Swallowing-related muscle inflammation and fibrosis induced by a single dose of radiation exposure in mice.

BACKGROUND: Although radiotherapy is commonly used to treat head and neck cancer, it may lead to radiation-associated dysphagia (RAD). There are various causes of RAD, however, the mechanism has not yet been fully identified. Currently, the only effective treatment for RAD is rehabilitation. Additionally, there are few available animal models of RAD, necessitating the development of new models to establish and evaluate RAD treatments. We hypothesize that radiation-induced neck muscle fibrosis could be one of the causes of RAD due to impairment of laryngeal elevation. Therefore, in this study, we focused on the changes in inflammation and fibrosis of the strap muscles (Sternohyoid, Sternothyroid, and Thyrohyoid muscles) after a single-dose irradiation. This research aims to provide a reference animal model for future studies on RAD. RESULTS: Compared to control mice, those treated with 72-Gy, but not 24-Gy, irradiation had significantly increased tumor necrosis factor-α (TNF-α) (p < 0.01) and α-smooth muscle actin (αSMA) (p < 0.05) expression at 10 days and significantly increased expression levels of motif chemokine ligand-2 (CCL2), α-SMA, tumor growth factor-ß1 (TGF-ß1), type1 collagen, and interleukin-1ß (IL-1ß) (p < 0.05) in the muscles at 1 month by real-time PCR analysis. The results of immunohistochemistry showed that the deposition of type 1 collagen gradually increased in extracellular space after radiation exposure, and the positive area was significantly increased at 3 months compared to non-irradiated control. CONCLUSIONS: A single dose of 72-Gy irradiation induced significant inflammation and fibrosis in the strap muscles of mice at 1 month, with immunohistochemical changes becoming evident at 3 months. This cervical irradiation-induced fibrosis model holds potential for establishing an animal model for RAD in future studies. LEVEL OF EVIDENCE: N/A.

Assessment of radio(chemo)therapy-related dysphagia in head and neck cancer patients based on cough-related acoustic features: a prospective phase II national clinical trial (ACCOUGH-P/A trial).

BACKGROUND: Radiation-associated dysphagia is defined as impaired swallowing efficiency/safety following (chemo)radiotherapy in head and neck cancer patients. In a dysphagia framework, impaired coughing may lead to lung aspiration and fatal lung infection. Although cough efficacy is a predictor of the risk of aspiration, cough investigation is minimal in patients with radiation-associated dysphagia. Because cough is a transient signal, existing software for speech analysis are not appropriate. The goal of our project is to develop an assessment method using acoustic features related to voluntary and reflexive coughs as biomarkers of the risk of penetration/aspiration in patients with radiation-associated dysphagia. METHODS: Healthy subjects and head and neck cancer patients with and without dysphagia will produce voluntary coughs, throat clearings and reflexive coughs. Recordings will be made using an acoustic microphone and a throat microphone. The recorded signals will be manually segmented and subsequently analysed with a software under development. Automatic final segmentation enables to measure cough duration. The first method of analysis includes temporal features: the amplitude contour, the sample entropy and the kurtosis. These features report respectively the strength, the unpredictability (turbulence noise due to the air jet) and the impulsive quality (burst) of the signal. The second method of analysis consists of a spectral decomposition of the relative cough signal energy into several frequency bands (0-400 Hz, 400-800 Hz, 800-1600 Hz, 1600-3200 Hz, > 3200 Hz). The primary outcome of this exploratory research project is the identification of a set of descriptive acoustic cough features in healthy subjects as reference data (ACCOUGH). The secondary outcome of this research in head and neck cancer patients with radiation-associated dysphagia includes the identification of (1) a set of descriptive acoustic cough features as biomarkers of penetration-aspiration (ACCOUGH-P/A), (2) swallowing scores, (3) voice features and (4) aerodynamic cough features. DISCUSSION: This study is expected to develop methods of acoustic cough analysis to enhance the assessment of radiation-associated dysphagia in head and neck cancer patients following (chemo)radiation. TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) registry ISRCTN16540497. Accepted on 23 June 2023.

Precision association of lymphatic disease spread with radiation-associated toxicity in oropharyngeal squamous carcinomas.

PURPOSE: To determine whether patient similarity in terms of head and neck cancer spread through lymph nodes correlates significantly with radiation-associated toxicity. MATERIALS AND METHODS: 582 head and neck cancer patients received radiotherapy for oropharyngeal cancer (OPC) and had non-metastatic affected lymph nodes in the head and neck. Affected lymph nodes were segmented from pretreatment contrast-enhanced tomography scans and categorized according to consensus guidelines. Similar patients were clustered into 4 groups according to a graph-based representation of disease spread through affected lymph nodes. Correlation between dysphagia-associated symptoms and patient groups was calculated. RESULTS: Out of 582 patients, 26% (152) experienced toxicity during a follow up evaluation 6 months after completion of radiotherapy treatment. Patient groups identified by our approach were significantly correlated with dysphagia, feeding tube, and aspiration toxicity (p < .0005). DISCUSSION: Our results suggest that structural geometry-aware characterization of affected lymph nodes can be used to better predict radiation-associated dysphagia at time of diagnosis, and better inform treatment guidelines. CONCLUSION: Our work successfully stratified a patient cohort into similar groups using a structural geometry, graph-encoding of affected lymph nodes in oropharyngeal cancer patients, that were predictive of late radiation-associated dysphagia and toxicity.

Reflex vs. volitional cough differences amongst head and neck cancer survivors characterized by time since treatment and aspiration status.

BACKGROUND: The aim of this study was to investigate differences in reflexive and volitional cough airflows in advanced stage head and neck cancer survivors as it relates to aspiration status and time since treatment. The hypothesis is that those who aspirate several years after treatment completion would demonstrate reduced airflows for all cough parameters compared to those recently status post treatment completion given the known progressive deterioration associated with radiotherapy. METHODS: Demographic and airflow data during both reflexive and volitional cough tasks and aspiration status as determined during fiberoptic endoscopic evaluation of swallow function were collected from 33 Head and Neck Cancer (HNC) survivors. RESULTS: Omnibus MANOVA for dependent airflow variables and independent variables aspiration status, time since treatment and cough type (reflex or volitional) was significant (F(3,1) = 184, p < 0.000) indicating that peak expiratory flow rates (PEFR) were reduced under reflex (mean PEFR 1.88 SD 0.7) versus volitional (mean PEFR 2.3, SD 0.7) cough types; reduced for aspirators versus non-aspirators (F(2,1) = 4.1, p = 0.04) and reduced for those in the subacute versus chronic phase status post Intensity Modulated Radiotherapy (IMRT) (F(2,1) = 10.05, p = 0.002). CONCLUSION: Findings of reduced reflexive compared to volitional cough airflows in head and neck cancer survivors are consistent with those from both healthy and other diseased populations. Additional findings that aspirators demonstrate reduced cough airflows compared to non-aspirators supports the hypothesis. Surprisingly, those recently status post treatment completion show worse cough airflows compared to those remotely status post treatment completion.

Pharyngeal Swallowing Pressures in Patients with Radiation-Associated Dysphagia.

Dysphagia associated with radiotherapy for head and neck cancer is complex and can be difficult to treat. Videofluoroscopic swallow studies (VFSS) are the current gold-standard instrumented swallow assessment. High-resolution manometry (HRM) is an additional approach that provides objective measurements of swallowing-related pressures in the pharynx and esophagus. This can provide functional information on the pressure gradients underlying bolus propulsion, and is relevant for this patient population, where radiation-related fibrosis can lead to weakness and impaired pressure generation. The purpose of this preliminary study was to describe pharyngeal swallowing pressures in patients with radiation-associated dysphagia (RAD) and late radiation-associated dysphagia (LRAD) using HRM. RAD occurs during and immediately following treatment, whereas LRAD is a more recently described phenomenon in which the patient experiences an onset of dysphagia at least 5 years post-treatment. We performed a retrospective analysis of pharyngeal swallowing pressures from 21 patients with RAD or LRAD and 21 healthy sex/age-matched controls. Patients with RAD or LRAD exhibited decreased swallowing pressure durations throughout the pharynx (p ≤ 0.002), as well as decreased hypopharynx maximum pressure (p = 0.003) and pharyngeal contractile integral ( p < 0.0001). Understanding how pharyngeal pressure generation is altered in patients with a history of radiotherapy can help clinicians form more precise treatment plans.

Effect of tongue-strengthening exercises on tongue strength and swallowing-related parameters in chronic radiation-associated dysphagia.

BACKGROUND: Radiation-associated dysphagia (RAD) is highly prevalent in head and neck cancer (HNC) patients, with insufficient tongue strength (TS) as a characteristic of this disabling complication. The effects of tongue-strengthening exercises (TSE) on TS, swallowing, and quality of life (QoL) have not been studied in this population. METHODS: A prospective phase 2 study using an 8 weeks during TSE protocol was carried out in 15 patients with chronic RAD. Outcome parameters were maximal isometric pressure (MIP), TS during swallowing (Pswal), swallowing function, and QoL. All parameters were evaluated at baseline, after 4 and 8 weeks of training, and 4 weeks after the last training session. RESULTS: MIP increased significantly, without detraining effects. Pswal did not increase significantly, but relevant effect sizes were measured. Swallowing function ameliorated, but did not result in increased functional oral intake, self-reported outcome or QoL. CONCLUSION: TSE in patients with RAD results in increased strength and swallowing function.

A prospective longitudinal assessment of MRI signal intensity kinetics of non-target muscles in patients with advanced stage oropharyngeal cancer in relationship to radiotherapy dose and post-treatment radiation-associated dysphagia: Preliminary findings from a randomized trial.

PURPOSE: To assess quantitative signal intensity (SI) kinetics obtained from serial MRI of swallowing muscles as a potential imaging biomarker of radiation-induced dysphagia in oropharyngeal cancer (OPC) patients receiving radiotherapy (RT). METHODS: Patients were enrolled under an IRB approved Phase II/III randomized trial. Patients underwent serial MRIs at pre-, mid-, and post-RT. Normalized T1, T1+ contrast (T1 + C), and T2 SI for swallowing muscle volumes-of-interest (VOIs) were collected and delta SI changes (Δ) were calculated. Mid- and post-RT SI relative to baseline were assessed and correlations between radiation dose and percent change in SI were calculated. Independent samples' t-tests were used to compare the percent change of SI between patients divided into two groups based on dysphagia status post-RT. RESULTS: Forty-six patients with stage III/IV HPV+ OPC were included in this study. Relative to baseline, mean T2 and T1 + C SIs for middle pharyngeal constrictor were both significantly higher at mid- and post-RT (p < 0.004 for all). Superior pharyngeal constrictor also showed a significant increase in T1 + C SI at mid-RT (p = 0.0004). Additional muscle VOIs showed significant changes post-RT, but not earlier at mid-RT. Both mid- and post-RT doses were significantly correlated with the percent change of normalized T2 and T1 + C SI for examined muscle VOIs (p < 0.002). Mean percent changes of normalized T2 SI at mid-RT relative to baseline for all muscle VOIs were significantly higher in patients who developed grade ≥2 dysphagia relative to patients with no/mild dysphasia (mean Δ%: 8.2% vs 1.9%; respectively, p = 0.002). However, at post-RT, these changes were only significant in T1 SI (11.2% vs -1.3%; p < 0.0001). CONCLUSION: Signal intensity kinetics of radiation injury can be broadly correlated with the functional muscular defect. Serial MRI during the course of RT may provide an opportunity to quantitatively track muscular pathology for subclinical detection of patients at high risk to develop dysphagia.

Late radiation-associated dysphagia in head and neck cancer patients: evidence, research and management.

In head and neck cancer (HNC) scenario, newer radiotherapy (RT) techniques, such as intensity modulated RT (IMRT), aim to reduce acute and late toxicity without impair tumor response and loco-regional control rates. However, late radiation-associated dysphagia (RAD) remains a major clinical problem and has gained a growing importance in the last few years, especially due to human papilloma virus (HPV)-related HNC favorable prognosis. The aim of this review was to provide clinical information about late RAD. The main anatomical structures involved in swallowing were described, in order to define potential organ at risk and available radiation-dose constraints in IMRT plan. Finally, possible rehabilitation strategies were proposed. This is expected to represent an opportunity for improved multidisciplinary management in HNC patients.