The FiGHTINGF!T trial is a prospective, single centre, randomised controlled (RCT) cross over trial. Following baseline assessments, participants will be randomised to either immediate exercise or delayed exercise (usual care) for an initial period of 10 weeks. Following an interim assessment at 10 weeks, participants will cross over to the opposing group and either commence exercise (delayed exercise group) or commence usual care. There will be no wash out period between groups. The study is registered at the Australia New Zealand Clinical Trial Registry (ANZCTR) (ACTRN12620000663954) with participant recruitment for the trial now initiated. Proposed study activities are outlined as per SPIRIT guidelines (Table 1; Additional file 2). The RCT will be conducted over three years at the Sir Charles Gairdner Hospital, Perth, Australia. Figure 1. depicts the study design as per the CONSORT guidelines for randomised crossover trials.(27)
Table 1. Proposed study activities and summary of assessments
Exercise prescription
All exercise sessions will be multi-modal and follow the same format throughout the 10-week intervention. Participants will commence each session with a five-minute warm up, followed by aerobic bouts, a resistance training component and concluding with a 5-minute cool down and static stretching period of major muscle groups. The aerobic component of the program will be based on the participant’s physical capabilities and preference of the modalities available within the gym (including cycling on an upright/recumbent bike, treadmill walking/jogging and/or skipping) and aim to accumulate 20–30 minutes at moderate intensity over the duration of the session. Intensity will be monitored using heart rate (HR) and rating of perceived exertion (RPE).(28) Moderate intensity aerobic exercise is considered 60–85% of maximal heart rate (220-age)(29) or an RPE of 12–14. Participants who are unable to complete 20 minutes continuously will aim to accumulate the required load in bouts of 5 to 10 minutes as tolerated. The resistance training component will comprise of 6–8 exercises targeting the major muscle groups of the body. Participants will complete 2–4 sets of 8–15 repetitions, at 60–80% of 1 repetition maximum (1RM) or an RPE of 12–14.(29) Based on the thorough baseline assessment, any pre-existing injuries or treatment-related effects will be considered when prescribing and progressing all exercises. The sessions will aim to increase in exercise intensity as tolerated. Participants will also be encouraged to engage in aerobic exercise outside of supervised exercise sessions and asked to document their activity in exercise journals to meet exercise recommendations for cancer survivors.(16, 21) Exercise programs will be modified on a weekly basis as required relative to participants’ treatment schedules and related side effects, as well as changes in their individual physical conditioning throughout the program. Participants’ vital signs and most recent full blood picture will be reviewed prior to commencing each and every exercise session, to determine their safety for exercise and any need for program modification.(30)
Primary outcome measure
The primary outcome of this RCT is cardiorespiratory fitness (V02peak) as measured by a submaximal cardiopulmonary exercise test (CPET). The submaximal test will be conducted in a research setting by trained exercise specialists only, who will be blinded to the participant group allocation.(31) Participants will be instructed to follow their usual diet and incidental activity and abstain from formal exercise in the 24 hours prior to testing. Additionally, the study team will review participants’ recent blood test results prior to assessments to ensure results are within the safe parameters for exercise.(30) Prior to commencing the test, participants’ resting heart rate and blood pressure will measured and a heart rate monitor will be attached to the participant (Wahoo Tickr heart rate monitor, Wahoo Fitness LLC, Georgia, USA). Target heart rate (THR) will be calculated using the formula (220-age)(32) x 0.85 which will be used as criteria to terminate the test unless volitional exhaustion is met prior to this. Participants will be sat on a front access Exertech Ex-10 cycle ergometer (Repco Cycle Company, Huntingdale, Victoria, Australia) and familiarised with the testing protocol. The ramped protocol will have participants commence cycling at 20 watts(W) for 1 minute and continue to increase by 20W per minute until they reach their THR or volitional exhaustion. Participants will complete the stage in which they reach their THR unless concluded prior to this. At the end of each minute, heart rate and RPE will be recorded.(28) Participants will complete a 3-minute cool down on the bike pedalling with no resistance at a self-selected slow speed. Recovery heart rate and blood pressure will be recorded 10 minutes after the cessation of the test.
During the test, participants will be required to breathe through a mouthpiece connected to a computerised gas analysis system. The system includes a ventilometer (Universal ventilation meter, Vacumed, Ventura, CA,USA) and oxygen and gas analysers (Ametek Applied Electrochemistry S-3A/1 and CD-3A, AEI Technologies, Pittsburgh, PA) which calculate minute ventilation (VE), respiratory exchange ratios (RER) and oxygen and carbon dioxide in expired air at 15 second intervals respectively. Calibration of the equipment will be conducted prior to and following each test using a standard reference gas of known concentration. Values at the conclusion of the test will be recorded in absolute (L/Min) and relative (mL/kg/min) terms. Predicted peak oxygen consumption (V02peak) will be extrapolated using the participants’ heart rate (HR) and V02 from two submaximal stages from the test where a steady state heart rate between 115–150 beats per minute is recorded. The slope will be calculated using the ratio of difference between the two submaximal V02 measures and their corresponding heart rates and then be used to extrapolate to predicted maximal heart rate (220- age).(32–35)
Secondary outcome measures
Strength and physical function
Gross muscular strength will be assessed using a one-repetition maximum test for chest press, decline leg press and seated row, recorded in kilograms (kg). Participants with any known bone metastases will be excluded from completing tests that load the location of affected bone.(16) Testing will be conducted by an AEP in accordance with standard ACSM guidelines.(29) Bilateral grip strength will be assessed using a grip strength dynamometer (Jamar Plus Digital, Paterson Medical, IL, USA) with the best of three attempts recorded in kilograms. Functional upper limb and lower limb endurance will be assessed using 30-second push ups and sit ups and a 5-repeated sit to stand (STS) test.(29)
Anthropometry, body composition and body mass index
Body mass (kg), height (cm), body mass index (BMI, m2) and body surface area (m2) will be recorded as anthropometric measures. Body mass will be measured to the nearest 0.1 kg on electronic scales (Sauter Model EB60, FSE Scientific, Sydney, Australia) with participants asked to remove their shoes and heavy clothing. Body surface area (m2) will be obtained from the participants’ chemotherapy charts from within their medical records as it will be used to analyse chemotherapy-related toxicities. Height will be measured using a wall mounted stadiometer to the nearest 0.1 cm (Seca 216 Measuring Pole, Birmingham, UK) and BMI will be calculated using recorded body mass and height by dividing body mass (kg) by height in metres squared (m2). Waist and hip circumference will be measured using standardised testing protocols.(34) Dual-energy X-ray absorptiometry will be used to record total lean mass (kg) (LM), total fat mass (kg) (FM), proportion of total mass being body fat (%) (%FM) and bone mineral density (BMD) (DXA; Lunar Prodigy, GE Medical Systems, Madison, WI, USA).
Patient reported activity and quality of life (QoL)
Patient reported physical function, emotional and social wellbeing, fatigue and quality of life will be evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30),(36) the Hospital Anxiety and Depression Score (HADS)(37) and an age-specific version of the PEDS-QL and Multidimensional fatigue scale questionnaires.(38–40) Each of the quality of life tools are commonly used and have been validated in AYAs. Participant self-reported physical activity will be assessed using the International Physical Activity Questionnaire.(41)
Patient reported treatment-related toxicities
In order to determine that participants meet the safety requirements to complete exercise sessions, they will be required to undergo weekly full blood count (FBC), urea and electrolyte (U&E) and liver function (LFT) blood tests. These results will be reviewed prior to each exercise session to ensure participants meet predetermined safety parameters for exercise.(30) The results will also be reviewed and graded as per the Common Terminology Criteria for Adverse Events (CTCAE Version 5.0)(42) to determine any impact exercise may have on these variables. Further, participants will be contacted weekly by a member of the research team blinded to group allocation to determine if the participant has experienced any additional treatment-related side effects, including but not limited to nausea, vomiting, constipation, pain and fatigue (Additional file 1).(42) These participant-reported side effects will also be graded by the research team as per the CTCAE version 5.0.(42)
Feasibility
The feasibility of the exercise intervention will be determined based on eligibility rate, recruitment rate, compliance to the study protocol, adherence to the exercise intervention and withdrawal rates. Safety will be assessed by monitoring for any adverse or serious adverse events during any of the assessments or supervised exercise sessions. Any adverse events will be reported to the appropriate HREC bodies within an expedient time frame. All data will be collected, input and stored in accordance with HREC guidelines as outlined in FiGHTINGF!T Protocol Version 2 03012019.
Statistical Consideration
A total of 40 participants will be recruited, evaluated and analysed as part of this study. Analysis will be performed using an intention to treat approach.(43) A power analysis using PS Power and sample size calculations Version 3.1.2 has been performed to calculate the sample size required for this study, based on the primary outcome variable VO2peak (ml.kg.min− 1). In the absence of comparable published data in AYA patients, similar studies undertaken by Thorsteinsson et al.(44) and West et al.(45) in paediatric and adult patients demonstrated an effect size of 0.80. The standard deviation across multiple studies utilising VO2peak as the primary outcome measure varies from 1.5 ml.kg.min− 1 to 5.7 ml.kg.min− 1 and, therefore, a median value (3.6 ml.kg.min− 1) has been utilised for this trials sample size calculation. Assuming a 5% significance level and a power of 0.8, a sample size of 36 patients (18 per group) will be required. An additional 10% has been included (n = 4) to allow for attrition or unusable data.
Standard descriptive statistics (M, SD, n,%) will be calculated to summarise data on participant demographics and recruitment rates. Outcome analyses will include Student’s t-test, chi-square, correlation, regression and repeated measures ANOVA to examine differences over time. Further statistical analysis will be employed to investigate any associations between exercise related changes and TRTs. Any clinically relevant covariates will be included in the analyses. All statistical analyses will be conducted using SPSS software (version 20.0, IBM, Armonk, NY, USA) and significance will be set at p ≤ 0.05.
Dissemination
The results for the primary and secondary outcomes of this RCT will be shared regardless of the direction or magnitude of the effect. These outcomes are planned to be published in international high-quality, peer reviewed journals. Results will also be presented at national and international conferences as well as used for teaching purposes to community and university led forums.