Heart and Blood Diseases

All Conditions

Symptoms and General Pathology

Substance Related Disorders

Wounds and Injuries

Heart Failure

Heart Diseases

Ventricular Dysfunction, Left

Cardiotoxicity

Ventricular Dysfunction

Micronutrients

All Drugs and Chemicals

Bone Density Conservation Agents

Hematinics

Vitamins

Iron

Vitamin D

Cholecalciferol

Folic Acid

Liver Extracts

Vitamin B Complex

Vitamin B 12

Hydroxocobalamin

Folinic Acid

Vitamin D3

Calciferol

Folate

Vitamin B9

Vitamin B12

Cobalamin

Cyanocobalamin

All pediatric cancer survivors are evaluated with cardiological examination, ECG, transthoracic echocardiography (transesophageal echocardiography when required), NT-proBNP, cTnI, kidney function tests, liver function tests, fasting blood glucose, cholesterol panel, iron, iron binding capacity, ferritin, transferrin saturation, B12, vitamin D, folic acid, urinanalysis, hemogram and a questionnaire about living with heart failure.

ECG, Echocardiography, cTnI, NT-ProBNP

Cafer Zorkun, MD PhD

The goal of this observational study is to evaluate cardiac and vascular health status of pediatric cancer survivors.

All pediatric cancer survivors were evaluated with cardiological examination, ECG, transthoracic echocardiography (transesophageal echocardiography when required), NT-proBNP, cTnI, kidney function tests, liver function tests, fasting blood glucose, cholesterol panel, iron, iron binding capacity, ferritin, transferrin saturation, B12, vitamin D, folic acid, urinanalysis, hemogram and a questionnaire about living with heart failure.

Cardiovascular Assessment of Pediatric Cancer Survivors

Cardiovascular Assessment of Pediatric Cancer Survivors: Understanding Long-Term Effects and Risks

Sharing study data in a public place, requires additional (written) permission from all participants, and then from local IRB.

Echocardiographic evaluation of left ventricular functions

Istanbul University

Head, Division of CardioOncology

Neoplasms

Skin and Connective Tissue Diseases

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Breast Neoplasms

Lymphoma

Breast Diseases

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Skin Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Lymphosarcoma

Patients completing the exercise training concurrent to anthracycline chemotherapy treatment during months 1 to 3

Patients will be encouraged to continue with their regular physical activity routine and will be medically managed as per standard of care by their Cardiologist and Oncologists.

Participants from the experimental study arm are assigned to a 12-week exercise training programme integrated in a multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun, or Bürgerspital Solothurn. The exercise programme will comprise 2 weekly exercise sessions lasting 90 min, supervised by experienced exercise therapists. The sessions start with approximately 40 min cycling on an ergometer at moderate intensity, increasing on a weekly basis if possible. After the cycling training, patients continue the exercise session with 40 min of strength training, stretching, relaxation, coordination and balance training. In addition, patients will be instructed to perform at least one additional endurance-related activity per week in their own time with a duration of 30-60 min at moderate intensity levels (e.g. walking, bicycling).

Exercise Training

Matthias Wilhelm, Prof. Dr.

Breast cancer is the most common cancer among women worldwide. Similarly, Hodgkin and non- Hodgkin lymphomas make up two of the most prevalent cancers in men and women. Even though remarkable improvements in cancer-free survival have been achieved in the last decades, the development of cardiac toxicity, associated with anthracycline-based chemotherapy (Anth-bC) counteracts the improvements in survival in these patient groups. One of the first clinical manifestation of Anth-bC cardiotoxicity is diastolic dysfunction, with further symptoms being left ventricular dysfunction and heart failure as well as a decline in exercise tolerance. Besides the direct cardiotoxic effects of anticancer treatment, many drugs also have adverse effects on the vascular endothelium.

The concept of 'Exercise is Medicine' has become well established in exercise-oncology research. Exercise therapy is now considered a safe and well-tolerated adjunct therapy inducing beneficial effects on body composition, aerobic fitness and muscular strength, pain and fatigue, quality of life (QoL), depressive symptoms, and all cause survival. However, there is insufficient data on the superiority of performing exercise training therapy before and during chemotherapy with regard to cardiotoxic and cardiovascular side effects. Further, there is no data on patient preference for and barriers toward different timings of exercise training therapy.

Therefore, the aim of the study is to compare left ventricular (LV) function measured by LV global longitudinal strain (GLS) in breast cancer and lymphoma patients undergoing Anth-bC randomised to completing an exercise-based rehabilitation programme during chemotherapy to those randomised to complete the programme after chemotherapy. Further, blood samples will be drawn to analyse biomarkers of myocardial injury (brain natriuretic peptide and high-sensitive cardiac troponin).

Additional measurements include aortic distensibility as part of the echocardiographic examination and exercise capacity through cardiopulmonary exercise testing. QoL and fatigue will be assessed in a questionnaire, compliance with exercise training through monitoring and patient preference at 3 and 6 months will be evaluated through an interview. Cardiovascular risk factors will be assessed through body composition, 24h ambulatory blood pressure monitoring, 24h electrocardiogram and the analysis of established blood markers.

Women and men aged 18 years and older with histologically confirmed breast cancer or lymphoma (ECOG grade 0-2) who are Anth-bC naïve and with reasonable life expectancy will be included in the study.

The exercise programme is part of onco-rehabilitation programmes at the Inselspital Bern, the Spital AG Thun and the Bürgerspital Solothurn. Programmes last for 12 weeks and offer two supervised sessions per week (@ 60-90 min). They usually contain an endurance component (e.g. 40 min of cycling) and a strength, agility or relaxation component. Patients are encouraged to complete a third exercise session per week at home or elsewhere. Home-based training and general physical activity will be assessed by a questionnaire and an activity monitor.

A total of 120 patients will be recruited. Measurements will be performed at baseline, after 3 months (week 13) and after 6 months (week 26).

Study Design: A single-center, two-arm, parallel group with standard of care controlled trial with a balanced 1:1 randomization will be conducted at University Hospital Inselspital, Berne, Switzerland. A total of 120 women (60 participants per study arm) who are scheduled for first- line Anthracycline based chemotherapy (Anth-bc) presenting either at the Inselspital or Lindenhofspital Berne, the Spital AG Thun or the Bürgerspital Solothurn will be enrolled. After baseline assessments, eligible participants will be randomized to one of two arms including the exercise rehabilitation programme during chemotherapy or the control group (exercise training intervention after conclusion of chemotherapy).

Patient Population: Women and men aged 18 years and older with histologically confirmed breast cancer or lymphoma who are Anth-bC naïve and are scheduled for first-line Anth-bC, Eastern Cooperative Oncology Group (ECOG) grade 0-2, curative or palliative approach with reasonable life expectancy and a willingness to attend exercise sessions twice per week for 12 weeks (24 sessions in total).

Procedures: The following measurements will be collected at the beginning (T0), following the 12 week intervention (T1) and after another 12 weeks (T2). Participants will also be expected to attend two weekly supervised exercise sessions integrated in a multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun, and Bürgerspital Solothurn, and will be expected to complete one additional exercise training session at home or in the community each week.

T0: All participants will undergo baseline assessments at the University Hospital Inselspital, Berne. This includes cardiac assessment by a skilled clinical cardiac sonographer to obtain left ventricular (LV) global longitudinal strain (GLS) and aortic distensibility. Further, cardiopulmonary exercise testing (CPET) will be completed on a cycle ergometer to obtain VO2peak and to calculate corresponding training zones. Standard measures conducted during the intake process including height, weight, body composition (assessed by bio-impedance- measurement) and waist circumference will also be collected. Blood samples will be obtained from each participant and analyzed for biomarkers of myocardial injury as well as lipid profile and HbA1C. Following each visit, twenty-four-hour ambulatory blood pressure monitoring and 24h Holter ECG will be performed. The questionnaires for physical activity patterns (GPAQ) and fatigue (FACIT-F), a health history questionnaire and the activity tracking devices will also be administered by the research coordinator upon their initial visit.

T1: All measurements from T0 will be repeated. Additionally, patients from the ExEarly (experimental) group will be interviewed by the study coordinator to assess barriers for missed exercise sessions. Simultaneously, patients from the ExStandard group will be asked to anticipate barriers which may impede their participation in regular exercise training during the next 12 weeks. It will further be assessed whether it would have been feasible for them to complete the exercise programme concurrently to chemotherapy.

T2: All measurements from T0 will be repeated. Additionally, patients from the ExStandard (active comparator) group will be interviewed by the study coordinator to assess barriers for missed exercise sessions. Simultaneously, patients from the ExEarly group will be asked to indicate their preferred time point for the completion of the exercise programme.

Throughout the programme: Information regarding adherence to the exercise programme will also be collected by the research coordinator each month via the exercise training diaries and activity tracking devices from each participant. The study coordinator will also assess reasons for missed exercise sessions. Lastly, chemotherapy adherence will be assessed by dose adjustments in percent of the intended dose and reason for adjustment.

Intervention (ExEarly): The 12-week exercise training programme will be integrated in a multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun, and Bürgerspital Solothurn. The exercise programme will comprise 2 weekly exercise sessions lasting 90 min, supervised by experienced exercise therapists. The sessions start with approximately 40 min cycling on an ergometer at moderate intensity, increasing on a weekly basis if possible. After the cycling training, patients continue the exercise session with 40 min of strength training, stretching, relaxation, coordination and balance training. In addition, patients will be instructed to perform at least one additional endurance-related activity per week in their own time with a duration of 30-60 min at moderate intensity levels (e.g. walking, bicycling). In the ExEarly group, patients start in the week preceding the first dose of Anth-bC. They perform exercise training therapy for 12 weeks during which they will normally have 4 cycles of Anth-bC.

Control Group (ExStandard): Participants who are randomized to the control group will undergo baseline and follow up assessments at 13 and 26 weeks. They will be encouraged to continue with their regular physical activity routine and will be medically managed as per standard of care by their Cardiologist and Oncologists. All participants will also complete the GPAQ Questionnaire to determine if there are potential increases in physical activity in the exercise and control group, which may account for changes in all outcome measures. 1-4 weeks after completion of their last dose of Anth-bc the participants will commence exercise training. All participants in both groups will also be asked to wear an activity-tracking device, namely a step counter (Fitbit Zip) during the intervention and control period (25 weeks) to objectively quantify their daily physical activity.

Randomization: Randomization will occur at the central site, the University Hospital, Inselspital Berne, using minimisation based on strata recruiting center, age, therapy (adjuvant/ neoadjuvant), Global Longitudinal Strain (GLS), HER2 status and metastases, with an allocation ratio of 1:1.

Blinding: The participants will not be blinded to their intervention arm. Assessors of outcome data and analysis will be blinded to the study arm.

Analytical Plan: The primary outcome, change in global longitudinal strain (GLS) from before Anth-bC to immediately after Anth-bC (T1 vs T0), will be compared between the two groups (ExEarly and ExStandard) by independent one-sided t-test (or Wilcoxon two-sample test as appropriate) with alpha set at 0.05. Values from baseline (before Anth-bC, T0), completion of Anth-bC (week 13, T1), and follow-up (T2) will be compared between groups using ANCOVA with repeated measures (or mixed models in case of missing data) including baseline values as covariate and post-hoc testing for different time points. Intention-to-treat (ITT) analysis will be performed with group allocation according to randomization to assess the effectiveness of ExEarly in the clinical setting. Per-protocol analysis will be performed with patients allocated with regard to time period they completed more supervised sessions in, with a minimum requirement of 15 of the 24 (60%) scheduled training sessions within one or the other time period to assess the potential effects of an optimal training. Linear models will be performed to find independent baseline parameters to predict negative outcome of cardiac function (LV GLS, NT-proBNP, hsTnT). Secondary endpoints will be analysed accordingly. Statistical analyses will be performed using the software R (Version 3.3.1, R Core Team, 2016).

Significance: Outcomes from this project will improve long term care of patients with early breast cancer and lymphoma as well as other cancers, such that patients can be offered the possibility of active involvement towards mitigating undesirable side effects of a very effective cancer treatment. The assessment of barriers to training therapy may help to adapt the offered physical training programmes to reduce these barriers.

Randomised, controlled; parallel arm design.

Assessors of outcome data and analysis will be blinded to the intervention arm.

Cancer Adverse Effects PReventIon With Care & Exercise: the CAPRICE Study

Importance of Exercise Training Therapy Timing With Regard to Cardiotoxicity and Patient Preference in Early Breast Cancer and Lymphoma Patients Undergoing Adjuvant Chemotherapy

Upon request, de-identified individual participant data for research purposes will be made available as far as legally permissible.

GLS assessed by speckle tracking echocardiography is an established marker for LV systolic function with a good reproducibility, which has also been found in the investigators' laboratory. In breast cancer and lymphoma patients LV global longitudinal strain is an established measure to assess cardiotoxicity of Anth-bC.

Blood samples will be collected to determine concentration of Brain Natriuretic Peptide (NT- proBNP) and high- sensitive cardiac Troponin (hsTnT). Cardiac troponin release after high-dose chemotherapy is a marker for chemotherapy-induced cardiotoxicity in cancer patients and identifies patients at different risks of cardiac events in the years thereafter. The increment of hs-TnT has been found to be predictive for cardiotoxicity in breast cancer patients at 3 months after initiation of Anth-bC. Both, NT-proBNP and hs-TnT have been recommended as early biomarkers of cardiotoxicity by the European Society of Cardiology in the guidelines on cancer treatments and cardiovascular toxicity.

Barriers toward exercise training therapy will be identified by a self-designed questionnaire.

Number of attended center-based sessions will be monitored by the attending physiotherapists. Additional home-based training and general physical activity will be assessed by the GPAQ- questionnaire. It collects information on physical activity participation in three domains (work, transport and recreational activities) as well as sedentary behaviour, comprising 16 questions (P1-P16). Within the work and discretionary domains, questions assess the frequency and duration of activity defined by the energy requirement or intensity (vigorous- or moderate-intensity). In the transport domain, the frequency and duration of all walking and cycling for transport is captured. The main outcome variables from GPAQ analysis include a categorical variable of total physical activity (high, moderate and low) and a continuous variable of total physical activity within each domain (reported as Median METmin/week), which will be used to quantify the volume of weekly physical activity.

The FACIT-F (version 4.0) is a 41-item compilation of general questions divided into four domains of cancer-specific quality of life (physical well-being ranging from 0-28, social/family well-being ranging from 0-28, emotional well-being ranging from 0-24 and functional well-being ranging from 0-28) and a module for fatigue (13 items, ranging from 0- 52).FACIT-F total score ranges from 0- 160. It is considered appropriate to use in patients with any form of cancer. This questionnaire has been validated and used extensively, including reference data for clinically meaningful changes. Change in fatigue will be tested as primary quality of life endpoint.

Vascular function will be assessed by distensibility of the ascending aorta measured on the echocardiography. This is an established measure of arterial stiffness and has recently been shown to decrease from before to after Anth-bC in women with breast cancer. Increased arterial stiffness has been proposed to increase LV afterload, which may lead to LV hypertrophy and in its worst case LV failure.

Cardiopulmonary exercise testing (CPET) will be performed on a cycle ergometer according to the recommendations of the American Heart Association. VO2peak has been found to be reduced after chemotherapy. It is an established marker for physical function and survival.

It has been suggested that the presence of cardiovascular risk factors increase the risk of developing Anth-bC associated cardiac dysfunction. Twenty-four-hour ambulatory blood pressure monitoring will be performed using validated recorders (Spacelabs model 90217, USA) during usual daily activities. Lipid profile and HbA1C will be determined from blood samples. Body composition will be measured by bio-impedance measurement (InBody 720, Biospace Co., Seoul, Korea) and smoking status will be assessed. Also, a 24-hour Holter electrocardiogram will be performed. Both 24-hour monitors will be worn after each visit on two separate days.

Spital STS AG

Bürgerspital Solothurn

Lindenhofspital

University of Bern

Insel Gruppe AG, University Hospital Bern

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Antihypertensive Agents

Vasodilator Agents

Nebivolol

Adrenergic Agents

Adrenergic beta-Agonists

Adrenergic Agonists

Neurotransmitter Agents

nebivolol, capsule, 5 mg once daily, for 12 months

placebo, capsule, once daily, for 12 months

Nebivolol, capsule, 5 mg once daily, for 12 months

Placebo, capsule, once daily, for 12 months

Placebo

Gianluigi Condorelli, MD,PhD,Prof

Giulio G Stefanini, MD,PhD,Prof

Carmelo Carlo-Stella, MD,Prof

As the cancer-related prognosis improves thanks to recent advances in cancer-targeted therapies, the prognostic burden of chemotherapy-related complications - including cardiotoxicity - is increasingly recognised. So far, the evidence supporting pharmacological preventive strategies in cardio-oncology has been inconsistent and conflicting, and there is a clear need for well-designed trials with novel interventions. In this study, by using cardiac magnetic resonance, the investigators want to assess if a commonly used beta-blocker with a unique pharmacological profile, i.e. nebivolol, can prevent cardiac dysfunction in patients with breast cancer or diffuse large B-cell lymphoma undergoing chemotherapy with anthracyclines.

During the last decades, major efforts have been made in the field of cancer therapy to improve prognosis and quality of life of patients treated with any sort of chemotherapy. Cardiotoxicity represents one of the most relevant adverse effects of chemotherapy, primarily in patients treated with anthracyclines. The potential protective role of cardiovascular medications in the prevention of cardiotoxicity associated with anthracyclines chemotherapy is still a matter of debate since evidence in this field are scarce and largely inconclusive. Indeed, prior studies were often limited by a non-blinded design or an echocardiography-based assessment of left ventricular ejection fraction (with a relevant inter and intra-operator variability). The primary objective of the trial is to evaluate the cardioprotective effects of the betablocker nebivolol in an individually randomized, parallel, placebo-controlled, double-blinded (patient, treating physician, investigator, outcomes assessor, statistician), superiority trial in patients with a solid tumor (i.e., breast cancer) or a hematologic malignancy (i.e., diffuse large B cell lymphoma) who have a normal cardiac function as assessed by echocardiography and will receive anthracyclines as part of their first-line chemotherapy program. Indeed, recent evidence suggests that anthracycline cardiotoxicity seems mainly due to an anthracycline-induced dysregulation of mitochondrial activity and metabolism in cardiomyocytes. Nebivolol has a distinctive profile among beta-blockers, with the unique power of increasing the nitric oxide bioavailability. Nebivolol-induced nitric oxide release has shown favourable effects in terms of antioxidant activity, cardiac neo-angiogenesis, mitochondrial and endothelial protection. On this basis, the individually randomized, parallel, placebo-controlled, double-blinded (patient, treating physician, investigator, outcomes assessor, statistician), superiority CONTROL trial will assess the cardioprotective effects of a commonly used betablocker (nebivolol) in patients with baseline normal left ventricular systolic function receiving anthracycline chemotherapy as first-line chemotherapy for breast cancer or diffuse large B-cell lymphoma. The assessment of left ventricular ejection fraction and related endpoints will be performed with cardiac magnetic resonance.

Participants are randomized 1:1 to two groups in parallel for the duration of the study

Patients, treating physicians, investigators, and outcome assessors are masked to the allocated treatment.

Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines

Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines (CONTROL Trial)

The primary endpoint is defined as Left Ventricular Ejection Fraction (LVEF) reduction (unit of measurement: %) assessed by Cardiac Magnetic Resonance at 12 months of follow-up.

LVEF reduction is defined as the difference between LVEF at baseline and LVEF at 12 months follow-up (LVEF reduction = Baseline LVEF - 12 months LVEF).

Left ventricular ejection fraction (unit of measurement: %) assessed by Cardiac Magnetic Resonance at 12-month follow-up.

Myocardial fibrosis assessed by Cardiac Magnetic Resonance with T1-mapping sequences and with Late Gadolinium Enhancement images.

Myocardial edema assessed by Cardiac Magnetic Resonance with T2 sequences.

Right ventricular ejection fraction (unit of measurement: %) assessed by Cardiac Magnetic Resonance

Left ventricular end-diastolic volume (unit of measurement: ml) assessed by Cardiac Magnetic Resonance

Left ventricular end-systolic volume (unit of measurement: ml) assessed by Cardiac Magnetic Resonance

Left ventricular mass (unit of measurement: g/m²) assessed by Cardiac Magnetic Resonance

Left ventricular ejection fraction (unit of measurement: %) assessed by Echocardiography

Left ventricular diastolic function assessed by Echocardiography according to Guidelines of European Association of Cardiovascular Imaging / American Society of Echocardiography

Right ventricular systolic function assessed by Echocardiography according to Guidelines of European Association of Cardiovascular Imaging / American Society of Echocardiography

Left ventricular end-diastolic volume (unit of measurement: ml) assessed by Echocardiography

Left ventricular end-systolic volume (unit of measurement: ml) assessed by Echocardiography

Serum high-sensitivity cardiac troponin I levels (unit of measurement: ng/L)

Serum B-type natriuretic peptide (BNP) (unit of measurement: pg/mL)

Serum N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP) levels (unit of measurement: pg/mL)

Cardiovascular mortality or death will be defined as any death due to immediate cardiovascular cause (e.g. myocardial infarction, low-output failure, arrhythmia). Unwitnessed death and death of unknown cause will be classified as cardiac death.

Myocardial infarction will be defined according to the 3rd Universal Definition.

Cerebrovascular events will be defined as follows:

* Transient ischemic attack: rapidly developed clinical signs of global disturbance of cerebral function lasting fewer \<24 hours, regardless of the presence of an acute clinically relevant brain lesion in imaging.
* Ischemic stroke: rapidly developed clinical signs of focal or global disturbance of cerebral function lasting \>24 hours with imaging of an acute clinically relevant brain lesion.
* Intracerebral haemorrhage: diagnosis must be confirmed by cerebral imaging.

Hospitalization for heart failure will be defined as any unplanned hospital readmission due to signs and symptoms of heart failure.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cardiovascular Assessment of Pediatric Cancer Survivors	NCT05939089	Left Ventricula... Heart Failure	ECG, Echocardio...	18 Years -	Istanbul University
Cancer Adverse Effects PReventIon With Care & Exercise: the CAPRICE Study	NCT03850171	Breast Neoplasm... Lymphoma Cardiotoxicity Anthracyclines Physical Activi...	Exercise Traini...	18 Years -	Insel Gruppe AG, University Hospital Bern
Cardiovascular Assessment of Pediatric Cancer Survivors	NCT05939089	Left Ventricula... Heart Failure	ECG, Echocardio...	18 Years -	Istanbul University
Cardioprotective Effects of Nebivolol Versus Placebo in Patients Undergoing Chemotherapy With Anthracyclines	NCT05728632	Breast Cancer Lymphoma, Large... Cardiotoxicity Left Ventricula... Chemotherapy Ef...	Nebivolol Placebo	18 Years -	Humanitas Hospital, Italy

Spots Global Cancer Trial Database for left ventricular dysfunction