Heart and Blood Diseases

All Conditions

Symptoms and General Pathology

Substance Related Disorders

Wounds and Injuries

Heart Failure

Cardiotoxicity

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Radiation Injuries

Central Nervous System Depressants

All Drugs and Chemicals

Other Dietary Supplements

Benzocaine

Tannic Acid

CORE consists of exercise therapy, CVD risk factor management, and behavioural support for 3 months.

Exercise therapy: Staff will prescribe and deliver a standardized, yet individually tailored (based on CPET results), aerobic exercise programs consisting of two days of supervised, facility- and home-based high-intensity interval training (HIIT) and one day of supervised home-based moderate-intensity continuous training (MICT) per week. Exercise HRs and durations will be monitored using an accurate commercially available wrist-worn HR monitor and PA tracker.

CVD risk factor management: CVD risk factors will be assessed and treated according to Canadian guidelines.

Behavioural support: All participants will receive a planned sequence of educational and instructional material via email and ongoing PAYA-CS tailored education and peer support during the follow-up period using a peer support online system.

The Support group will receive the behavioural support only. The timing and nature of all education, information provided to Support participants will be identical to what is provided to CORE participants. All Support participants will receive the same wrist-worn HR monitor and PA tracker as the CORE participants and will be given the challenge of meeting and maintaining the updated PA guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

Exercise therapy, CVD risk factor management for the first 6 months (as per current standards in CR models) and behavioural support for the entire 2-year intervention period

Cardio-oncology Rehabilitation (CORE)

Behavioural support via professionals and peer support and recommended physical activity guidelines for cancer survivors, to encourage physical activity.

Support

Cardiovascular disease (CVD) is a major contributor to morbidity and mortality in pediatric, adolescent and young adult (AYA) cancer survivors (hereafter referred to as PAYA-CS). Exercise is a cornerstone of CVD prevention and treatment; yet, exercise has not been adopted as a standard of care in PAYA-CS at high CVD risk. The HIMALAYAS trial is designed to evaluate the feasibility and preliminary impact of an exercise-based CR on cardiovascular (CV) and psychosocial health, as well as CVD risk, in PAYA-CS with mild heart dysfunction (stage B heart failure (SBHF)). The primary objective of the HIMALAYAS pilot study is to assess the feasibility of a two-phase randomized controlled trial designed to evaluate impact of a 'CR-like' cardio-oncology rehabilitation (CORE) intervention on CV, psychosocial, and behavioural outcomes at 6 and 24 months, compared to behavioural support only (Support) in PAYA-CS. Screened PAYA-CS without SBHF and those with SBHF who do not participate in the RCT will be enrolled in a passive behavioural support (Support) group. The primary outcome is study feasibility, defined according to three primary criteria (i.e., participant recruitment, safety, and adherence). Secondary outcomes include additional feasibility metrics (e.g., intervention safety and tolerability) and exploratory efficacy outcomes including peak cardiorespiratory fitness (VO2peak), cardiac function (e.g., global longitudinal strain (GLS)), CVD risk factor control (e.g. insulin resistance), and patient-reported outcomes (e.g. anxiety). Our central hypothesis is that the conduct of a larger RCT comparing the impact of CORE versus non-intervention control will be feasible indicated by the achievement of our primary feasibility criteria. Our exploratory hypothesis is that we will generate preliminary evidence that CORE can improve VO2peak, cardiac function, CVD risk factor, and patient-reported outcomes over 6- and 24-month timepoints, relative to control.

Over 90,000 North Americans are diagnosed with cancer before the age of 40. Improved cancer therapies have led to an exponential growth in the number of pediatric, adolescent, and young adult cancer survivors (PAYA-CS) who are expected to live 50-60 years beyond diagnosis. However, PAYA-CS are at increased risk of developing multiple cancer- and treatment-related morbidities including poor fitness (e.g., low VO2peak), hypertension (HTN), diabetes, and poor mental health, which all contribute to premature cardiovascular disease (CVD). The prevalence of CVD events (e.g. heart failure, heart attack, stroke) is up to 23.8% in adult survivors of pediatric cancers with long term follow-up after treatment. The incidence of subclinical CVD, which is a precursor to CVD events, is even higher in PAYA-CS; up to 40%, 11%, and 5% experience subclinical cardiomyopathy measured by abnormal global longitudinal strain (GLS), diastolic dysfunction (DD) or mild reduction in left ventricular ejection fraction (LVEF), respectively, and 18% experience reduced aerobic fitness. The treatment of modifiable CVD risk factors must be considered a fundamental target for improving CVD health-related outcomes in PAYA-CS. To this end, exercise and best-practices for CVD risk factor modification are integral to a cardiac rehabilitation (CR) model. Traditional cardiac rehabilitation models for patients with CVD (consisting of exercise, CVD risk factor treatment, and patient education) are safe and effective in improving HRQoL, morbidity, and mortality risk. However, by virtue of their age and low short-term CVD risk, PAYA-CS do not meet traditional criteria for initiating CR and are less likely to receive treatments to reduce CVD risk.

PAYA-CS with stage B heart failure (SB¬HF): (1) are at high risk for subsequent HF/CVD death; (2) have lower cardiopulmonary fitness; and (3) are more likely to benefit from CVD risk factor management. Considering that PAYA-CS have an estimated 33% prevalence of SBHF, this vulnerable cohort of cancer survivors represent an opportunity for intervention that is highly feasible and potentially impactful. Exercise is a preferred method for optimizing health and survival in PAYA-CS. However, we need models that safely and effectively deliver exercise interventions that meet the unique needs of this population. The cardio-oncology rehabilitation (CORE) model is an intervention that would provide PAYA-CS with SBHF a supervised and home-based exercise therapy, CVD risk factor modification, and behavioural support to reduce the risk of CVD. Nevertheless, due to the ambitious nature of the study, it is vital that we conduct a pilot version of the study to determine the feasibility and needed changes to achieve the best possible results.

The primary objective of the HIMALAYAS pilot study is to assess the feasibility, safety, and tolerability of a (1) two-arm RCT-based comparison of the CORE and Support interventions in PAYA-CS with SBHF, and (2) parallel passive behavioural support (PBS) cohort of PAYA-CS at high-risk of cancer-related CVD. The exploratory objectives of the study include (1) to compare the changes in primary exploratory outcome (VO2peak) and secondary exploratory outcomes (markers of cardiac function, CVD risk factor management, and patient-reported outcomes) between a CORE and Support intervention for PAYA-CS from baseline (T0) to 6-month (T1) follow-up and (2) to compare the changes in the primary and secondary exploratory outcomes between (1) CORE and Support from T0 to 12-month (T2) and 24-month (T3) follow-up, and (2) CORE, Support, and PBS from T0 to T3.

Cardio-oncology Rehabilitation (CORE) Group: CORE consists of exercise therapy, CVD risk factor management for the first 6 months (as per current standards in CR models) and behavioural support for the entire 2-year intervention period.

Support Group: The Support group will receive the behavioural support only. The timing and nature of all education, information, and peer support provided to Support participants will be identical to what is provided to CORE participants. The key difference in the long-term behavioural support strategy between CORE and Support participants is how weekly exercise goals are defined. Unlike the CORE participants who will be encouraged to use the personal activity intelligence (PAI) Score, Support participants will be given the challenge of meeting and maintaining the updated physical activity (PA) guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous-intensity PA per week).

Passive Behavioural Support (PBS) Groups: All PBS cohort participants will receive the same wrist-worn heart rate monitor and PA tracker as the CORE and Support participants. However, PBS participants will be blindly randomized to one of two passive behavioural support interventions (PBS1 and PBS2). PBS1 participants will be asked to download the same PAI Health application as CORE participants and will similarly be given the challenge of meeting and maintaining a weekly PAI Score ≥100 throughout the 18-month follow-up period. PBS2 participants will be asked to download and use the Map My Walk (Under Armour, Baltimore) application and will be challenged to meet and maintain the updated PA guidelines for cancer survivors (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

The Harmonized Interventions to Maintain Health Via Appropriate Risk Factor Modification and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Pilot Study

Measured with an average of 3 readings (after discarding an initial test reading) by an automated measurement device as per the Hypertension Canada guidelines.

Measured with an average of 2 readings taken via ECG during the resting period during the cardiac screening procedures.

Measured through fasting cholesterol profile and Apo B levels

Measured through whole-body insulin sensitivity (Matsuda index)

Measured through hepatic insulin sensitivity (HOMA-IR)

Measured through pancreatic beta-cell function (ISSI-2).

Measured through Godin Leisure Time PA Questionnaire (GLTPAQ). Score of \>24 = active, score of 14-23 = moderately active, score of \<14 = insufficiently active

Measured through wrist-worn heart rate with physical activity monitor

Measured using the Social Support Survey-Clinical (SSS-C) form, a 5-item survey designed to measure five dimensions of social support (listening, task challenge, emotional reality confirmation, and tangible assistance); higher score = more social support

Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping; Scale 0-90, higher score indicates higher self-efficacy for exercise.

Measured using the National Health and Nutrition Examination Survey (NHANES) Food Frequency Questionnaire (FFQ), a 139-item, semi-quantitative inventory to assess the potential influence of dietary changes on primary and secondary outcomes.

Measured using self-reported measures to determine the potential influence of changes in smoking habits on primary and secondary outcomes.

Measured using the Generalized Anxiety Disorder (GAD-7), a 7-item inventory that assesses 2-week anxiety symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. A cut-off of ≥10 indicates some degree of clinical anxiety

Measured using the Patient Health Questionnaire (PHQ-9), a 9-item inventory that assesses 2-week depressive symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. The PHQ-9 has been validated in cancer survivors using a cut-off of ≥8 to indicate some degree of clinical depression.

Measured using the Medical Outcomes Survey Short-Form, (SF-12).

Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form. Increased score indicates therapeutic alliance.

Defined as the percent of consenting patients based on the total number of otherwise eligible participants (OEP; patients meeting all eligibility criteria) approached

Defined as the number and frequency of testing- and intervention-related serious adverse events (SAEs) according to the Common Terminology Criteria for Adverse Events

Defined as relative dose intensity as the percent of total dose of exercise performed relative to the total planned dose prescribed and quantified according to metabolic equivalents

Defined as the average number of OEP identified each month

Defined as the percent of consenting patients who successfully complete baseline assessments based on the total number of consenting patients

Defined as the number and frequency of testing- and intervention-related non-serious adverse events

Defined as the percent completion of all cardiopulmonary exercise tests (CPETs) tests at baseline (T0) and primary follow-up (T1)

Defined as the percent of all tests which are adapted for functional or safety reasons

Defined as the percent of all exercise sessions which are adapted for functional or safety reasons

Defined as the percent of patients who discontinue intervention participation prior to the planned end of the intervention period

Defined as the percent of patients who miss =\>3 consecutive sessions within the intervention period

Defined as the percent of exercise sessions requiring a dose reduction during training (i.e., intensity or duration) relative to the total number of sessions completed. Total number of exercise sessions with a reduction in intensity or a reduction in duration will be combined into the numerator when calculating the percentage of affected sessions.

Defined as the percent of exercise sessions requiring unplanned early termination

Defined as the percent of sessions which required pre-exercise modification of the target exercise intensity due to a pre-exercise screening indication (e.g., fatigue, pain)

Defined as the percent of exercise sessions completed based on the total number of sessions prescribed.

Defined as the percent of pharmaceutical doses taken based on the total number of doses prescribed (applicable only to those that are provided pharmaceutical therapy for CVD risk factor modification.

Defined as the percent of behavioural support resources accessed, based on the number of doses prescribed

defined as the average number of participants achieving their weekly PA goals of meeting and maintaining either a PAI-Score of ≥100 or weekly cancer exercise guidelines (i.e., 90 to 150 minutes of moderate to vigorous intensity PA per week).

Defined as the percent loss to follow-up (not completing follow-up assessments)

University Health Network, Toronto

Participants in the CORE group will have

1. A personalized, supervised exercise program ((in-person at intuition and virtual/ homebased exercises)
2. CV risk factor management,
3. behavioural support for the first 6 months. The behavioural support will continue for CORE participants from months 7-24. Behavioural support includes professionally guided and peer-enhanced exercise behavioural support based on behaviour change stage theories.

CORE participants will be provided a wrist-worn heart and physical activity monitor to use throughout the 24-month observation period.

Participants in the CON group will receive standard medical care and physical activity will be monitored by a wrist-worn activity tracker for 2 years.

Paaladinesh Thavendiranathan, MD

Krishna Mohan Chirra CRC

Krishna Mohan CRC

Pediatric, adolescent and young adult cancer survivors (PAYA-CS) are at higher risk of cardiovascular (CV) morbidity and mortality. This is a consequence of prior cancer-related therapies that have the potential of producing cardiac dysfunction, reducing cardiorespiratory fitness (reduced VO2peak) and psychosocial morbidities (i.e., anxiety and depression). A reduction of physical activity levels can evoke functional limitations resulting in a vicious cycle of reduced exercise tolerance and physical deterioration. To date, there is limited evidence on the use of non-pharmacological strategies such as Cardio-Oncology Rehabilitation (CORE) including structured exercise, behavioural support and risk factor management to improve the outcomes of this underserved population. The HIMALAYAS study is a randomized controlled trial designed to evaluate the impact of a CORE intervention (consisting of six-months home and onsite-based structured moderate to high-intensity aerobic exercise training and CVD risk factor management) on CV and psychosocial health, and the cardiovascular disease risk in PAYA-CS with mild heart dysfunction (stage B heart failure) compared to standard of care (i.e. providing guidance on the current exercise recommendations for cancer survivors). The primary objective of the HIMALAYAS study is to determine whether a six-month supervised CORE intervention, consisting of individualized moderate to high-intensity aerobic exercise training, CVD risk factor modification and enhanced online behavioral support, improves cardiorespiratory fitness (VO2peak; primary outcome), cardiac function, CVD risk factors and biomarkers, and patient-reported outcomes (PROs) at six- months follow-up compared to standard of care (CON) in PAYA-CS with stage B heart failure. The secondary objective is to assess the same outcomes at 12- and 24-months follow-up. We will recruit 336 patients across 5 sites in Canada and upto 134 patients at UHN in 3 years and conclude in 6 years.

Over 90,000 North Americans are diagnosed with cancer before the age of 40. Improved cancer therapies have led to an exponential growth in the number of pediatric, adolescent, and young adult cancer survivors (AYA-CS) who are expected to live 50-60 years beyond diagnosis. However, AYA-CS are at increased risk of developing multiple cancer- and treatment-related morbidities including poor fitness (e.g., low VO2peak), hypertension (HTN), diabetes, and poor mental health, which all contribute to premature cardiovascular disease (CVD). The prevalence of CVD events (e.g. heart failure, heart attack, stroke) is up to 23.8% in adult survivors of pediatric cancers with long term follow-up after treatment. The incidence of subclinical CVD, which is a precursor to CVD events, is even higher in AYA-CS; up to 40%, 11%, and 5% experience subclinical cardiomyopathy measured by abnormal global longitudinal strain (GLS), diastolic dysfunction (DD) or mild reduction in left ventricular ejection fraction (LVEF), respectively, and 18% experience reduced aerobic fitness. The treatment of modifiable CVD risk factors must be considered a fundamental target for improving CVD health-related outcomes in AYA-CS. To this end, exercise and best-practices for CVD risk factor modification are integral to a cardiac rehabilitation model. Traditional cardiac rehabilitation models for patients with CVD (consisting of exercise, CVD risk factor treatment, and patient education) are safe and effective in improving HRQoL, morbidity, and mortality risk. However, by virtue of their age and low short-term CVD risk, AYA-CS do not meet traditional criteria for initiating cardiac rehabilitation (CR) and are less likely to receive treatments to reduce CVD risk. AYA-CS with stage B heart failure (SBHF): (1) are at high risk for subsequent HF/CVD death; (2) have lower cardiopulmonary fitness; and (3) are more likely to benefit from CVD risk factor management. Considering that AYA-CS have an estimated 33% prevalence of SBHF, this vulnerable cohort of cancer survivors represent an opportunity for intervention that is highly feasible and potentially impactful. Exercise is a preferred method for optimizing health and survival in PAYA-CS. However, we need models that safely and effectively deliver exercise interventions that meet the unique needs of this population. The cardio-oncology rehabilitation (CORE) model is an intervention that would provide AYA-CS with SBHF a supervised and home-based high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) exercise therapy, CVD risk factor modification, and behavioural support to reduce the risk of CVD. The primary objective of the HIMALAYAS study is to determine whether supervised CORE (Group 1A) improves cardiorespiratory fitness (VO2peak; primary outcome), cardiac function, CVD risk factors and biomarkers, and PROs at 6 months (primary timepoint) as well as 12 and 24 months compared to standard of care group control group (CON) in AYA-CS with SBHF.

The secondary objective of the study is to assess the ongoing behavioural support strategy based on the exercise guidelines for cancer survivors (i.e. 90 to 150 minutes of moderate to vigorous PA per week) on VO2peak, cardiac function, CVD risk factors and biomarkers, and PROs at 24 months compared to standard of care \[CON\] in AYA-CS with SBHF. Due to the COVID-19 pandemic, CORE intervention will involve a facility-based HIIT session and home-based HIIT session (described as "HIIT at Home") per week.

The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial

The Harmonized Interventions to Maintain Health Via Appropriate Risk Factor Modification and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial

Measured using the Working Alliance Inventory Short-Revised (WAI-SR) form.

Defined as the percent of tests that achieve 'peak' termination criteria relative to the total number of tests completed across all time points

Defined as the number and frequency of testing-, intervention-, and non-intervention-related serious (i.e. Grade 3 to 5; NCI-CTCAE criteria) and non-serious (i.e. Grade 1 to 2; NCI-CTCAE criteria)

This variable applies only to CORE participants. Exercise adherence is defined as the relative dose intensity (i.e. the percent of total dose of exercise performed, relative to the total dose prescribed) and quantified according to metabolic equivalents.

Defined as the percent of pharmaceutical doses taken based on the total number of doses prescribed (applicable only to those that are provided pharmaceutical therapy for CVD risk factor modification)

Defined as the percent of behavioural support resources accessed, based on the number recommended (one per month)

Quantified as timepoint measures of oxygen utilization assessed via portable metabolic measurement system within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions

Quantified as power output (watts) assessed cycle ergometer within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions

Quantified via heart rate monitor or single-lead ECG within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions

Quantified as total metabolic equivalent of task following HIIT sessions

Assessed via rating of perceived exertion scale (6-20) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions

Affective arousal is evaluated via the felt arousal scale that assesses energy/arousal level on a scale of 1 (low arousal) to 6 (high arousal) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified HIIT sessions

The feeling scale is used to assess affective valence (pleasure/displeasure; feeling good/bad) on a scale of -5 (vey bad) to +5 (very good) within the final 30 seconds of the warm-up, work and recovery periods, and the cool down during pre-specified high-intensity interval training sessions

Measured using the Brief Relilience Scale (BRS), a 6-item inventory that assesses recovery, resistance, adaptation, and thriving.

Measured using two items based on the Canadian Community Health Survey assessing the average daily stress experienced that day and over the past week.

Assessed via ecological momentary assessments using brief reports completed 6 times a day on intervention weeks 1, 7, 16, 22, four weeks post intervention, and 26 weeks post intervention

Assessed via cardiopulmonary exercise test and quantified as VO2peak

Estimated using the V-slope method and according to the following criteria: i) an exaggerated response in the volume of carbon-dioxide (i.e., VCO2) relative to the volume of oxygen (i.e., VO2), and ii) the first identifiable break-point in in the minute ventilation (i.e., VE/VO2 vs work rate relationship).

Estimated according to the three-criterion discrimination technique: i) an excess VCO2 response relative to the VO2 response identified per the modified V-slope criteria; ii) the VE/VO2 to VO2 relationship having been flat or decreasing begins to increase without returning to baseline; and iii) there is no reciprocal decrease in PETCO2 at the point where PETO2 starts to rise systematically.

One-minute HR recovery (HRR; an index of post-exercise parasympathetic reactivation) will be calculated as the HR-difference between peak exercise and following one minute of quiet standing on the treadmill immediately post-test.

Assessed via tissue Doppler imaging (TDI)

Calculated using the average of the TDI septal and lateral annular velocities (e')

Assessed via Devereux formula and quantified as LV mass/body surface area: \>95 g/m2 for women or \>115 g/m2 for men

Assessed as \>0.42 relative wall thickness

Calculated as average of 3 readings measured via automated sphygmomanometer per the Hypertension Canada guidelines.

Assessed via homeostasis model assessment insulin resistance (HOMA-IR)

Assessed via the insulin secretion-sensitivity index-2 (ISSI-2)

Calculated as body weight (kg) divided by height (m) squared

Objectively assessed via wrist-worn physical activity/heart rate monitor to measure the intensity and duration of all planned and unplanned exercise during the study period

Subjectively assessed via Godin Leisure Time Physical Activity Questionnaire and reported as moderate-to-vigorous intensity physical activity (MVPA)

Measured using the Social Support Survey-Clinical (SSS-C) form, a 5-item survey designed to measure five dimensions of social support + a single item to assess cancer-specific social support.

Measured using the Multidimensional Self-Efficacy for Exercise Scale (MSES) to measure three behavioural subdomains: task, scheduling, and coping

Measured using the Generalized Anxiety Disorder (GAD-7), a 7-item inventory that assesses 2-week anxiety symptom frequency on a 0-3 scale, with higher scores reflecting higher symptom frequency. A cut-off of ≥10 indicates some degree of clinical anxiety.

Measured using the Medical Outcomes Survey Short-Form (SF-12).

Measured using the Health Service Utilization Inventory.

Centre hospitalier de l'Université de Montréal (CHUM)

Queen Elizabeth II Health Sciences Centre

Alberta Health services

Vancouver General Hospital

Université de Montréal

Dalhousie University

University of Alberta

University of British Columbia

University of Toronto

1. Baseline consultation with physiatrist specialized in CRP - addressing CVRF control, comorbidities and disabilities; case-by-case discussion with a cardiologist specialized in CR will be undertaken, for tailoring exercise prescription. Nutritional individualized plan addressing dietary goals. Psychological management addressing psychosocial outcomes and motivation for healthy lifestyle habits
2. Multidisciplinary team educational meeting: periodic group sessions with health education purposes
3. Exercise intervention - 2 times/week sessions at CR facilities, supervised by a physiatrist, conducted by physiotherapist. Heart rate (HR) continuously monitored during each session by remote electrocardiographic monitoring or HR monitor. Exercise intensity estimated according to CR guidelines, determined after CV risk stratification, using CPET results.

a) Besides standard medical and supportive care, psychological and nutritional individual support will be offered on demand, in hospital setting, according to the attending physician standard clinical assessment and usual care.

Exercise intervention - Performed at a community-based facility, comprising 2 sessions/week, prescribed according to current physical activity guidelines for cancer survivors. Exercise intervention will be conducted by an exercise physiologist, internationally certified in exercise for cancer patients

In addition to standard medical care, for an 8-week period, patients will have access to the core components of a CRP, delivered by a multidisciplinary rehabilitation team

Cardiac Rehabilitation Program

In addition to standard medical care, for an 8-week period, patients will have access to a community exercise intervention oriented by a sports professional

Community exercise intervention

Many cancer survivors are at risk for cardiovascular disease (CVD); it is therefore important to identify patients at increased risk for cardiotoxicity, especially in the setting of CVRF or pre-existing CVD, and to design personalized interventions to prevent cardiovascular morbidity. In this background, cardio-oncology rehabilitation frameworks for specific cancer patients have been proposed. Given potential beneficial effects of exercise among cancer patients (including those at higher risk of CVD), data pertaining to optimal program designs are of paramount contemporary importance.

Thus, the aim of this study is to compare the impact of a Cardiac Rehabilitation Program (CRP) model versus a community-based exercise intervention plus usual care on cardiorespiratory fitness (CRF), physical function domains and CVRF control in adult cancer survivors who have been exposed to cardiotoxic cancer treatment and/or with cardiovascular medical background. Study outcomes will be assessed at baseline (M0) and after an 8 weeks-intervention (M1), comprising maximal aerobic capacity (peak oxygen uptake), muscular strength, neuromuscular function, single CVRF control including physical activity measurements and psychosocial parameters, health-related quality of life, fatigue, health literacy, inflammatory response and feasibility metrics; an economic evaluation will provide quantitative comparison, for a cost-effectiveness analysis

Impact of a Comprehensive Cardiac Rehabilitation Program Framework Among High Cardiovascular Risk Cancer Survivors

minute ventilation to carbon dioxide production slope (VE/VCO2 slope) assessed by CPET

muscle strength measured with manual dynamometers (Kgf)

Changes in body composition assessed by bioelectrical impedance analysis

Measured with an average of 3 readings by an automated measurement device as per the ESC guidelines (mmHg)

Measured with an average of 3 readings by an automated measurement device (bpm)

Measured through fasting Blood biochemistry including total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), triglycerides (TG)

Measured through glycated haemoglobin (%) in fasting state

Self-reported through the International Physical Activity Questionnaire, classifying the activity in three categories (low activity levels, moderate activity levels or high activity levels)

objectively assessed by accelerometer, to wear for seven consecutive days

Cigarette smoking habits quantified in pack-year and cigarettes per day, to measure exposure to tobacco

Psychosocial parameters assessed through the Hospital Anxiety and Depression Score questionnaire. Scores 0-14. A sub-scale score \> 8 denotes anxiety or depression symptoms

Evaluated using the EuroQuol Five- Dimensional questionnaire ( EQ-5D-5L). It consists in five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. The EQ - Visual Analog Scale records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'.

Fatigue score evaluated by the specific item on the EORTC QLQ-C30 questionnaire (high score representing high level of symptomatology)

Assessed by the Newest Vital Sign questionnaire; range score 0-6 (high score corresponding to high health literacy)

Blood samples collected to access plasma levels of IL-6

Blood samples collected to access plasma levels of high-sensitivity C-reactive protein

number of patients who met inclusion criteria divided by the number who consented in writing to participate. Reasons for not participating in the study will be registered.

all the events will be recorded and registered as "related" or "unrelated" to the intervention itself, as well as the impact for exercise concerns or other health intervention required

number of participants who remained in the study (without formally drop out during intervention).

total number of exercise sessions attended by participants allocated to this intervention group. Reasons for dropping out will be registered.

number of patients that completed all the evaluations during the defined timeline.

Incremental cost per quality-adjusted life. Costs will be calculated from the provider perspective, which includes the costs incurred by the health institution providing health services; and from the societal perspective

Centro Hospitalar de Vila Nova de Gaia/Espinho, E.P.E.

University Institute of Maia

Associacao de Investigacao de Cuidados de Suporte em Oncologia

Neoplasms

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Amy A Kirkham, PhD

Paul Oh, MD

Amy Kirkham, PhD

Women with breast cancer who are referred to the cardiac rehabilitation program at the Toronto Rehabilitation Institute will be invited to enrol in this observational study. Participants will take part in an established 16-week multimodal cardiac rehabilitation program (HEALTh program) at Toronto Rehabilitation Institute and outcome measures will be assessed before and after program participation to determine the effectiveness of the program in improving cardio metabolic health. Change in VO₂peak will be assessed using Cardiopulmonary Exercise Test (CPET). Traditional cardiac risk factors, lifestyle behaviours, exercise adherence, health-related quality of life, and fatigue will also be assessed.

Cardio-Oncology Rehabilitation Exercise

A Single Arm Intervention Study to Assess the Role of Structured Cardio-Oncology Rehabilitation Exercise to Improve Cardiovascular Health in Early Stage Breast Cancer Survivors (CORE Study)

PiezoRx® will be worn by participants for 7 days with data used to assess moderate activity time (\>100 steps per minute)

PiezoRx® will be worn by participants for 7 days with data used to assess vigorous activity time (\>120 steps per minute)

PiezoRx® will be worn by participants for 7 days with data used to assess bouts of physical activity per day (greater than 10 minutes of moderate/vigorous activity)

PiezoRx® will be worn by participants for 7 days with data used to assess total daily steps

Godin Leisure Time Physical Activity Questionnaire

Rapid Eating and Activity Assessment for Participants (REAP) questionnaire. Minimum score = 13, maximum score = 39, with a higher score indicating a higher diet quality.

VO2peak assessed using cardiopulmonary exercise test

Measured only in a subset (n=30) of participants via 1.5T MRI.

Functional Assessment of Cancer Therapy (FACT) questionnaire. Minimum score = 0, maximum score = 108, with higher score representing better quality of life.

Patient Health Questionnaire 9 scale. Minimum value = 0, maximum value = 27, where higher score represents more depressive symptoms.

Perceived Stress Scale (PSS). Minimum value = 0, maximum value = 56, where higher score represents more perceived stress.

Fatigue sub-scale of the Functional Assessment of Cancer Therapy (FACT) questionnaire. Minimum score = 0, maximum score = 52, with higher score representing less fatigue.

Toronto Rehabilitation Institute

Assistant Professor

Digestive System Diseases

Blood and Lymph Conditions

Rare Diseases

Stomach Neoplasms

Leukemia

Cardiomyopathies

Stomach Cancer

Doxorubicin Induced Cardiomyopathy

Patients will participate in a 10 week outpatient cardiac rehabilitation program. Exercise will consist of 3 days per week of interval training on a treadmill or bike at an intensity between 50-90% of heart rate reserve. Additionally patients will perform resistance exercises 1-2 days per week and attend 8 nutrition and lifestyle classes.

Control group will not be instructed on exercise, but encouraged to follow standard medical advice.

Intervention will include 10 weeks of a standard cardiac rehabilitation program consisting of thrice a week aerobic exercise and 1-2 days per week resistance exercises.

Exercise

The purpose of this study is to identify patients at risk for future heart failure using novel markers of early cardiac damage and determine if exercise training can improve these emerging markers as well as overall fitness and quality of life.

With more than 14 million cancer survivors in the United States, more patients than ever are living well beyond their initial cancer diagnosis. However despite the tremendous progress, cancer treatments often come with adverse side-effects, perhaps none are more serious or devastating than chemotherapy induced heart failure.

In many patients, the clinical manifestation of heart failure may not appear until a year, or several years, after completion of chemotherapy. While an echocardiogram is part of standardized surveillance for patients on these drugs, current echocardiogram parameters may not be sensitive enough to quickly detect early heart damage which, in some cases, is irreversible.

Unfortunately, even if detected early, there is no uniformity in terms of how to best treat patients with subclinical cardiac dysfunction who are at risk for heart failure. The use of certain blood pressure drugs show promise, especially in patients with hypertension. However, in addition to drug side-effects (e.g. dizziness/lightheadedness), they do not target the underlying mechanism of chemotherapy induced cardiotoxicity.

Exercise, in various forms, has shown promise in animal studies as a potential cardio-protective therapy to counteract drug toxicity. In general, exercise has many pleiotropic effects for patients receiving chemotherapy (e.g. reduces fatigue, improves endurance, reduces frailty, and enhances quality of life). Relative to DOX toxicity, research involving animals has also shown that exercise protects against deleterious heart dysfunction while showing an enhancement of potential mechanisms involved in chemotherapy induced heart failure (i.e. anti-oxidant and anti-apoptosis pathways).

Patients with cancer who receive either doxorubicin (DOX) or trastuzumab will be screened by one of two methods: 1) a strain echo or 2) a high sensitivity troponin. If either test is positive, patients will meet with a board-certified cardiologist who will determine if the patient may participate in the exercise trial. Under the supervision of a trained clinical exercise physiologist patients will undergo baseline testing, which includes: a quality of life assessment via questionaires, a body composition test, cardiopulmonary stress test and a muscle strength test. These assessment will be performed at baseline and at 12 weeks. Also performed at 12 weeks will be a repeat strain echo and high sensitivity troponin.

Following baseline testing patients will be randomized into exercise training versus standard care. The exercise training will include 12 weeks of cardiac rehabilitation which can be offered in Detroit, Livonia, or West Bloomfield. Exercise will consist of 3 days per week of an interval training aerobic exercise on a treadmill and/or bike for 30-60 minutes and 1-2 days per week of an individualized resistance training program.

Prevention Using Exercise Rehabilitation to Offset Cardiac Toxicities Induced Via Chemotherapy

Spectral Doppler measure with General Electric software analysis of global longitudinal strain.

During a graded treadmill test, breath-by-breath sampling of expired air will be measured using a MGC Diagnostics gas exchange analysis system.

Body fat will be analyzed using air displacement plethysmography (BodPod/Cosmed)

Peak torque will be measured using the Biodex Isokinetic dynamometer.

Quality of life will be assessed using the Functional Assessment of Cancer Therapy (FACT-G).

High sensitivity cardiac troponin will be analyzed using a commercial immunoassay.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Harmonized Interventions to Maintain Health Via Appropriate Risk Factor Modification and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Pilot Study	NCT04598646	Heart Failure Cardiotoxicity Cancer	Cardio-oncology... Support	18 Years - 45 Years	University Health Network, Toronto
The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial	NCT05023785	Heart Failure Cardiotoxicity Cancer	Cardio-oncology...	18 Years - 45 Years	University Health Network, Toronto
The HIMALAYAS Trial and Lifestyle Changes in Pediatric, Adolescent and Young Adult Cancer Survivors Study: A Multicentre Randomized Controlled Trial	NCT05023785	Heart Failure Cardiotoxicity Cancer	Cardio-oncology...	18 Years - 45 Years	University Health Network, Toronto
Impact of a Comprehensive Cardiac Rehabilitation Program Framework Among High Cardiovascular Risk Cancer Survivors	NCT05132998	Oncologic Disor... Cardiovascular ...	Cardiac Rehabil... Community exerc...	18 Years -	Associacao de Investigacao de Cuidados de Suporte em Oncologia
Cardio-Oncology Rehabilitation Exercise	NCT05522959	Breast Cancer		18 Years -	University of Toronto
Prevention Using Exercise Rehabilitation to Offset Cardiac Toxicities Induced Via Chemotherapy	NCT02796365	Doxorubicin Ind... Breast Cancer Gastric Cancer Leukemia	Exercise	18 Years - 75 Years	Henry Ford Health System
Exercise-based Cardiac Rehabilitation for the Prevention of Breast Cancer Chemotherapy-induced Cardiotoxicity	NCT03964142	Cardiotoxicity Cardiac Rehabil...	Cardiac rehabil...	18 Years - 69 Years	Hospital Clinico Universitario de Santiago
Exercise-based Cardiac Rehabilitation for the Prevention of Breast Cancer Chemotherapy-induced Cardiotoxicity	NCT03964142	Cardiotoxicity Cardiac Rehabil...	Cardiac rehabil...	18 Years - 69 Years	Hospital Clinico Universitario de Santiago

Spots Global Cancer Trial Database for cardiac rehabilitation