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

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.

Inclusion Criteria:

1. Be a PAYA-CS, defined as ≤39 years of age at the time of cancer diagnosis;

2. Be 18-45 years of age at the time of enrolment;

3. Received cancer treatment(s) with known cardiovascular risks (e.g., anthracyclines, trastuzumab, radiotherapy, platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors);

4. Be cancer-free at the time of enrollment;

5. Stage B Heart Failure (SBHF)

   • In patients with availability of pre-treatment imaging:

     • ≥10% decrease in LVEF at post-treatment compared to pre-treatment
     • ≥15% decrease in GLS at post-treatment compared to pre-treatment

   • No pre-treatment imaging:

     • LVEF ≤53% in women/51% in men
     • GLS >-18%
     • Left ventricular hypertrophy (LV mass/body surface area: >95 g/m2 for women or >115 g/m2 for men)
     • Concentric remodelling (>0.42 relative wall thickness)
     • Diastolic dysfunction (≥ grade 1)
     • BNP ≥35pg/ml or NT-proBNP ≥125pg/ml

Exclusion Criteria:

1. Have an absolute or unresolved relative contraindication to exercise according to the American College of Sports Medicine guidelines;
2. Have an untreated physical or mental health concern that precludes safe and effective exercise participation;
3. Have established CVD (excluding mildly reduced LVEF as described above);
4. Be pregnant at time of recruitment;
5. Be currently engaging in frequent high-intensity exercise (>1 high-intensity exercise session per week);
6. Have substantial barriers to participating, including (1) living too far from study centre or (2) being unable or willing to comply with the study protocol.