Pre-post feasibility trial of a telephone-delivered exercise intervention for patients during chemotherapy for recurrent ovarian cancer: the ECHO-R trial protocol

Introduction

Ovarian cancer is a term often used to describe cancers that arise in the ovaries, peritoneum or Fallopian tubes. Although the primary site differs, these carcinomas are histologically similar and treated in the same way, typically with a combination of surgical cytoreduction and chemotherapy.1 Approximately two-thirds of women with ovarian cancer are diagnosed with advanced stage disease (stage III or stage IV)1 and have an expected 5-year survival rate just over 30%2 (5-year relative survival for all stages combined is 49%3). Most (>80%) women who present with advanced ovarian cancer will relapse with a median time to recurrence of 16 months.1 Recurrent disease is typically incurable. The aim of treatment is to maximise length and quality of life (QoL).

Evidence from studies involving people with common cancers, such as breast and prostate, and people diagnosed with early stage disease, indicates that exercise can reduce treatment-related morbidity and improve QoL.4–6 This evidence has contributed to oncology societies and peak exercise organisations recommending exercise therapy for all people with cancer.7–9 However, whether these guidelines apply to people with rare or advanced cancers is unknown. While it is plausible that cancer cohorts typically characterised by poorer prognosis and higher morbidity have the most to gain through exercise therapy, it is also plausible that the risk of harm (whether that be related to adverse physical or psychosocial effects) outweighs the potential for benefit. Therefore, the primary objective of this trial is to evaluate the feasibility and safety of an evidence-based exercise intervention delivered via the telephone for women undergoing chemotherapy for recurrent ovarian cancer.8 Second, we aim to provide evidence on potential changes in patient and translation-relevant outcomes (including QoL and physical function), up to 3 months following intervention completion.

Methods and analysis

Trial design

The Exercise During Chemotherapy for Recurrent Ovarian Cancer (ECHO-R) trial is a phase II, pre/postintervention trial evaluating the feasibility and safety of a 6-month, telephone-delivered exercise intervention for women diagnosed with recurrent ovarian cancer who are undergoing chemotherapy. Data collection of patient-reported and objectively measured outcomes are scheduled at three time points: baseline (prior to the start of the intervention), immediately postintervention (6 months postbaseline) and 3 months postintervention (9 months postbaseline) (figure 1). The Standard Protocol Items: Recommendations for Interventional Trials checklist is provided in online supplemental file 1.

Supplemental material

Figure 1
Figure 1

Exercise During Chemotherapy for Recurrent Ovarian Cancer (ECHO-R) trial design flow chart.

Patient and public involvement

Consumer representatives (authors HO’N, MW) provided perspectives on study design, chosen outcomes of interest, and the timing, duration and delivery mode of the intervention. They also reviewed and provided feedback on all participant-facing study documentation to minimise participant burden and pilot tested the online survey procedure.

Eligibility criteria

Women diagnosed with recurrent ovarian, peritoneal or Fallopian tube cancer of all histotypes (including epithelial, germ, stromal and granulosa cells) and who will receive chemotherapy treatment, have had a platinum-free interval of at least 6 months (platinum-sensitive disease), are aged 18 years or older and are sufficiently fluent in English to comprehend with data collection and intervention requirements are eligible for participation. Those with serious medical or psychiatric conditions that might limit the ability to comply with the protocol are excluded from participating.

Recruitment and trial processes

Eligible women, presenting at one of six hospitals in South-East Queensland, Australia (ie, Royal Brisbane and Women’s Hospital, Mater Hospital Brisbane (Public and Private), Wesley Hospital, St Andrew’s War Memorial Hospital and Gold Coast University Hospital), are identified by Queensland Centre for Gynaecological Cancer (QCGC) clinical trial staff. Potentially eligible women, who are diagnosed and treated outside these hospital sites, may also self-refer to ECHO-R after hearing about the trial through advertisements on social media. Following confirmation of eligibility by the treating clinician, clinical staff discuss the trial with QCGC-identified eligible women. Interested women are then provided with the participant information and consent form, and written informed consent is collected. Women who self-refer to the trial are required to provide the signed consent prior to their treating clinician confirming eligibility (as proof of willingness to join the trial, with the knowledge that enrolment is dependent on the clinician’s response to eligibility criteria). The recruitment period commenced in January 2021 through to the end of May 2023.

Following trial enrolment, participants are phoned to obtain health history information relevant to the safe testing and prescription of exercise. This includes information about treatment schedule, disease and treatment-related side effects, comorbidities and conditions that may influence exercise participation. At baseline, and then at 6 and 9 months postbaseline, participants are asked to complete a survey (participant choice for completing survey online or via a mailed hard copy with a reply-paid envelope supplied for return) and participate in a face-to-face data collection assessment. Objective assessments of physical function are conducted for participants who reside within 50 km of the university research centre by our trial exercise professionals (ExP) at participants’ homes or the university clinic. These data collection sessions take approximately 60 min to complete. Trial data are collected and managed using the secure web-based Research Electronic Data Capture (REDCap) platform hosted at Griffith University, Queensland, Australia.10 11 Study materials designed to assist with the delivery of the exercise intervention, including a personal exercise tracker logbook (to record exercise prescription and weekly exercise completed) and a rating of perceived exertion scale (6–20) to assist with identifying intensity level, are mailed to each participant. Following baseline assessment, an assigned, tertiary and study-trained ExP contacts the participant via the telephone to introduce themselves and commence the intervention.

Exercise intervention

The assigned ExP delivers an evidence-based exercise intervention,8 using a patient-centred approach by following the Chronic Disease Self-management Intervention Model (CDSM), adapted from our previous work.12–14 The CDSM emphasises collaborative interactions with the ExP providing education, support and exercise prescription guidance according to each patient’s individual circumstances (considering health history, previous exercise behaviours, diagnosis and treatment characteristics and treatment-related side effects), while concurrently acknowledging the participant’s expertise in knowing what works best in the context of their life and their effort versus reward willingness and expectations.

The exercise intervention involves the individualised prescription of aerobic and resistance-based exercise. The assigned ExP works with each participant to prescribe and monitor exercise mode and intensity, and session duration and frequency. The target dosage for the exercise intervention is at least 150 min/week of moderate-intensity exercise (or the equivalent of 450 metabolic equivalent minutes per week) which is based on current exercise oncology guidelines.8 15 The starting exercise dosage and pace of progression to this weekly target are individualised according to each participant’s circumstances and preferences. The ExP will support the participant to progress towards the target dosage throughout the intervention at a pace appropriate for them, and/or to maintain a minimum weekly exercise dose consistent with the target. It is the goal of the ExP to ensure that by intervention completion, each participant has the experience, knowledge and self-efficacy to independently regulate their weekly exercise appropriately.

The foundation intervention is delivered via 12 telephone sessions, scheduled across the 6-month intervention period, with the option to use online videoconferencing platforms (such as Microsoft Teams or Zoom) as desired by the participant or ExP. The intervention schedule follows weekly sessions for the first month, fortnightly sessions for 3 months and a monthly session for the remaining 2 months (table 1). The duration of each session will be between 30 and 60 min. The intervention will be supported by up to five additional in-person, face-to-face sessions with their ExP or a community-based ExP in their local area. This intervention feature is optional for a participant and aligns with Australia’s Chronic Disease Management Plan, which allows for up to five reimbursable visits per year with an accredited exercise physiologist or physiotherapist.

Table 1

The foundation ECHO-R intervention session contact schedule

The foundation intervention schedule reflects lessons learnt with the telephone delivery of exercise interventions in our prior trials involving women with breast cancer13 16 and ovarian cancer,14 17 and discussions with study investigators (which included consumers) regarding what may work best in the context of treatment for recurrent ovarian cancer. The schedule is purposely flexible to ensure the ExP and participant can modify timing according to individual circumstances and preferences. In the context of this pragmatic trial, women having trouble adhering to the prescribed exercise dosage can be provided with more frequent sessions (maximum number of sessions: 20) should this be perceived useful.

Each intervention session will involve an exercise prescription (developed in conjunction with the participant) including exercise mode (aerobic and resistance), frequency, duration and intensity, considering participant’s exercise history, current health status and preferences for types of exercise. The exercise prescription is modified according to the presentation of treatment-related symptoms, symptom response to exercise and by adhering to the exercise principle of gradual progression. An example exercise prescription for a deconditioned, inactive participant and a participant with a history of physical activity is shown in table 2. The ExP will proactively discuss barriers to exercise adherence and discuss strategies to optimise adherence with the participant. Educational content relevant to exercise and information related to behaviour change (barriers, motivators, goals) will be integrated into the routine delivery of the intervention.

Table 2

Intervention target exercise dosage, compliance criteria and example exercise prescriptions and parameters

Participants are prompted at each session to report their completed exercise (session date, mode and type, frequency, duration and intensity), barriers to exercise adherence and the occurrence of any adverse events (AE) at any time between sessions with the ExP. AEs are classified as any untoward medical occurrence or symptom in a participant and that does not necessarily have a causal relationship with the trial.18 AEs are deemed to be exercise related if they occurred during or within 2 hours of exercise or judged by the ExP as having a reasonable causal relationship with the trial intervention (ie, exercise). Exercise-related AEs could include injuries (including falls), medical events (eg, unstable angina) and/or exacerbations of treatment-related side effects. The ExP will respond to AEs with administration of first aid, cessation or modification of exercise or referral to other healthcare professionals as required.18

AEs will be categorised according to the Common Terminology Criteria for Adverse Events19 recording type, grade, causality (how likely the event was caused by exercise), impact on the participant and/or impact to the intervention and recommendations to alter exercise prescription (if any are required). AEs will be classified as grade 3 if they lead to hospitalisation and/or lead to limitations in self-care activities of daily living. ExPs will prompt participants at each session to update progress on the AE until it is resolved. The ExP will record the data in a case management folder, which is subsequently entered into REDCap. All case management folders are audited by a senior ExP to check for missing data and review the appropriateness of exercise prescription. To maintain intervention fidelity, the senior ExP leads monthly meetings with all study ExPs to discuss cases (with a focus on cases having difficulty adhering to the intervention) and to provide continuing education.

Study outcomes

Information relevant to the primary outcomes of interest is extracted from the ExP case management folders maintained throughout the exercise intervention. Secondary outcomes measuring intervention effectiveness are obtained through patient-reported (surveys) and objectively measured (physical assessments). Diagnosis and treatment details are abstracted from participants’ medical records.

Primary outcome measures

Feasibility and safety

Intervention feasibility measures include recruitment rate, retention, adherence to scheduled sessions (telephone and/or face to face), compliance with weekly exercise dosage prescribed and level of satisfaction with the intervention. Safety of the intervention will be assessed by the number, severity and grade of exercise-related and non-exercise-related AEs. The a priori criteria for determining whether the intervention is deemed feasible and safe are presented in table 3.

Table 3

Assessment criteria for feasibility and safety

Secondary outcomes of interest

Quantification of the potential magnitude of benefit to be gained through exercise will be addressed via our secondary outcomes of interest, including: QoL, level of physical activity, physical function and fitness and treatment-related symptoms.

Quality of life

Self-reported QoL is assessed using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).20 The FACT-O assesses four dimensions of well-being: physical, functional, social/family and emotional, as well as an ovarian cancer-specific subscale. Scores obtained by the subscales combine to form a total score ranging from 0 to 152; higher scores indicating better QoL. The Euro-Qol-5D is a standardised instrument for use as a generic measure of health utility21 and will be used in conjunction with cost estimates to inform cost-effectiveness.

Level of physical activity

Level of physical activity is assessed using the Active Australia Survey.22 The survey asks respondents about the amount of physical activity completed ‘in the last week’ covering (1) walking (continuously, for at least 10 min, for recreation, exercise or to get to or from places), (2) vigorous gardening or heavy work around the yard (which made you breathe harder or puff and pant), (3) vigorous physical activity (which made you breathe harder or puff and pant) and (4) any other physical activities of moderate intensity. In line with methods used in previous studies, an additional question was added to ask about the amount of strength/resistance exercise completed ‘in the last week’.23 For each of the above, participants are asked to record the number of times they carried out the activity in the last week along with the total time spent doing the activity (in hours and minutes).

Treatment-related symptoms

Fatigue, peripheral neuropathy, anxiety and depression, sleep disturbance and hope are being assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue,24 Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity Scale,25 the Hospital Anxiety and Depression Scale,26 the Pittsburgh Sleep Quality Index27 and the abbreviated Herth Hope Index,28 respectively. Lower limb lymphoedema is objectively measured with bioimpedance spectroscopy29 using the SOZO Digital Health Platform (ImpediMed). Self-reported lymphoedema and swelling is assessed using survey items successfully used in a previous longitudinal cohort study.30 The Measure of Ovarian Symptoms and Treatment Concerns,31 which is a valid measure that quantifies patient-reported symptom burden, benefit and adverse effects in recurrent ovarian cancer, is also being used to assess symptoms. The measure contains 24 items generating five indexes related to abdominal symptoms, disease or treatment-related symptoms, chemotherapy-specific symptoms, psychological symptoms and well-being.

Physical function and fitness

Physical function and fitness outcomes are assessed using standard exercise testing protocols.32 Objective aerobic function is assessed using the 6 min walk test, 30 s sit to stand and the 2 min step test. Hand grip strength is assessed using a portable TTM Advanced Hand Dynamometer. Chest strength and leg strength (knee flexion) are assessed using the Activ5 digital dynamometer. Balance is assessed using the single-leg stance test. Body composition is measured via bioimpedance spectroscopy using the SOZO Digital Health Platform.

Intervention cost

A record of resources required for implementing the intervention (staffing, travel, administration) is being maintained by trial staff. Costs the participant may have incurred through the voluntary purchase of exercise equipment to assist them during the intervention (eg, purchase of exercise shoes, free weights, etc) are assessed via standardised questions in the postintervention data collection survey.

Table 4 provides a summary of the primary and secondary outcomes assessed during the trial.

Table 4

ECHO-R trial outcome measures, data collection tools and assessment timing

Exploratory outcomes of interest

Qualitative data collected via semistructured interviews with a subgroup of the sample following completion of the intervention will provide an in-depth understanding of the barriers, facilitators, perceptions and preferences influencing their exercise participation throughout the intervention period and more broadly during cancer survivorship (online supplemental file 2). Using quantitative data collected we will also explore associations between exercise dose completed and changes in efficacy outcomes of interest, which may provide indications of minimum exercise thresholds needed to achieve benefit.

Supplemental material

Treatment and medical history

Information on cancer and treatment-related details will be collected via extracting data from medical records at trial enrolment and at 9-month follow-up. All data will be entered into the centralised REDCap database via an electronic case report form. Patient status will be confirmed at a 2-year follow-up via medical records.

Sample size

The target sample size for the ECHO-R trial is 80 women, with a recruitment period of two and a half years (January 2021 to May 2023). This sample size is more than adequate for providing data on feasibility and safety, which reflects the primary outcomes for this phase II trial.33 A target sample size of 80 women would also provide >80% power to detect a minimum difference of interest between preintervention and postintervention efficacy outcomes (allowing for attrition). QoL requires the greatest sample size of all secondary outcomes, with 80 women allowing for >80% power to detect a change in QoL of 6 units (assuming an SD of change in FACT-O in women with recurrent ovarian cancer of 15, 5% type I error (two tailed)).

Statistical analysis

Summary baseline statistics to describe the sample will be presented using counts and percentages for categorical variables or means (SDs) and medians (minimum, maximums) for parametric and non-parametric continuously scaled variables, respectively. The primary outcome of feasibility (including recruitment rate, exercise adherence and compliance and intervention satisfaction) and safety will be reported descriptively, as counts and percentages and group medians (minimum, maximum). Secondary outcomes will be assessed using generalised estimating equations to determine changes in outcome measures over time (preintervention, postintervention, 3-month follow-up). Estimated means, 95% CIs and p values will be reported. Semistructured interviews will be transcribed verbatim and an adaptive approach will be used in thematic analysis to search for common themes across participants.

Ethics and dissemination

Ethical approval for the ECHO-R trial has been obtained by the Metro North Health Human Research Ethics Committee (HREC/2020/QRBW/67223) and the relevant hospital sites: Gold Coast University Hospital (SSA/2020/QGC/67223), Mater Hospitals (MSSA/MRGO/67223), Royal Brisbane and Women’s Hospital (SSA/2021/QRBW/67223), Uniting Care Health (202108) and Griffith University (2020/913). Treating clinicians were required to confirm patient eligibility criteria and suitability for the trial prior to obtaining written informed consent from all patients.

Establishing that women diagnosed with recurrent ovarian cancer are interested in participating in an exercise intervention and can safely do so, is the necessary first research step in determining the applicability of exercise therapy for this unique and under-researched cancer group. As identified by the consumer investigators on this trial, it also seems unreasonable and potentially unethical to restrict access to an intervention with potential to reduce morbidity outcomes and improve QoL in a group who have high unmet supportive care needs, particularly in relationship to fatigue and not being able to do the things they use to do.34 35 The trial design (phase II over a phase III, randomised controlled trial) and our chosen primary outcomes (feasibility and safety) reflect these important research and consumer-driven considerations. Quantifying the potential magnitude of benefit to be gained through exercise therapy is relevant to patients and their clinicians and is addressed through our secondary outcomes of interest.

ECHO-R will generate the necessary preliminary evidence to show whether exercise is feasible and safe to improve the lives of women receiving treatment for recurrent ovarian cancer. The evidence to answer this question is currently absent; opinions are equivocal with some stating that every patient should exercise regardless of stage of disease, while others point to the risk of exhaustion, aggravation of treatment-related side effects such as pain and fatigue, as well as reduced ability to cope with treatment. Findings from this trial will inform to what extent, if at all, changes to national and international physical activity and exercise prescription guidelines for people with cancer are required to accommodate women with recurrent ovarian cancer. The dissemination plan involves publication of peer-reviewed manuscripts (at least two) and presentation of findings at exercise and oncology conferences.

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