Effects of prophylactic swallowing exercises on dysphagia and quality of life in patients with head and neck cancer receiving (chemo) radiotherapy: the Redyor study, a protocol for a randomized clinical trial

Background Radiation-induced dysphagia is common in patients with head and neck cancer (HNC). Available evidence suggests that exercise therapy prior to oncological treatment could potentially improve deglutition and quality of life; however, a randomized clinical trial is needed to confirm this observation. Methods/design The Redyor study is a single-blind randomized clinical trial designed to compare the effect of prophylactic oropharyngeal exercises on quality of life and dysphagia of 52 patients with HNC referred to the Radiotherapy Department. The intervention will consist of respiratory muscle training (3 times/day, 5 days/week, 21 weeks) added to the standard swallow therapy. All patients will perform the same exercise intervention, but at different times: before chemoradiotherapy (CRT; early intervention group) or immediately after completing CRT (late intervention group). The main outcome will be change in dysphagia severity assessed with the Penetration-Aspiration Scale in videofluoroscopy study; quality of life will be assessed with the EORTC-QLQ-C30 and its Head and Neck Cancer Module (QLQ-H&N35) at 3, 6, and 12 months after completing CRT. Discussion This ongoing clinical trial, registered in 2016, is based on the hypothesis that undergoing a pre-radiotherapy rehabilitation (pre-habilitation) program will have greater benefits (less decrease in quality of life, less delay in swallowing parameters, and less severe dysphagia) compared to post-CRT rehabilitation. The main objective is to assess dysphagia severity in HNC patients; and secondly, to evaluate changes in dysphagia-related quality of life, and to determine the correlation between a clinical variable and instrumental parameters during this period. Trial registration NCT0209009911. Electronic supplementary material The online version of this article (10.1186/s13063-019-3587-x) contains supplementary material, which is available to authorized users.

3 rehabilitation. The primary objective is to assess dysphagia severity and evaluate quality of life due to swallowing dysfunction in HNC patients. Secondary objectives are to assess the correlation between a clinical variable and instrumental parameters in this period Background Squamous head and neck cancer (HNC) has high incidence in developed countries. HNC is categorized according to the area of the head or neck in which it occurs, with greater incidence in the larynx, followed by the oropharynx, oral cavity, and hypopharynx. Although chemo-radiation therapy (CRT) protocols have been designed to preserve swallowing function and essential speech organs, dysphagia is a frequent symptom in these patients and the primary adverse effects are usually associated with acute or late swallowing disturbances. (2)(3)(4)(5)(6) Preservation of underlying anatomical structures does not guarantee normal function. CRT affects target areas and may result in lack of coordination of swallowing phases, lack of swallow coordination with respiratory function, reduced elevation of larynx, delayed laryngeal closure, loss of tongue strength, and prolonged oral and pharyngeal time in swallowing. (6)(7)(8)(9) Radiation-induced dysphagia pathogenesis includes an initial process of acute inflammation with the appearance of edema, which may be followed by fibrosis of the soft tissues resulting in neurological alteration and muscle damage. Xerostomia, pain, and pharynx obliteration are the key elements of acute-phase dysphagia. At 3 months, many patients have regained swallowing function. In later stages, with the appearance of diffuse fibrosis of the connective tissue and skin in the irradiated area, changes are observed in the efficacy and safety of swallowing. It is 4 believed that hypoxia and chronic oxidative stress could perpetuate tissue damage even long after the end of treatment, which would explain the appearance of dysphagia in the chronic phase.(10) These side-effects contribute to higher rates of malnourishment, weight loss, and bronchoaspiration, (6), (11) resulting in a need for alternative or supplementary methods for feeding and hydration, both early and long-term. (8) For years, delays have been reported in referring HNC patients undergoing CRT to Rehabilitation Departments. Patients were only referred when they presented with obvious swallow deficits or the consequent malnourishment, weight loss, changes in voice characteristics, etc., often months or years post-CRT. (12) The greater the delay, the worse is the patient's detrimental muscle disuse and swallow dysfunction. (13,14) In recent years, there has been a growing interest in swallowing interventions. Potential benefits of prophylactic exercises conducted during (15)(16)(17), soon after (18), or before the CRT intervention (19) have been described, and an improvement in functional swallow outcomes and quality of life parameters after respiratory therapy (RT) intervention has been reported. (14) Nevertheless, supportive care for earlier dysphagia management in rehabilitation departments continues to play a secondary role in HNC diagnosis in most health systems. (9,12) New ways to treat HNC dysphagia in an early intervention are now being explored, using Inspiratory and Expiratory Muscle Training (IEMT) -an "old" technique developed for patients with chronic obstructive pulmonary disease (COPD) (20) that has shown its usefulness in patients with dysphagia (21)(22)(23)(24)(25). Designed to improve respiratory muscle strength, IEMT also trains muscles involved in coughing, speech, and swallowing. (26) The hypothesis of the ongoing ReDyOr (Rehabilitation Dysphagia Oropharyngeal Cancer) study is that improvement of the swallowing function is due to the strengthening of the suprahyoid muscle (anterior portion of the digastric, mylohyoid, and geniohyoid). The suprahyoid/submental muscles participate in the pharyngeal phase of swallowing. Their weakness or lack of coordination can decrease the amplitude of the hyoid, causing an inadequate opening of the upper esophageal sphincter that exposes the airway to the passage of the bolus. Some authors have evaluated the effect of IEMT on the swallow muscles by videofluoroscopy swallow studies (VFSS), noting that the amplitude of the hyoid movements increase during training, both in the oral (jaw and tongue) and pharyngeal phases. (27) The usefulness of IEMT to train respiratory, cough, speech, and swallowing muscles is well established in pathologies other than COPD, such as strokerelated dysphagia,(28) but the most recent neurophysiological findings suggest the capacity for improving motor recruitment of the suprahyoid musculature, the activity of pharyngeal musculature, and the palate, as well as an increase in the amplitude of the movements of the hyoid,(29),(30) could be considered and included as a new therapeutic tool for the treatment of HNC swallowing disturbances in the acute stage after diagnosis.
Available data suggest that pre-habilitation exercises could further improve these results. (18,19) The ReDyOr study is based on the hypothesis that an early intervention could promote a sustainable improvement in preservation of swallow function and quality of life.
The main objective of this study is to explore the benefits of an early 8-week rehabilitation program (IEMT added to standard swallowing exercises), compared with participation in the same program after CRT completion. Secondly, this study aims to compare the effectiveness of the VFSS and Volume-Viscosity Swallow Test (V-VST) for screening dysphagia and to evaluate the effect of an IEMT and standard swallow exercises in a home-based dysphagia rehabilitation program in patients with HNC undergoing CRT.

Trial Design
The ReDyor study is a prospective randomized single-blind clinical trial aimed to determine the benefits of early rehabilitation to preserve swallow function and quality of 6 life in patients with HNC receiving radiotherapy. The study is carried out in the Physical Medicine and Rehabilitation Department (Hospital de l'Esperança, Parc de Salut Mar, Barcelona), following the SPIRIT guidelines (Standard Protocol Items: Recommendations for Interventional Trials).(31) Throughout the recruitment period, patients who provide their informed consent (Additional file 1) to participate will be randomized to one of two groups: early intervention or post-CRT intervention. No major changes to methods after the start of the study are planned. This trial has been approved by the local Clinical Ethics Committee (Additional File 2).

Subjects
Patients with advanced HNC receiving radiotherapy will be eligible to participate in this clinical trial. Potential participants will be excluded if they have previous history of HNC and/or head or neck radiation therapy or surgical treatment, or of dysphagia due to causes other than cancer. Inclusion and exclusion criteria are listed in Table 1.

Settings and locations
Recruitment will be carried out in the Radiotherapy Department at the Parc de Salut Mar During the study period, the patient will be excluded from the study if any of the following occurs: emergence of any of the exclusion criteria, onset of any disease or medical condition that will make it difficult for the patient to continue participation, decision to 7 withdraw from the study for any reason, transfer out of the service area, or death, impossibility to practice exercises due to medical condition.

Intervention
The training protocol consists of IEMT and standard swallowing exercises. Patients are instructed to maintain a rate of 15-20 breaths/min using the Orygen-Dual® valve (described elsewhere in detail) (21,22), a respiratory device that allows patients to train inspiratory and expiratory muscles simultaneously. Training loads will be set at a pressure equivalent to 10 maximal repetitions (if tolerated). These external pressures will be regulated weekly at 30% of maximal inspiration/expiration respiratory measures obtained.
Patients will be instructed to perform 3 sets of 5 repetitions and standard swallowing exercises (mobility and tonicity exercises of the tongue, palate, larynx, and constrictor muscles), 3 times/day, 5 days/week, for 21 weeks. An experienced swallowing therapist will supervise IEMT weekly. The protocol will be the same for both groups, but one group will start 2 weeks before CRT and the other one will begin immediately after completing CRT ( Figure 1 · Volume-Viscosity Swallow Test, a screening test to detect swallowing disturbances. The V-VST evaluates impaired security (tone of voice, coughing during or after eating, or desaturation >3% compared to baseline pulse oximetry) and efficacy in oral and pharyngeal phases.
· Subjective difficulty of swallowing will be assessed by a Visual Analogic Scale (VAS). This scale ranges from 0 to 10; a low score indicates no difficulties in eating and a high score, no oral intake. · Peak Cough flow (PCF) will be used to evaluate the effect on respiratory muscle training on voluntary cough. It is measured with spirometer in liters/minute. Patients will be instructed to perform 3 repetitions of voluntary cough, the best one will be chosen.

Study protocols
Patients eligible for inclusion who do not meet any exclusion criteria will be referred for baseline function assessment to the Rehabilitation Department. The study outcomes will be assessed at baseline (pre-RT, tx), at the beginning of RT (t1), at the end of RT (t3), and thereafter at 3 months (t4), 6 months (t5), and 12 months (t6). The Redyor schedule of enrollment is shown in Figure 2.

Randomization and blinding
Participant randomization to study groups will be performed independently of the hospital's physical therapists. When a new patient meets the eligibility criteria, a researcher (PF) in the Radiotherapy department will inform the licensed physical therapist (OPC), who will assign the anonymized patient record to one of the study groups using a random number generator program. The interdisciplinary researchers (EM, AGS, PF) will be 9 blinded to study group assignments over the entire study period. After data analysis has been completed, results will be released to all patients and to participating clinicians and researchers.

Sample size calculation
Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a bilateral contrast, and assuming a 20% loss to follow-up, a total sample size of 52 patients (26 in each group) will be required to detect a difference ≥10 units in the test of quality of life and 2 units in the PAS.

Statistical analysis
Numerical variables will be expressed descriptively as mean and standard deviation (SD).
The evaluation of the correlations between variables will be based on the quantitative variables obtained from the various studies and bivariate (ordered Spearman correlation) and multivariate (multiple regression) analysis. Student t-test for paired data will be used for comparison of the quantitative variables before and after the intervention. The level of alpha risk accepted for all tests will be 0.05.

Ethics and dissemination
National and international research ethics guidelines will be followed, including the Deontological Code of Ethics, Declaration of Helsinki, and current confidentiality laws concerning personal data in Spain (Ley Orgánica 15/1999, 13 December) and the European Union (European Parliament and Council Regulation EU 2016/619). Detailed, understandable oral and written information will be provided to patients and family members, and informed consent to participate will be signed by all participants. In patients with dementia, written informed consent will be obtained from the main caregiver

Limitations of the study (Pros and cons)
The study has several potential limitations that must be considered. First, losses to followup are common in cancer studies; to address this concern, sample size estimation assumed a loss of about 20% of patients (higher than the usual 10-15% used in previous studies). Second, the study lacks a control group; however, this design is justified by the available evidence of the benefits of swallow and speech therapy in patients with HNCrelated dysphagia.

Repercussions of the Redyor Study
Interventions to help patients confront, manage, and treat dysphagia are urgently needed.
The lack of randomized controlled trials in the early diagnosis of HNC and the high number of patients lost to follow-up due to CRT side-effects highlight the potential scientific

Declaration Section
Ethical approval and consent to participate National and international research ethics guidelines will be followed, including the Deontological Code of Ethics, Declaration of Helsinki, and current confidentiality laws concerning personal data in Spain (Ley Orgánica 15/1999, 13 December)  2015/6288/I) (Additional file 2). Standard Protocol followed SPIRIT guidelines will be followed throughout (Additional file 3) and was registered at www.clinicaltrials.gov with code NCT0209009911 on February 9, 2016. Informed Consent (Additional file 1) was obtained from all individual participants included in the study.

Data availability statements
The datasets generated and/or analyzed during the current study are not publicly available due to the amount of data generated but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was funded by Asociación Española contra el cáncer (AECC), Proyectos Singulares 2014, PS14152556FORO AECC-Asociación Española contra el Cáncer. No additional funding support was received. AECC only participates in economical support of the study not in design, collection, analysis of data or writing.
Authors' contributions PF and AGS are the principal investigators for this trial. They designed the protocol and are responsible for oversight of all aspects of the study. NBS is the physiatrist coinvestigator for this study, and this study is included as a part of her doctoral thesis and research profile. She is responsible for oversight of the primary data collection site and has contributed to study design and manuscript preparation and review. OPC is a research associate working on this study. He has designed the database used for data collection and will randomize the patients. EMN is a research associate. She has contributed to protocol design and manuscript preparation and review. All authors read and approved the final manuscript.  SPIRIT_checklist.doc Informed Consent.pdf