Study protocol for a randomized controlled trial: prophylactic swallowing exercises in head-and-neck cancer patients treated with (chemo)radiotherapy (PRESTO trial)

Patients with a stage III or IVA-B (TNM7) newly diagnosed squamous cell carcinoma of the oropharynx are considered as possible participants. Inclusion criteria are: patients treated with radiotherapy or concomitant CRT (CCRT) with or without induction chemotherapy and demonstrating sufficient cognitive and language abilities. The presence of a recurrent carcinoma or metastasis from another carcinoma and previous CRT or surgery in the head-neck region, with possible impact on swallowing function, are exclusion criteria. The patients will be recruited by a radiation oncologist and SLP. The SLP explains the study protocol and study design and assigns participants to the interventions.

All subjects who give consent for participation and who fulfill the inclusion criteria are randomly assigned to one of the three groups with a 1:1:1 allocation by means of the program QMinim. It is an online minimization service supported by the Information and Communication Technology (ICT) Unit of the Antwerp University Hospital. Minimization factors are age (20–60 years vs. ≥ 60 years), treating center, presence of baseline dysphagia and treatment (radiotherapy vs. CCRT).

As this is an open-label trial, the minimization procedure and outcome assessment will not be blinded.

The study will be a multicenter RCT. All patients will be training five times a week during the first 4 weeks of CRT. Baseline measurements will be done before the start of CRT. Every week during the training, immediately after CRT and at 1 and 3 months following treatment, patients will be evaluated by radiation therapists and SLPs. Table 1 shows an overview of the study visits and evaluations during the study. Prophylactic swallowing exercises are the same in all groups and comprise evidence-based exercises targeting the main muscle groups involved in swallowing; namely, muscles involved in tongue strength, pharyngeal contraction and laryngeal elevation/upper esophageal sphincter opening. These strengthening exercises include tongue-strengthening exercises (TSE) and chin-tuck against resistance (CTAR) combined with an effortful swallow. First, TSE will be performed since tongue strength is the main bolus-driving force and reduced tongue strength can cause oral and pharyngeal residue and aspiration [34‐36]. Second, CTAR exercises are used since they have a significant impact on the suprahyoid muscles, with a positive effect on laryngeal elevation and upper esophageal sphincter opening [37, 38]. The third exercise consists of effortful swallows in combination with the chin-tuck. Effortful swallows have been shown to improve the tongue-base posterior motion and can increase tongue-base pharyngeal-wall pressures [39]. It is hypothesized that the chin-tuck in combination with an effortful swallow stimulates the pharyngeal musculature [38].

The different exercises described above alternate during the sessions: all subjects start their first session with TSE and perform CTAR exercises and effortful swallowing in the next session. Tongue-strengthening exercises consist of 120 tongue presses and are divided into 12 sets of 10 repetitions with a 30-s rest between sets and with the target level set at 80% of 1 repetition maximum (1RM, i.e., the maximum amount of pressure that can be generated in one repetition) [34, 40‐44]. The next session CTAR exercises and effortful swallows are performed. Each CTAR session consists of 150 chin-tucks against resistance at a target level of 60–70% [45] of the 1RM (i.e., in this study, the maximum chin-tuck strength that can be generated). These chin-tucks are divided into 30 sets of five repetitions with an effortful swallow at every fifth repetition. In both tongue and chin-tuck exercises, a successful repetition was defined as reaching the target level and holding the contraction for 3 s, using the green light (TSE) as biofeedback or tactile biofeedback (CTAR). According to the principle of progressive overload, maximal tongue strength and strength of the suprahyoid muscles and correspondent levels of resistance are measured at baseline and recalculated subsequently every week [44].

All subjects will be randomly assigned into the previously defined groups: control group, app group and therapist group. The groups differ in degree and kind of adherence-improving measures. All groups have some of these measures in common. Restricting the duration to the first 4 weeks of CRT is a first method to increase compliance since the literature shows that in the last 2–3 weeks of therapy the feasibility of completing exercises decreases [20, 33]. Receiving visual and tactile feedback on their performance via the therapeutic devices is a second method. The differences in adherence-improving measures between the groups are illustrated in Table 2. The first group (control group) will perform the exercises at home, without supervision of a SLP but with a counseling session of 10 min every week. Group 2 (app group) practices at home but receives continuous counseling and gets instructions by videos via an application on a tablet, developed in collaboration with Cyborn, Antwerp, Belgium (www.​cyborn.​be). Generally, mobile health applications are considered to be possible tools to improve traditional health care [46]. By means of gamification, the app helps, supports and motivates the patients to practice. The app registers when the patients practice, how many repetitions they do and when they succeed in doing the exercises. Group 3 (therapist group) is given face-to-face therapy and will be counseled by a SLP five times per week. All patients will complete the first session with supervision of the SLP, irrespective of their group. The intervention will be discontinued on participant request or in case of worsening disease, requiring major changes in treatment. Reasons for discontinuing will be stored in a database.

Maximal tongue strength is measured by the Iowa Oral Performance Instrument (IOPI) Pro, model 3.1 (IOPI Medical LLC, Woodinville, WA, USA). This is a small, portable instrument connected to an air-filled bulb. Maximal isometric pressure can be measured anteriorly and posteriorly, MIP_a and MIP_p, respectively. The digital display shows the amount of pressure that the tongue produces (in kilopascal, kPa) when squeezing the bulb against the palate. In the anterior position, the proximal end of the bulb is placed immediately behind the upper teeth at the midline of the palate. In the posterior position, the bulb is placed at the level of the transition from the hard to the soft palate. The subjects are instructed to push the bulb as hard as possible against the palate. The highest value of three trials is considered the MIP. Tongue-strengthening exercises are done using the IOPI Trainer, model 3.2 (Fig. 1), which is similar to model 3.1. The device allows the therapist to set a target manually. There is a vertical series of small lights providing visual feedback: the upper light becomes green when the subject reaches the target. The TSE only consists of anterior tongue presses since previous research shows that the increase in tongue strength depends on the localization of the bulb: higher increases of anterior and posterior tongue strength are obtained when training exclusively anteriorly [47]. Patients are instructed to squeeze the bulb against the hard palate until the upper light becomes green and are asked to hold this effort for 3 s [48].

Maximal chin-tuck strength (in Newtons, N) is measured by means of a dynamometer (Microfet™, Biometrics, Almere, The Netherlands) (Fig. 2). Patients are asked to place their chin on the chin bar and keep their mouth and teeth closed. A fixed belt stabilizes the patients’ head. They are instructed to press their chin down as hard as possible. The highest value of three trials is considered the maximal isometric chin-tuck strength. Based on this value, the resistance level can be assessed using the conversion table from Kraaijenga et al. (value from 1 to 6) [38, 45]. The CTAR exercises are performed using the Swallowing Exercise Aid (SEA) (Fig. 3). It is a medical device remodeled by a technician of the Netherlands Cancer Institute by adding a chest bar to one of the mouthpieces of the commercially available TheraBite Jaw Mobilization device (Atos Medical, Hörby, Sweden) [38]. The ActiveBand can be placed at various, marked positions depending on the desired resistance. The minimal resistive load is 4 N (position 1) and the maximal resistive load is 50 N (position 6). Subjects are asked to hold the device with one hand, place the chest bar against the chest and put their chin on the chin bar. They are instructed to press the chin bar towards the chest bar and hold this effort for 3 s. At every fifth repetition, patients are asked to press the chin bar against the chest bar and swallow as hard as they can (effortful swallow).

The primary outcome measure of this study is the swallowing function, based on scores of the Mann Assessment of Swallowing Ability-Cancer (MASA-C) [49]. Next to this measurement, patients are asked to fill out the Eating Assessment Tool-10 [50] and a Visual Analog Scale. The Functional Oral Intake Scale [51] is filled in by a SLP. The swallowing function is assessed at baseline, weekly during the weeks of exercise, immediately after CRT and 1 and 3 months after CRT (Table 1).

There are three secondary outcome measures: (1) degree of compliance, (2) muscle strength and (3) QOL.

The degree of compliance is expressed as the total number of exercises performed per week, based on daily patient (group 1 and 2) and therapist (group 3) registration. The number of performed tongue-strengthening exercises is recorded automatically by means of the IOPI. In group 2, the degree of compliance is also expressed by the time spent on the app, which is registered automatically. The compliance is assessed during the first 4 weeks of CRT. MIP_a, MIP_p and strength of the suprahyoid muscles are examined at the same time as the swallowing function (Table 1) and are measured using the IOPI and a dynamometer. The Swallowing Quality-of-Life Questionnaire [52] and the Dysphagia Handicap Index [53] examine the swallowing-related QOL and are assessed at baseline, at the end of CRT and 1 and 3 months after CRT (Table 1).

All these evaluations are performed by a SLP.

The datasets generated during the study will be stored in a non-publicly available repository. All clinical record forms are collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Ghent University Hospital [58]. This is a secure, web-based application designed to support data capture for research studies. All patient information (except identifying information), questionnaires and measurements are stored for 20 years. The researchers from each participating institution have access to the data of their patients. All data is pseudonymized and patients’ details are encoded. The principle investigator and the researcher at the University Hospital in Ghent manage the entire database.

In order to avoid introducing bias, no interim analyses will be performed. As the experimental interventions caries minimal risks, no data monitoring committee will be implemented, nor will there be a stopping procedure.

There is no anticipated harm and so no compensation for trial participation. After completing the trial, participants will be followed by the radiation oncologist and head and neck surgeon or otolaryngologist and, if necessary, they will be referred to any other specialist.

Serious adverse events will be reported to the Ethical Committee of the central study center by means of a yearly line-listing system.

Pre-recruitment there has been a try-out with a small number of patients. They were questioned about the feasibility of the exercise protocol. Also, during the study all participants are asked about their experiences regarding the exercises. In the context of the application, all patients are questioned about their familiarity with smartphones, tablets and computers. Before the start of the study, the application has been tested by a number of people from different age groups.

This multicenter study will be conducted at the following sites: Antwerp University Hospital, Ghent University Hospital, University Hospital Leuven, Academic Hospital Sint-Jan Bruges, Sint-Augustinus Antwerp and other partners of the Iridium Cancer Network.

All participating centers have extensive experience in research on head-and-neck cancer and dysphagia. Data collection in these hospitals enables the study to include enough patients and gives the study sufficient power.