Effectiveness of mHealth intervention for trismus exercise in patients with head and neck cancer undergoing proton and heavy ion therapy: a randomized control trial.

PURPOSE: This study aimed to compare the effects of a mobile health intervention based on social cognitive theory with standard care on maximal mouth opening, exercise compliance, and self-efficacy in patients receiving proton and heavy ion therapy for head and neck cancer. METHODS: This open-label, parallel-group, randomized, superiority trial involved a self-developed "Health Enjoy System" intervention. We assessed maximal mouth opening, exercise compliance, and self-efficacy at baseline (T0), post-treatment (T1), and at 1 month (T2) and 3 months (T3) after radiotherapy. Generalized estimating equations were used to analyze differences between the groups over time, with results reported as P values and 95% confidence intervals (CIs). RESULTS: The study included 44 participants. At T3, the intervention group showed a 6 mm greater increase in maximal interincisal opening than the control group (mean difference = 6.0, 95% CI = 2.4 to 9.5, P = 0.001). There was also a significant difference in exercise compliance between the groups (mean difference = 31.7, 95% CI = 4.6 to 58.8, P = 0.022). However, no significant difference in self-efficacy was found between the groups. CONCLUSION: This study demonstrated that an mHealth intervention incorporating behavior change theory could effectively enhance or maintain maximal mouth opening in patients undergoing proton and heavy ion therapy for head and neck cancer in China. This approach provides valuable support during and after treatment. TRIAL REGISTRATION: ChiCTR: ChiCTR2300067550. Registered 11 Jan 2023.

Development of a risk prediction model for radiation dermatitis following proton radiotherapy in head and neck cancer using ensemble machine learning.

PURPOSE: This study aims to develop an ensemble machine learning-based (EML-based) risk prediction model for radiation dermatitis (RD) in patients with head and neck cancer undergoing proton radiotherapy, with the goal of achieving superior predictive performance compared to traditional models. MATERIALS AND METHODS: Data from 57 head and neck cancer patients treated with intensity-modulated proton therapy at Kaohsiung Chang Gung Memorial Hospital were analyzed. The study incorporated 11 clinical and 9 dosimetric parameters. Pearson's correlation was used to eliminate highly correlated variables, followed by feature selection via LASSO to focus on potential RD predictors. Model training involved traditional logistic regression (LR) and advanced ensemble methods such as Random Forest and XGBoost, which were optimized through hyperparameter tuning. RESULTS: Feature selection identified six key predictors, including smoking history and specific dosimetric parameters. Ensemble machine learning models, particularly XGBoost, demonstrated superior performance, achieving the highest AUC of 0.890. Feature importance was assessed using SHAP (SHapley Additive exPlanations) values, which underscored the relevance of various clinical and dosimetric factors in predicting RD. CONCLUSION: The study confirms that EML methods, especially XGBoost with its boosting algorithm, provide superior predictive accuracy, enhanced feature selection, and improved data handling compared to traditional LR. While LR offers greater interpretability, the precision and broader applicability of EML make it more suitable for complex medical prediction tasks, such as predicting radiation dermatitis. Given these advantages, EML is highly recommended for further research and application in clinical settings.

Rebamipide gargle and benzydamine gargle in prevention and management of chemo-radiotherapy and radiotherapy-induced oral mucositis in head and neck cancer patients (randomized clinical trial).

OBJECTIVES: This study aimed to evaluate the preventive and therapeutic effects of rebamipide gargle in comparison with benzydamine in head and neck cancer patients undergoing radiotherapy with or without chemotherapy. MATERIALS AND METHODS: Phase III randomized clinical trial was conducted from January 2021 till August 2022 on one hundred patients with head and neck cancer receiving high doses of radiotherapy. These patients were equally allocated into either rebamipide group or benzydamine group, The measured outcomes were the incidence of oral mucositis ≥ grade1, according to the WHO mucositis scale, in addition to the duration, and the onset of oral mucositis. RESULTS: There was no statistically significant difference between the two groups, regarding the incidence of a severe grade of oral mucositis (WHO grades 3), as well as the onset and duration of oral mucositis. Both gargles succeeded to prevent the development of WHO grade 4 oral mucositis. Side effects reported were mainly burning sensation in benzydamine group and nausea in rebamipide group. CONCLUSION: Rebamipide mouthwash was as beneficial as benzydamine mouthwash in minimizing the incidence of severe oral mucositis induced by treatment of head and neck cancer. However, rebamipide gargle proved to be superior to benzydamine in terms of reduction in the severity of the radiation-induced oral mucositis. TRIAL REGISTRATION: The trial was registered in the protocol Registration and Result system of Clinical Trials (Registration ID: NCT04685395)0.28-12-2020.

Enhancing the Contouring Efficiency for Head and Neck Cancer Radiotherapy Using Atlas-based Auto-segmentation and Scripting.

BACKGROUND/AIM: Intensity-modulated radiation therapy can deliver a highly conformal dose to a target while minimizing the dose to the organs at risk (OARs). Delineating the contours of OARs is time-consuming, and various automatic contouring software programs have been employed to reduce the delineation time. However, some software operations are manual, and further reduction in time is possible. This study aimed to automate running atlas-based auto-segmentation (ABAS) and software operations using a scripting function, thereby reducing work time. MATERIALS AND METHODS: Dice coefficient and Hausdorff distance were used to determine geometric accuracy. The manual delineation, automatic delineation, and modification times were measured. While modifying the contours, the degree of subjective correction was rated on a four-point scale. RESULTS: The model exhibited generally good geometric accuracy. However, some OARs, such as the chiasm, optic nerve, retina, lens, and brain require improvement. The average contour delineation time was reduced from 57 to 29 min (p<0.05). The subjective revision degree results indicated that all OARs required minor modifications; only the submandibular gland, thyroid, and esophagus were rated as modified from scratch. CONCLUSION: The ABAS model and scripted automation in head and neck cancer reduced the work time and software operations. The time can be further reduced by improving contour accuracy.

Longitudinal study of the role of salivary proteins on radiation-related caries onset in head and neck cancer patients using 5000 ppm fluoride dentifrice up to one-year post-intensity modulated radiotherapy.

OBJECTIVES: Longitudinal assessment of the role of specific proteins on radiotherapy caries (RC) onset in head and neck cancer patients(HNC) up to one-year post-IMRT using a 5000ppm fluoride paste daily. MATERIALS AND METHODS: Dental status/salivary protein data were obtained from 40 HNC patients pre-IMRT, six months (T1) and 12 months (T2) post-IMRT (ethical approval/consent). DMFT/salivary parameters were quantified, including flow rate, mucin 5B/7, Immunoglobulin A (IgA), cystatin S and α-amylase. RESULTS: 45% patients had at least one carious lesion at T2, a significant reduction in the number of remaining teeth (65% <21), salivary flow rate (< 50%) and, protein secretion (< 0.05) post-IMRT. T1 IgA concentration/secretion rate was associated with RC (p < 0.05). Finally, IgA and total protein concentration obtained at T1 could provide a predictive pattern (AUC 82.3%) for the patients more predisposed to developing RC at T2. CONCLUSIONS: This study demonstrated the significant association of RC with salivary proteins in HNC patients treated with IMRT, revealing the potential role of salivary proteins in the early diagnosis of RC. CLINICAL RELEVANCE: This research contributes to revealing salivary proteins association with RC, and its role in early diagnosis. Therefore, this could be the first step towards personalized medicine approaches to improve this group quality-of-life.

Effective Radiosensitization of HNSCC Cell Lines by DNA-PKcs Inhibitor AZD7648 and PARP Inhibitors Talazoparib and Niraparib.

(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.

Preliminary outcomes of boron neutron capture therapy for head and neck cancers as a treatment covered by public health insurance system in Japan: Real-world experiences over a 2-year period.

PURPOSE: Since June 2020, boron neutron capture therapy (BNCT) has been a health care service covered by health insurance in Japan to treat locally advanced or recurrent unresectable head and neck cancers. Therefore, we aimed to assess the clinical outcomes of BNCT as a health insurance treatment and explore its role among the standard treatment modalities for head and neck cancers. MATERIALS AND METHODS: We retrospectively analyzed data from patients who were treated using BNCT at Kansai BNCT Medical Center, Osaka Medical and Pharmaceutical University, between June 2020 and May 2022. We assessed objective response rates based on the Response Evaluation Criteria in Solid Tumors version 1.1, and adverse events based on the Common Terminology Criteria for Adverse Events, version 5.0. Additionally, we conducted a survival analysis and explored the factors that contributed to the treatment results. RESULTS: Sixty-nine patients (72 treatments) were included in the study, with a median observation period of 15 months. The objective response rate was 80.5%, and the 1-year locoregional control, progression-free survival, and overall survival rates were 57.1% (95% confidence interval [CI]: 43.9%-68.3%), 42.2% (95% CI: 30.1%-53.8%), and 75.4% (95% CI: 62.5%-84.5%), respectively. Locoregional control was significantly longer in patients with earlier TNM staging and no history of chemotherapy. CONCLUSIONS: BNCT may be an effective treatment option for locally advanced or recurrent unresectable head and neck cancers with no other definitive therapies. If definitive surgery or radiation therapy are not feasible, BNCT should be considered at early disease stages.

Proton therapy re-irradiation outcomes and genomic landscape of patients with recurrent head and neck cancer.

INTRODUCTION: Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is challenging. We describe clinical outcomes and toxicity of proton therapy (PT) for recurrent HNC, and report genomic alterations associated with patterns of failure. MATERIALS & METHODS: We performed a retrospective analysis of rHNC patients treated with PT. Outcomes were estimated using the Kaplan-Meier method. Univariate (UVA) and multivariate analyses (MVA) were performed to assess multiple patient factors. Next-generation sequencing and genomic analyses were performed on available samples. RESULTS: Eighty-nine patients treated with PBS-PT for rHNC with a median follow-up of 12 mo (0-71 mo) were included. The 1- and 2-y local control (LC) rates were 80.8 % (95 % CI: 70.8-90.8) and 66.2 % (95 % CI: 50.7-81.7), and 1- and 2-y distant metastasis-free survival (DMFS) were 41.0 % (95 % CI: 30.0-52.0) and 26.3 % (95 % CI: 15.7-36.9). The median overall survival (OS) was 13 mo (95 % CI: 9.3-16.7). On UVA and MVA, smaller gross tumor volume (GTV) was associated with improved OS (HR 1.002, P = 0.004), DMFS (HR 1.002, P = 0.004), and PFS (HR 1.002, P = 0.014). There were 35 late Gr3 + toxicity events (30.3 %). Patients with higher candidate gene-specific mutation burden (genes with [OR] > 2, P < 0.05) had inferior PFS. TP53, NOTCH4, and ARID1B mutations were associated with inferior DMFS (OR > 2, P < 0.05). CONCLUSIONS: PBS-PT is effective at achieving LC for rHNC with favorable toxicity. Distant metastases are common, and associated with TP53, NOTCH4, and ARID1B mutations. Inclusion of genomic alterations in the clinical decision process may be warranted.

Autophagy is the main driver of radioresistance of HNSCC cells in mild hypoxia.

Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x-ray radioresistance in HPV-negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia-inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF-1α and HIF-1ß leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia-induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC.

Effects of early nutritional intervention on oral mucositis and basic conditions in patients receiving radiotherapy for head and neck cancer: Randomized controlled trial (ChiCTR2000031418).

BACKGROUND & AIMS: This study aims to observe the effects of early nutritional intervention on radiation-induced oral mucositis (OM) and the nutritional status of patients with head and neck cancer (HNC) receiving radiotherapy. METHODS: Eligible patients receiving radiotherapy for HNC were randomly divided into an early nutritional intervention group (enteral nutritional intervention was administered at the beginning of radiotherapy) and a late nutritional intervention group (enteral nutritional intervention was administered at the beginning of eating restriction) in a 1:1 ratio. The primary endpoint was radiation-induced OM. Secondary endpoints included nutrition-related indicators, immune function, overall survival (OS), progression-free survival (PFS), quality of life, and other radiotherapy-induced adverse effects. RESULTS: A total of 100 patients were enrolled between 2020 and 2021, including 50 each in the early nutritional intervention group and in the late group. The incidence of Grade-III/IV OM was lower in the early treatment group than in the late treatment group (2% vs 14%, P = 0.059). By week 7 weight loss was significantly lower in the early group than in the late group (1.08 kg, 95% CI: 0.08-2.09, P = 0.035). Regarding the PG-SGA scores after receiving radiotherapy, the early group comprised more well-nourished and fewer malnourished patients than those in the late group (P = 0.002). The scores of the immune function indices of T cell CD3+, CD4+/CD8+, and B cell CD19+ were slightly higher in the early group than in the late group; however, the difference was not statistically significant (all P > 0.05). PFS and OS were better in the early group than in the late group; however, the differences were not statistically significant (P > 0.05). CONCLUSIONS: Early nutritional intervention can effectively improve the nutritional status and reduce the incidence of high-grade OM in patients with HNC receiving radiotherapy. TRIAL REGISTRATION: Chinese Clinical Trials Registry (http://www.chictr.org.cn). CHICTR-ID: ChiCTR2000031418.

Fatigue following head and neck cancer radiotherapy: a systematic review of dose correlates.

INTRODUCTIONS: Radical radiotherapy (RT) is the cornerstone of Head and Neck (H&N) cancer treatment, but it often leads to fatigue due to irradiation of brain structures, impacting patient quality of life. OBJECTIVE: This study aimed to systematically investigate the dose correlates of fatigue after H&N RT in brain structures. METHODS: The systematic review included studies that examined the correlation between fatigue outcomes in H&N cancer patients undergoing RT at different time intervals and brain structures. PubMed, Scopus, and WOS databases were used in the systematic review. A methodological quality assessment of the included studies was conducted following the PRISMA guidelines. After RT, the cohort of H&N cancer patients was analyzed for dose correlations with brain structures and substructures, such as the posterior fossa, brainstem, cerebellum, pituitary gland, medulla, and basal ganglia. RESULT: Thirteen studies meeting the inclusion criteria were identified in the search. These studies evaluated the correlation between fatigue and RT dose following H&N RT. The RT dose ranged from 40 Gy to 70 Gy. Most of the studies indicated a correlation between the trajectory of fatigue and the dose effect, with higher levels of fatigue associated with increasing doses. Furthermore, five studies found that acute and late fatigue was associated with dose volume in specific brain structures, such as the brain stem, posterior fossa, cerebellum, pituitary gland, hippocampus, and basal ganglia. CONCLUSION: Fatigue in H&N RT patients is related to the radiation dose received in specific brain areas, particularly in the posterior fossa, brain stem, cerebellum, pituitary gland, medulla, and basal ganglia. Dose reduction in these areas may help alleviate fatigue. Monitoring fatigue in high-risk patients after radiation therapy could be beneficial, especially for those experiencing late fatigue.

Does adaptive radiotherapy for head and neck cancer favorably impact dosimetric, clinical, and toxicity outcomes?: A review.

PURPOSE: The current review aims to summarize the international experience of the impact of adaptive radiotherapy on dosimetry and clinical and toxicity outcomes. Additionally, it might trigger Radiation Oncologists to use ART and evaluate whether ART improves target volume coverage and/or normal tissue sparing and, consequently, therapeutic results. MATERIALS AND METHODS: We conducted an electronic literature search of PubMed/MEDLINE and ScienceDirect from January 2007 to January 2023. The search adhered to the PRISMA guidelines and employed keywords such as ART, HNC, parotid gland, and target volume. Furthermore, we examined the reference lists for studies pertinent to the present review. This study included both retrospective and prospective studies that were considered for inclusion. CONCLUSION: ART replanning appears to be a sustainable strategy to minimize toxicity by improving normal tissue sparing. Furthermore, it can enhance target volume coverage by correctly determining the specific dose to be delivered to the tumor. In conclusion, this review confirmed that ART benefits dosimetric, clinical/therapeutic, and toxicity outcomes.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: Implementation of a Risk-Based Model.

PURPOSE: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. METHODS: Consecutive patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. CONCLUSION: We identified risk factors for ORN and proposed a novel ORN classification system on the basis of vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN and may facilitate clinical care and clinical trials.

Post-Radiotherapy Dysphagia in Head and Neck Cancer: Current Management by Speech-Language Pathologists.

OPINION STATEMENT: Dysphagia, difficulty in eating and drinking, remains the most common side effect of radiotherapy treatment for head and neck cancer (HNC) with devastating consequences for function and quality of life (QOL). Over the past decade, 5-year survival has improved due to multiple factors including treatment advances, reduction in smoking, introduction of the human papillomavirus (HPV) vaccine and more favourable prognosis of HPV-related cancers. Increased prevalence of HPV-positive disease, which tends to affect younger individuals, has led to an elevated number of people living for longer with the sequelae of cancer and its treatment. Symptoms are compounded by late effects of radiotherapy which may lead to worsening of dysphagia for some long-term survivors or new-onset dysphagia for others. Speech-language pathology (SLP) input remains core to the assessment and management of dysphagia following HNC treatment. In this article, we present current SLP management of dysphagia post-radiotherapy. We discuss conventional treatment approaches, the emergence of therapy adjuncts and current service delivery models. The impact of adherence on therapy outcomes is highlighted. Despite treatment advancements, patients continue to present with dysphagia which is resistant to existing intervention approaches. There is wide variation in treatment programmes, with a paucity of evidence to support optimal type, timing and intensity of treatment. We discuss the need for further research, including exploration of the impact of radiotherapy on the central nervous system (CNS), the link between sarcopenia and radiotherapy-induced dysphagia and the benefits of visual biofeedback in rehabilitation.