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).

Inclusion Criteria:

• Be a PAYA-CS, defined as ≤39 years of age at the time of cancer diagnosis;
• Be 18-45 years of age at the time of enrolment;
• Received cancer treatment(s) with known cardiovascular risks (e.g. anthracyclines, radiotherapy, trastuzumab, platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors);
• Be cancer-free at the time of enrollment.
• Diagnosed with SBHF prior to or at baseline (LVEF<53/54%, GLS >-18%, or diastolic dysfunction).

Exclusion Criteria:

• An absolute or relative contraindication to exercise according to the American College of Sports Medicine (ACSM) guidelines;
• Untreated physical or mental health concerns that preclude safe and effective exercise participation;
• Established CVD (excluding mildly reduced LVEF as described above);
• Be currently engaging in high-intensity exercise (>1 high-intensity exercise session per week);
• Substantial barriers to completing study protocol (e.g. living too far away and being unable to attend testing and exercise training sessions) or unwillingness to comply with the study protocol (e.g. individual intends to start performing regular HIIT exercise regardless of randomization).