Administrative information

Title

EffEx-HN Trial: Study protocol for a randomized controlled trial on the effectiveness and feasibility of a comprehensive supervised exercise program (CSEP) during radiotherapy in head and neck cancer patients on health-related quality of life

Trial registration

ClinicalTrials.gov

Identifier: NCT05256238

February 25 2022

Protocol version

Version 2.2 January 20, 2022

Funding

Kom Op Tegen Kanker

Author details

sandra.nuyts@uzleuven.be

 + 32 16 347 600

an.degroef@kuleuven.be

 + 32 16 342 171

kaat.vanaperen@kuleuven.be

 + 32 16 345 196

Name and contact information for the trial sponsor

University Hospitals Leuven

Herestraat 49, 3000 Leuven, België

 + 32 16 33 22 11

Role of sponsor

The study is conducted at the University Hospitals Leuven

Introduction

Background and rationale

With over 500,000 annually reported new cases worldwide, head and neck cancer (HNC) is the seventh most common type of cancer worldwide [1, 2]. HNC contains a diverse group of malignancies originating from the mucosa in the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. Unfortunately, the majority of patients with HNC have locally advanced disease at diagnosis and are, therefore, treated with chemoradiotherapy (CRT) or with radical surgery followed by adjuvant (C)RT. Treatment of HNCs with (C)RT frequently results in serious and persistent impairments in physical and psychosocial functioning [3, 4].

The WHO International Classification of Functioning, Disability and Health (ICF) model offers a framework for understanding disability and health, e.g., during and after HNC [5]. At function level of the ICF, swallowing and speech impairments are specific morbidities experienced in over half of HNC patients at various intensities before, during, and after cancer treatment [3]. Additionally, a large part of HNC patients experience lymphedema, pain, stiffness, and/or weakness of the jaw, neck, and shoulder [3, 4]. These local impairments are mainly caused by radiotherapy-induced fibrosis and neck dissection surgery. All this contributes to activity limitations in neck and shoulder function in about two thirds of HNC patients [3, 4]. More general consequence including fatigue, decreased physical fitness, muscle wasting, and related weight loss are other activity limitations [4,5,6]. These impairments restrict physical functioning and participation in activities of daily living of many patients, consequently impeding their quality of life [6]. Besides the physical and psychosocial consequences of the cancer treatment, HNC patients typically start their cancer treatment already with poor physical and psychosocial health, compared to healthy controls, and hence, QOL is already impaired prior to starting any intervention [6, 7].

The awareness on the importance of exercise therapy for management of the side effects at the different levels of the ICF during and after cancer treatment in general is increasing rapidly [6,7,8,9]. It has been shown that a sufficient level of physical activity before, during, and after cancer treatment is associated with a better prognosis, a lower risk of recurrence, a lower risk of mortality [7,8,9,10], fewer negative treatment-related side effects [9], and a better quality of life [8,9,10,11]. At this moment, the guidelines of the American College of Sports Medicine recommend 2- or 3-weekly 20–30 min sessions of moderate aerobic exercise plus 2-weekly resistance training at moderate to vigorous intensity (2 sets of 8–15 repetitions at > 60% of the 1 repetition maximum for major muscle groups) to have effect of exercise on health-related quality of life in cancer populations. These guidelines are based on research in mostly breast, prostate, and colon cancer populations as these are the most prevalent populations [8,9,10].

Up to now, it has not yet been investigated properly whether these general guidelines for exercise programs are translatable to the HNC population. Given the specific physical and psychosocial needs in the HNC population described above, this should be investigated properly [6,7,8,9]. In addition, since HNC patients often start their treatment already with poor physical functioning [6], exercise therapy should be initiated at time of diagnosis and continue during and after treatment. In the currently available studies, the outcomes and the content of the exercise programs are very heterogeneous making it difficult to draw conclusions at this moment [8,9,10,11]. First, in a pilot study of Zhao S.G. et al. from 2016, HNC patients undergoing concurrent CRT and participating in a program designed to maintain physical activity during cancer treatment maintained or improved function and QOL. They also concluded that the exercise intervention was feasible, thereby providing the basis for larger future interventions with longer follow-up [12]. Second, a study of Samuel et al. (2019) showed that an 11-week structured exercise program for HNC patients receiving CRT helps in improving their functional capacity and quality of life up to 11 weeks after diagnosis [13]. The exercise program consisted of 5 trainings per week, with 7 weeks in the hospital and 4 weeks of home-based trainings. Limitations of this study are that there was no maintenance program and no follow-up period after the 11 weeks.

In addition, next to the effectiveness of an exercise program on different health-related outcomes, barriers and facilitators for participating in a CSEP starting from diagnosis should be properly investigated. In the trial of Samuel et al., patients attend 75% of the prescribed sessions [14]. Unfortunately, specific barriers and facilitators or reasons for non-adhering were not studied. Possibly, the intense schedule of 5 trainings per week may have decreased adherence in that study. Also, it may be interesting to explore whether the combination of in hospital with home-based trainings is more beneficial. Travel time to the hospital is indeed a barrier to exercise, which confirms the need of combining hospital and home-based exercise programs [14].

Given this, a comprehensive supervised exercise program (CSEP) starting early during CRT may be beneficial to prevent worsening of a person’s functioning and limit the physical impact of the treatments for HNC [6,7,8,9]. Such a program should consist of a combination of aerobic training, progressive resistance training for all major muscle groups and stretching exercises, in particular in the upper limb region. The program should combine in hospital training with home-based trainings and have a sufficiently long duration.

Objectives

There is a need to improve the integration of exercise programs into HNC care. The aim is to help HNC patients to prevent decline in and restore physical, mental and social functioning. Currently, no strong evidence is available for a program adapted to the specific needs of HNC patients, in particular during cancer treatment [3, 4, 6]. The primary objective is to examine the effectiveness of a CSEP, in addition to usual supportive care, on health-related quality of life during the treatment of HNC, compared to usual supportive care alone, up to 1 year after diagnosis. This will be performed through an open-label randomized controlled trial.

Secondary objectives entail gathering information on the effectiveness of the CSEP, in addition to usual supportive care on secondary outcome parameters including physical and mental functioning, activity level, and participation level of the ICF. In addition, the feasibility of such CSEP as well as possible barriers and facilitators for participating in a CSEP during HNC treatment will be studied.

Trial design

A parallel, two-arm, open label trial will be conducted. This single center prospective randomized clinical study will be performed to investigate the effectiveness and the feasibility of a comprehensive supervised exercise program (CSEP) in addition to usual supportive care compared to usual supportive care alone in patients undergoing CRT for HNC, the EffEx-HN trial. This is a superiority trial design because we aim to investigate whether a CSEP is more effective in improving health-related quality of life than the current standard of supportive care. To study the feasibility of the CSEP, a qualitative study will be performed in a subgroup of participants of the large prospective randomized clinical study described above. Quantitative data on feasibility will be collected in all participants.

Methods: participants, interventions, and outcomes

The SPIRIT guidelines were used [15].

The recruitment of the clinical trial started in January 2022 at the department of Radiation-Oncology of the University Hospitals in Leuven (Belgium). The supervised exercise sessions of the intervention group take place in the exercise room of the department of Physical Medicine and Rehabilitation of the University Hospitals in Leuven (Belgium). A flowchart of the EffEx-HN Trial is provided in Table 1.

Table 1 Trial flowchart: enrolment, intervention, and assessments of the EffEx-HN trial
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Patient and public involvement in trial design

The protocol was submitted and approved by the patient support group of HNC patients of the University Hospitals Leuven.

Eligibility criteria

HNC patients are eligible to participate if they are scheduled for radiotherapy at the Radiation-Oncology department of the University Hospitals Leuven. Inclusion criteria are as follows: (1) ≥ 18 years, (2) diagnosed with primary malignant tumor head and neck region, (3) ECOG performance score 0–1, (4) able to complete baseline assessments prior to start of (chemo)radiotherapy, (5) physically and mentally capable of taking part in an exercise program and motivated to engage in a supervised exercise program. Patients are excluded if one of the following exclusion criteria are present: (1) < 18 years, (2) ECOG performance score ≥ 2, (3) treated with palliative intent, (4) evidence of distant metastases, (5) no basic level of reading and writing in Dutch. Participation of a patient in the study can be discontinued based on the participant’s request or if the disease is worsening, to the extent that exclusion criteria are present (treatment with palliative intent, evidence of distant metastases).

Participant screening, recruitment, and consent

Participants are identified from scheduled consultation lists and screened for eligibility criteria. Potentially eligible participants are approached and recruited during the consultation at the department of Radiation Oncology of the University Hospitals Leuven, where the oncologist (principal investigator (PI)), SN, and patient discuss the suggested treatment option. The PI will inform every new patient, diagnosed with HNC eligible for this study, about the study. All eligible patients also receive a one-on-one explanation of the study by a member of the research team and an information letter during this consult. After obtaining informed consent, patients will randomly be assigned to receive either the usual supportive care + CSEP (intervention group) or usual supportive care only (control group).

Allocation and randomization

A 4-size permuted block randomization is used. The randomization is computer-generated, in particular the allocation to the intervention or the control group is concealed and performed by the randomization module of the Research Electronic Data Capture system (REDCap) before the start of the exercise program, ensuring blinding of the research team [16, 17]. The sequence of randomization is decided by the patient’s record identifier in REDCap, which is received after signing informed consent. An open label study is performed, which means that the therapist/assessor and patients are not masked for the allocation to the intervention or control group. The therapist giving the exercise program and the assessor are the same individual during the entire study period.

Interventions

Usual supportive care

Both groups will receive the current standard of supportive care including whenever required guidance by a dietician on oral food intake, smoking cessation counseling, and speech and language therapist guidance concerning swallowing exercises, follow-up by the social workers, psychologists, and nurse care team. Additionally, they will be informed at the start of treatment about the importance of physical activities, and a brochure with general advice for exercises will be provided.

Dedicated comprehensive supervised exercise program (CSEP)

The intervention group will receive the CSEP, additional to usual supportive care. The CSEP consists of a one-hour individualized exercise program three times a week, starting within 1 week after the start of the CRT, taking into account motivation, personal goals, and pre-diagnostic activity level. The program is tailored to the acute effects of CRT as well (e.g., intensity and number of sessions). The training sessions will be organized in small groups of 3–4 patients, consisting of a combination of 30 min aerobic training at moderate intensity (walking, cycling) and 30 min resistance strength training and stretching (exercises for all major muscle groups and in particular the upper limb, head and neck region). A total of 18 supervised sessions are held in the hospital twice a week in week 1 to 6 and once a week in week 7 to 12, while the remaining one or two weekly sessions are performed independently at home. During the maintenance program (from week 13), patients will exercise at home with a monthly tele-consultation. Patients will have online access to videos of exercises to be performed at home. A selection of exercises will be made for each individual patient based on preferences and tailored to their exercise tolerance. During the tele-consultation, the physiotherapist discusses the progression of the training program at home and if any adjustments are needed.

The CSEP is supervised by a physiotherapist, KVA. The therapist will be dedicated full time to this program to conduct the patient assessments, to supervise the exercise sessions at the hospital and the tele-consultations during the maintenance program, and to coordinate the project. In addition to the exercise program, the participants in the intervention group attend in the first month an educational session about exercise during and after cancer treatment.

Outcomes

Effectiveness study

At 5 time-points, evaluation moments are organized, during which self-reported questionnaires and clinical assessments are performed. The evaluation moments take place at baseline (T0), at 6 weeks (T1), at 12 weeks (T2), at 6 months (T3), and at 12 months (T4). The assessments will be performed at the Department Physical Medicine at the University Hospitals Leuven. Most of the questionnaires are conducted at home, through a digital link to the Research Electronic Data Capture (REDCap). The evaluation moments take place in the hospital. In total, administering the questionnaires through REDCap takes 60 min. The clinical assessment takes 45 to 60 min. The primary outcome parameter is health-related QOL measured with the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) at 6 months post-diagnosis. A key-secondary outcome is the physical functioning subscale of the EORTC QLQ-C30. The secondary outcome measures are also shown in Tables 2 and  3. In addition, personal factors, including patient-related factors (age, social status, work status), and cancer (treatment)-related factors will be collected from the participant’s medical file.

Table 2 Study outcome measures by assessment time-point: self-reported outcomes
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Table 3 Study outcome measures by assessment time-point: clinical assessments
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Feasibility study

The feasibility study exists of a quantitative and qualitative part. First, the quantitative feasibility outcome measures are collected in all participants of the clinical trial, at baseline (T0), 12 weeks (T2), and/or 6 months (T3) follow-up. The outcomes of interest are displayed in Table 4. Second, the qualitative part of the feasibility study consists of organizing focus groups. For the focus group, we anticipate to engage 15 participants out of the total group of 150 participants at each time point (baseline, 12 weeks, 6 months). Review of the literature indicates that data regarding feasibility is typically achieved within 2 to 3 cycles of focus groups [48]. Additionally, data saturation can usually be reached with samples as small as 5 to 7 participants per group. Therefore, we aim to recruit 15 consumers for 2 to 3 focus groups. The aim of these focus groups is to capture qualitative data regarding barriers and facilitators for participating in the CSEP that provided explanation and additional information to the quantitative questionnaire. The focus group leader will ask a series of open-ended questions based predefined subjects. Another researcher will observe the focus groups. All focus group sessions will be video recorded and transcribed.

Table 4 Feasibility outcomes: quantitative part
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Sample size

The study was powered to have at least 80% power to detect based on a two-sided test with alpha equal to 0.05 a difference of 10 points in general health-related quality of life measured with the EORTC QLQ-C30 (primary outcome) between both groups at the primary endpoint, i.e., 6 months post-diagnosis. A drop-out of 5%, 10%, and 20% is anticipated at 6 weeks, 12 weeks, and 6 months, respectively. Based on reference values for the EORTC QLQ-C30, a standard deviation of 22.7 was assumed [49]. Further, moderate correlations equal to 0.5 were assumed for the associations with the baseline measurement. Under these assumptions, 75 subjects per group are necessary. The study was also powered on one key-secondary outcome, i.e., the physical functioning subscale of the EORTC QLQ-C30. Since the assumed standard deviation for this subscale was slightly lower (based on the EORTC QLQ-C30 reference values 2008), this has no impact on the required sample size. Otherwise said, with 75 subjects per group, the power is higher than 80% for this secondary outcome, more specific 87.7%.

For the feasibility study, no sample size calculation was performed.

Data analysis

Effectiveness study

For the general health-related quality of life and the key-secondary outcome (physical functioning subscale), the mean value at 6 months will be compared between both groups after correction for the baseline value. To handle the presence of missing data, this ANCOVA approach will be implemented using a constrained longitudinal data analysis (cLDA) using all collected measurements over time (baseline, 6 weeks, 12 weeks, 6 months, 12 months). Both comparisons will be based on a two-sided test with alpha equal to 0.05.

Feasibility study

All video recorded interviews will be transcribed verbatim. Transcripts (audio and typed feedback) will be uploaded into NVivo 12 coding software. Framework matrix analysis will categorize themes, which will yield specific, recurring information regarding patient feedback [48].

Data security and management

Data will be prospectively collected from the participating patients by the co-investigators and stored in the Research Electronic Data Capture system (REDCap) [16, 17]. Only the patient number will be recorded in the database. The investigator will maintain a personal patient identification list (patient numbers with corresponding patient names) to enable records to be identified. Clinical patient data will include coded patient-related information, including (but not limited to) age, gender, pathological diagnoses, and clinical TNM stage. The electronic patient file system of the University Hospitals of Leuven will serve as the source for the clinical information, and electronic CRFs will be used for collection of these coded data. A dedicated, trained person will add all research information from this project to the REDCap database, which was specifically designed for this research. All study data will be kept by the principal investigator and the co-investigators. All data uploaded to the cloud system will be coded data; the key of the data will be stored separately from the data. Only coded information will be extracted and used for the downstream research analysis. During the project, research data will be preserved in the shared network drives. After the project, the research data will be preserved in archive drives and external hard disks. All data will be stored for a period of 25 years after the end of the project, according to the requirements of the Clinical Trial Centre of UZ Leuven. All data will be stored on the central servers of UZ Leuven. The final responsibility will be on the principal investigator, SN.

Trial monitoring

Regarding quality assurance, assessments and interventions will be performed by an experienced physical therapist, KVA, with a master’s degree in rehabilitation sciences. The physical therapist and PI have a GCP certificate. Besides, the PI and UZ Leuven will permit trial-related monitoring, audits, EC review, and regulatory inspections (where appropriate) by providing direct access to source data and other documents.

Discussion

The clinical trial is ongoing. The recruitment started in January 2022. There are no practical or operational issues involved in performing the study.

Trial status

This is version 2.2 of the protocol, written on January 20, 2022. The recruitment started in January 26 2022, directly after approval of the Ethics Committee. The approximate date when recruitment will be completed is estimated at the end of 2024.