Study Rationale:
Breast cancer (BC) is the most common diagnosed cancer in Australian females
(BreastScreen Australia Monitoring Report 2024, Summary, 2024). Although the 5-year
relative survival from a stage 1
- - 3 BC diagnosis is improving due to earlier screening
and more targeted treatment plans (Breast Cancer in Australia, 2012), females with a
previous BC diagnosis are more likely to develop cardiovascular disease (CVD) or
neurocognitive disease than age-matched counterparts without a previous BC diagnosis
(Lange et al.
, 2019).
Aging is a major risk factor for CVD (Deaths in Australia, Leading Causes of Death, 2024)
and neurocognitive disease (Dementia in Australia, Summary, 2024). Australians over the
age of 65 years old currently account for 16% of the population, but this is expected to
increase to 23% by 2066 (Older Australians, Demographic Profile
- - Australian Institute of
Health and Welfare, 2024).
Furthermore, the majority (69%) of BC cases are diagnosed in
females aged 40-69 (Breast Cancer in Australia, 2012). As such, the number of females
diagnosed with BC is expected to increase given the ageing population, and a as result,
so too will the number of long-term BC survivors diagnosed with either CVD,
neurocognitive disease, or both. Therefore, effective policies and therapeutic strategies
are needed to minimize the growing societal and economic burden of CVD and neurocognitive
disease, with particular focus on high-risk populations like BC survivors.
The clustering of CVD risk factors and the cardiotoxic effects of anti-cancer treatments
(e.g. anthracycline-based chemotherapy and radiotherapy to the left side of the chest)
contribute to the higher prevalence of CVD in BC survivors (Yeh & Bickford, 2009). While
the exact mechanisms are currently unclear, the increasing burden of neurocognitive
disease and cancer-related cognitive impairment (CCRI) in BC survivors may be related to
the 'vascular'-toxic effects of anti-cancer therapies (Cameron et al., 2016). Indeed,
both arterial stiffness and vascular function are impaired in BC patients within 15
months of initiating anti-cancer therapies (Anastasiou et al., 2023), which may be
followed by neurovascular dysfunction, brain hypo- or hyper-perfusion and impaired
glymphatic clearance, leading to the onset of cerebral small vessel disease and brain
atrophy (Andjelkovic et al., 2023; Reeve et al., 2024).
Neurovascular units tightly regulate cerebral blood flow (CBF) to match the metabolic
demands of the brain and maintain normal cognitive function (Iadecola, 2017), but damage
to the neurovascular unit is associated with a reduction in CBF and the progression of
and vascular-related cognitive impairment (Santisteban et al., 2023; van Dinther et al.,
2024). Accordingly, resting CBF may be a clinically useful biomarker to identify patients
at risk of vascular-related cognitive impairment (van Dinther et al., 2024). However,
little is known about the long-term trajectory of CBF and neurovascular function in BC
survivors or what interventional strategies may be effective at slowing the decline in
neurovascular and neurocognitive function in BC survivors.
Regular exercise training is recognised as an effective behavioural intervention to slow
or prevent the development of age-related CVD by lowering risk factors such as high blood
pressure and hyperlipidaemia (Arnett et al., 2019). Higher cardiorespiratory fitness is
also associated with lower dementia risk in older adults (Wang et al., 2024), which may
be mediated by a reduction in cerebrovascular resistance (Smith et al., 2021) and
maintenance of adequate cerebral perfusion (Tomoto et al., 2021). Furthermore, exercise
training during, or shortly following chemotherapy can improve vascular function (Vear et
al., 2023) and self-reported cognitive function in BC patients (Koevoets et al., 2022),
However, whether exercise training incorporated into a Cardio-Oncology Rehabilitation and
Exercise (CORE) programme can improve neurovascular function in long-term BC survivors is
unknown. Therefore, the primary aim of this study will be to determine the effect of a
CORE programme on neurovascular function in long-term breast cancer survivors.
Primary Objective:
The primary objective of this trial is to determine the effect of a CORE programme on
neurovascular function in long-term breast cancer survivors.
Secondary Objective:
The secondary objective of this trial is to determine the effect of a CORE programme on
neurocognitive function in long-term breast cancer survivors.
Exploratory Objective:
An exploratory objective of this study will be to determine if improvements in
cardiorespiratory fitness mediate improvements in neurocognitive function in long-term
breast cancer survivors.
Overall Design:
This study will be a randomised controlled trial to investigate the effect of a CORE
programme on neurovascular and neurocognitive function in long-term breast cancer
survivors. We will recruit n = 40 females aged 45
- - 75 years old who have previously been
diagnosed with stage 1 to 3 breast cancer 5 - 10 years prior to study enrolment.
Participants will complete phone-based study screening and two baseline study visits to
the Baker Heart and Diabetes Institute, before being randomised to a CORE programme (n =
20) or usual care (n = 20) at a 1:1 ratio. Baseline study visit one will include
questionnaires, clinic blood pressure (BP), Dual-Energy X-Ray Absorptiometry (DXA) and a
CPET. Participants will also be fitted with two physical activity monitors at the end of
study visit one to monitor their physical activity levels over the subsequent 7 days.
Baseline study visit two will include ultrasound assessments of arterial stiffness and
vascular function, a neurocognitive assessment and brain MRI assessments. The 6-month
CORE programme will include a 3-month exercise training programme supervised by an
accredited Exercise Physiologist at the Baker Heart and Diabetes Institute, followed by
3-months of exercise training where supervision from the Exercise Physiologist is
stepped-down. Exercise training adherence will be monitored throughout the step-down
period by a web-based platform (Fitabase). Usual care participants will continue
receiving treatment from their usual healthcare professionals. Participants will then
complete two follow-up study visits following completion of the 6-month intervention
period, with identical procedures to the baseline study visits. All visits and testing
will occur at the Baker Heart and Diabetes Specialist Clinics, Level 4 Alfred Centre, 99
Commercial Road. All study visits will be separated by at least 24 hours.
Trial Population:
The population of interest for this trial are females living in the greater Melbourne
area aged 45
- - 75 years old who have previously been diagnosed with stage 1 to 3 breast
cancer and have completed cardiotoxic anti-cancer therapies (e.g. anthracycline based
chemotherapy or targeted radiotherapy) 5 - 10 years prior to study enrolment.
Randomisation:
Participants will then be centrally randomized to a CORE programme or usual care (see
Figure 1 below) using a computerized protocol at a ratio of 1:1. Randomisation will take
place at Baker Heart and Diabetes Institute and will be applied through REDCap.
Usual Care:
Participants randomised to the usual care group will be provided with their usual care by
their usual healthcare professional(s). The usual care group will not be prescribed any
exercise training through the study. However, they will be informed that they should aim
to achieve the physical activity and exercise guidelines for Australian adults or older
adults depending on their age (Care, 2024). The usual care group will not be monitored
throughout the study intervention period, except for the reporting of adverse events
where necessary.
Cardio-Oncology Rehabilitation and Exercise Programme:
Participants randomised to the CORE programme will receive exercise training that is
analogous to cardiac rehabilitation, but Exercise Physiologists will individualise each
training program using the participants baseline CPET results to maximise adherence and
improve the effectiveness of the training program beyond typical cardiac rehabilitation
programs. An Exercise Physiologist will supervise two training sessions a week and
monitor adherence to one other independent session at home each week for the first 12
weeks of the training program whilst exercise frequency, intensity, and time is
progressively increased. Supervision of the exercise training will then be stepped down
gradually after 12 weeks to a fortnightly check-in to encourage intervention adherence.
Patients will be provided with a training calendar and objective tools for tracking
physical activity (e.g. heart rate monitor and diary). Adherence will be monitored in
real-time using a research web-based platform. A similar intervention led by the PI has
demonstrated excellent patient adherence (Howden et al., 2018).
Schedule of assessments.This study will involve four study visits, which will all take place at the Baker Heart
and Diabetes Institute specialist clinics in the Alfred Centre. Initially, participants
will be screened via telephone to assess their eligibility in the trial. Researchers will
follow an approved script during telephone screening. After this initial contact,
participants will be sent the PICF. Participants will then undergo the following schedule
of assessments:
STUDY VISIT ONE (week -1):
Individuals will visit the testing facility after the initial eligibility assessment.
Participants will be instructed to avoid caffeine for ≥ 12 hours prior to study visit 1.
Furthermore, participants will be asked to avoid alcohol and strenuous physical activity
for ≥ 24 hours prior to study visit 1. During study visit one, written informed consent
will be obtained after the participant is comfortable with the information that they have
received from the research team. After informed consent has been obtained, participants
will complete questionnaires concerned with physical activity levels and menstrual cycle
history. Anthropometric data will also be collected, including height, weight and body
composition measured via DXA. Participants will then complete assessments of clinic blood
pressure (BP), and a CPET to check their cardiorespiratory fitness. Participants will
then be fitted with a hip-worn accelerometer and thigh-worn inclinometer to monitor their
physical activity levels and sedentary behaviour over the subsequent seven days.
Participants will also be fitted with an ambulatory blood pressure monitor (ABPM) to
monitor the BP for the subsequent 24 hours.
STUDY VISIT TWO (week -1):
Participants will be instructed to fast and avoid caffeine for ≥ 12 hours prior to study
visit two. Furthermore, participants will be asked to avoid alcohol and strenuous
physical activity for ≥ 24 hours prior to the study visit. During study visit two,
participants will complete ≥ 15 minutes of supine rest, before completing non-invasive
assessments of central BP and central pulse wave velocity (cPWV) via automated
Sphygmomanometry and applanation tonometry. The participant will then complete a series
of duplex ultrasound scans to determine endothelium-dependent and -independent vascular
function. Participants will also complete a brief neurocognitive function assessment.
Participants will then complete a brain MRI protocol, compromising of 40 minutes of brain
imaging whilst the participant is resting, and 8 minutes of imaging whilst the
participant completes a series of 20 second breath-holds.
STUDY INTERVENTION PERIOD (weeks 1
- - 26):
STUDY VISIT THREE (week 27):
Participants will complete procedures identical to those described in 'STUDY VIST ONE
(week -1)'.
STUDY VISIT FOUR (week 27):
Participants will complete procedures identical to those described in 'STUDY VIST TWO
(week -1)'.
