatric/adolescent cancer specific HRQoL) (0 to 100 scale, with higher scores indicating better HRQoL)

Health-related QoL (HRQoL) (Paediatric Quality of Life Inventory \[abbreviated as PedsQL\] 3.0 Cancer Module, designed to measure paediatric/adolescent cancer specific HRQoL) (0 to 100 scale, with higher scores indicating better HRQoL)

Cancer-related fatigue (Paediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale) (0 to 100 score, higher scores meaning higher fatigue)

Cancer-related fatigue (Paediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale) (0 to 100 score, higher scores meaning higher fatigue

Stress coping (General form of the Adolescent Coping Scale) (0 to 20 scale, with higher scores indicating higher resilience to stress)

Anxiety (six-item short-form of the state scale of the Spielberger State-Trait Anxiety Inventory \[abbbreviated as STAI\]) (0 to 100 score, with higher scores reflecting higher anxiety levels)

Anxiety (six-item short-form of the state scale of the Spielberger State-Trait Anxiety Inventory \[abbreviated as STAI\]) (0 to 100 score, with higher scores reflecting higher anxiety levels)

Depression (Child Depression Scale) (0 to 52 scale, with higher scores reflecting more depression)

Survival (numebr of days from diagnosis to the end of the study or death)

Survival (number of days from diagnosis to the end of the study or death)

Treatment tolerability (number of days of treatment interruption/delay

Total hospitalisation length (number of days)

Common Toxicity Criteria for Adverse Events \[CTCAE, global score, 1 (low toxicity) to 5 (highest\])

Homeostasis model assessment-insulin resistance index (HOMA-IR) (molar units)

Panel of 21 cytokines/chemokines measured in serum using Luminex® (all assessed in the same units, micrograms/dL)

The investigators will use liquid chromatography coupled to tandem-mass spectrometry (LC-MS/MS) to measure levels in blood of thousands of proteins

Universidad Europea de Madrid

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Testicular Neoplasms

Seminoma

Germinoma

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Endocrine Gland Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Male Urogenital Diseases

Endocrine System Diseases

Testicular Diseases

Gonadal Disorders

Testicular Seminoma

Central Nervous System Germinoma

Testicular cancer patients who have received surgery and are scheduled for surveillance

Testicular cancer patients who have received surgery and are scheduled for chemotherapy

Mark Haykowsky, PhD

For many years, researchers and doctors have studied different kinds of treatments to improve the survival of men with testicular cancer. However, recent research has shown that many years later, men who had testicular cancer appear to be at higher risk for developing heart disease (heart attack or heart failure), especially if they received chemotherapy. Since these studies were done many years after men received treatment, there was no way to know if other factors contributed to the health problems they experienced. This study is being done because it would be helpful to study heart function and cardiovascular disease risk factors of men who have been diagnosed with testicular cancer, before and after they receive chemotherapy treatment compared to men who receive treatment with surgery alone.

The aim of this pilot study is to examine global and regional LV systolic and diastolic function, cardiac output, cardiac reserve, VO2peak and CVD risk profile in males recently diagnosed with testicular cancer treated with surgery alone or surgery and chemotherapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Exercise to Prevent AnthraCycline-based Cardio-Toxicity Study 2.0 (EXACT2)	NCT03748550	Cancer, Breast Cardiotoxicity Cardiovascular ...	Aerobic exercis...	18 Years -	Nova Scotia Health Authority
Effect of Anthracyclines and Cyclophosphamide on Cardiovascular Responses	NCT04568161	Cardiotoxicity Cardiovascular ... Neurovascular D... Endothelial Dis... Breast Cancer	Physical Charac... Muscular Sympat... Cardiac Functio... Heart rate Blood pressure Blood Assessmen... Muscle blood fl... Endothelium-dep... Vascular intima... Physical Capaci... Anthracycline &...	45 Years - 60 Years	University of Sao Paulo General Hospital
Exercise to Prevent AnthraCycline-based Cardio-Toxicity Study 2.0 (EXACT2)	NCT03748550	Cancer, Breast Cardiotoxicity Cardiovascular ...	Aerobic exercis...	18 Years -	Nova Scotia Health Authority
Biomarkers and Cardiac MRI as Early Indicators of Cardiac Exposure Following Breast Radiotherapy	NCT02496260	Breast Cancer	Research Cardia... Biomarkers	18 Years -	Henry Ford Health System
Cardiovascular Function in Adult Survivors of Childhood Malignancies	NCT01415999	Childhood Cance...		18 Years - 35 Years	The University of Hong Kong
Cardiovascular Function in Adult Survivors of Childhood Malignancies	NCT01415999	Childhood Cance...		18 Years - 35 Years	The University of Hong Kong
Effect of Anthracyclines and Cyclophosphamide on Cardiovascular Responses	NCT04568161	Cardiotoxicity Cardiovascular ... Neurovascular D... Endothelial Dis... Breast Cancer	Physical Charac... Muscular Sympat... Cardiac Functio... Heart rate Blood pressure Blood Assessmen... Muscle blood fl... Endothelium-dep... Vascular intima... Physical Capaci... Anthracycline &...	45 Years - 60 Years	University of Sao Paulo General Hospital
CARdiac Function Evaluation in Breast Cancer Patients	NCT03266809	Breast Cancer F...		18 Years -	Swansea University
Exercise and Lifestyle in Adolescent Cancer (HEALTHYADOL)	NCT05539794	Adolescent Canc...	lifestyle and p...	12 Years - 19 Years	Universidad Europea de Madrid
Cardiac Function and Cardiovascular Risk Profile in Testicular Cancer Patients	NCT00705094	Testicular Canc... Seminoma Non-seminomatou...		18 Years -	AHS Cancer Control Alberta

Spots Global Cancer Trial Database for cardiac function