Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers.

AIM: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers. METHODS: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy. RESULTS: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity. CONCLUSION: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation.

Post-operative intensity-modulated vs 3D conformal radiotherapy after conservative surgery for laryngeal tumours of the supraglottic region: a dosimetric analysis on 20 patients.

Objective: To perform a dosimetric comparison between intensity modulated radiotherapy (IMRT) and 3D conformal radiotherapy in patients with locally advanced (stage III and IV) tumours of the supraglottic region treated with conservative surgery and post-operative radiotherapy. Methods: An in-silico plan using a 3D conformal shrinking field technique was retrospectively produced for 20 patients and compared with actually delivered IMRT plans. Eighteen structures (arytenoids, constrictor muscles, base of tongue, floor of mouth, pharyngeal axis, oral cavity, submandibular glands and muscles of the swallowing functional units [SFU]) were considered. Results: IMRT allowed a reduction of maximum and mean doses to 9 and 14 structures, respectively (p < .05). Conclusions: IMRT achieved a reduction of unnecessary dose to the remnant larynx and the majority of surrounding SFUs. Further prospective analyses and correlations with functional clinical outcomes are required to confirm these dosimetric findings.

Oral Surgery and Osteoradionecrosis in Patients Undergoing Head and Neck Radiation Therapy: An Update of the Current Literature.

Osteoradionecrosis (ORN) is a serious long-term complication of head and neck radiotherapy (RT), which is often triggered by dental extractions. It results from avascular aseptic necrosis due to irradiated bone damage. ORN is challenging to treat and can lead to severe complications. Furthermore, ORN causes pain and distress, significantly reducing the patient's quality of life. There is currently no established preventive strategy. This narrative review aims to provide an update for the clinicians on the risk of ORN associated with oral surgery in head and neck RT patients, with a focus on the timing suitable for the oral surgery and possible ORN preventive treatments. An electronic search of articles was performed by consulting the PubMed database. Intervention and observational studies were included. A multidisciplinary approach to the patient is highly recommended to mitigate the risk of RT complications. A dental visit before commencing RT is highly advised to minimize the need for future dental extractions after irradiation, and thus the risk of ORN. Post-RT preventive strategies, in case of dento-alveolar surgery, have been proposed and include antibiotics, hyperbaric oxygen (HBO), and the combined use of pentoxifylline and tocopherol ("PENTO protocol"), but currently there is a lack of established standards of care. Some limitations in the use of HBO involve the low availability of HBO facilities, its high costs, and specific clinical contraindications; the PENTO protocol, on the other hand, although promising, lacks clinical trials to support its efficacy. Due to the enduring risk of ORN, removable prostheses are preferable to dental implants in these patients, as there is no consensus on the appropriate timing for their safe placement. Overall, established standards of care and high-quality evidence are lacking concerning both preventive strategies for ORN as well as the timing of the dental surgery. There is an urgent need to improve research for more efficacious clinical decision making.

High PD-L1 Expression on Tumor Cells Indicates Worse Overall Survival in Advanced Oral Squamous Cell Carcinomas of the Tongue and the Floor of the Mouth but Not in Other Oral Compartments.

The markers of the tumor microenvironment (TME) are promising prognostic and predictive factors in oral squamous cell carcinoma (OSCC). The current study aims to analyze the immunohistochemical expression of programmed cell death-ligand 1 (PD-L1) and interleukin-33 (IL-33) in a cohort of 95 chemonaïve OSCCs. PD-L1 and IL-33 were assessed separately in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). High PD-L1 expression in TILs was associated with better overall survival (OS) in univariate analysis. Tumors localized in the floor of the oral cavity and tongue tended to have a lower percentage of PD-L1-positive TCs when compared to other locations. PD-L1 expression on TCs had no prognostic significance when the whole cohort was analyzed. However, along with the T descriptor (TNM 8th), it was included in the multivariable model predicting death in carcinomas of the floor of the oral cavity and tongue (HR = 2.51, 95% CI = 1.97-5.28). In other locations, only nodal status was identified as an independent prognostic factor in multivariate analysis (HR = 0.24, 95% CI = 0.08-0.70). Expression of IL-33 had no impact on survival, but it was differently expressed in various locations. In conclusion, the prognostic significance of PD-L1 in oral cancer depends on the tumor site and type of cell expressing immune checkpoint receptor (TCs vs. TILs).

Methods of Topical Administration of Drugs and Biological Active Substances for Dental Implants-A Narrative Review.

Dental implants are, nowadays, established surgical devices for the restoration of lost teeth. Considered as an alternative for traditional prosthetic appliances, dental implants surpass them in reliability and patient feedback. Local drug delivery around the implants promotes osseointegration and reduces peri-implantitis. However, there are currently no methods of a multiple, precise topical administration of drugs to the implant area. Engineering coatings on the implants, drug application on carriers during implantation, or gingival pockets do not meet all requirements of dental surgeons. Therefore, there is a need to create porous implants and other medical devices that will allow a multiple drug delivery at a controlled dose and release profile without traumatic treatment. Due to the growing demand for the use of biologically active agents to support dental implant treatment at its various stages (implant placement, long-term use of dental superstructures, treatment of the peri-implant conditions) and due to the proven effectiveness of the topical application of pharmacological biologically active agents to the implant area, the authors would like to present a review and show the methods and devices that can be used by clinicians for local drug administration to facilitate dental implant treatment. Our review concludes that there is a need for research in the field of inventions such as new medical devices or implants with gradient solid-porous structures. These devices, in the future, will enable to perform repeatable, controllable, atraumatic, and repeatable injections of active factors that may affect the improvement of osteointegration and the longer survival of implants, as well as the treatment of peri-implantitis.

Oncological-Therapy Related Oral Mucositis as an Interdisciplinary Problem-Literature Review.

Oral mucositis is a toxic side effect of non-surgical cancer treatments: chemotherapy and radiotherapy, which strongly impair quality of life and can not only cause strong pain, but also lead to problems with basic physiological needs as eating and swallowing. Development of oral mucositis is associated with type, dosage, and schedule of radiation or chemotherapy and other factors related to patients. Management of oral mucositis is a valid problem, requiring topical application of anesthetics, coating agents, cryotherapy, low level laser therapy, pharmacological methods as usage of keratinocyte growth factors, supplementation of vitamins, and a proper diet. Another approach to oral mucositis measurement includesphotobiomodulation, which brings analgesic and anti-inflammatory effects.Although oral mucositis is a general health issues, the role of proper dental care is essential. It should include elimination of all potential sources of mucosal injury and microorganisms inhabiting theoral cavity through oral hygiene education,professional management ofdental plaque,and treatment of the caries and periodontium, which are necessary to reduce the risk of inflammation in the oral cavity. This paper describes the possibilities of monitoring oral mucositis,taking into account the latest therapeutic achievements.

Psychological Functioning of Patients Undergoing Oral Surgery Procedures during the Regime Related with SARS-CoV-2 Pandemic.

The coronavirus pandemic has become a huge global challenge medically, economically and psychologically. The COVID-19 pandemic shows that the population can experience general psychological distress. The sanitary regime in dental offices and lack of vaccine for coronavirus may have an impact on the level of dental anxiety among patients undergoing oral surgery procedures. A clinical study was conducted between November 2019 and September 2020. A total of 175 patients (n = 175) were enrolled in the research. The aim of the study was to assess the attitude of patients towards the new situation related to the reduced availability of dental offices providing oral surgery procedures. The level of anxiety associated with surgical intervention was measured using a self-made COVID-19 questionnaire and the MDAS scale. The ED-5Q questionnaire and EQ-VAS scale were also used in this research. The study showed that 21.9% of respondents presented with increased anxiety about a dental visit compared with the time before the pandemic. This epidemiological situation has led to an overwhelming increase in moderate dental anxiety (M: 11.4) among patients undergoing oral surgery procedures. The quality of patients' health (EQ-VAS) related to the impact of the coronavirus pandemic and the quarantine decreased by 10 percentage points. Oral surgeons should be prepared for more anxious patients in dental offices during the pandemic.

Lactobacillus brevis CD2 for Prevention of Oral Mucositis in Patients With Head and Neck Tumors: A Multicentric Randomized Study.

BACKGROUND: Oropharyngeal mucositis occurs in virtually all patients with head and neck cancer receiving radiochemotherapy. The manipulation of the oral cavity microbiota represents an intriguing and challenging target. PATIENTS AND METHODS: A total of 75 patients were enrolled to receive Lactobacillus brevis CD2 lozenges or oral care regimen with sodium bicarbonate mouthwashes. The primary endpoint was the incidence of grade 3 or 4 oropharyngeal mucositis during radiotherapy treatment. RESULTS: There was no statistical difference in the incidence of grade 3-4 oropharyngeal mucositis between the intervention and control groups (40.6% vs. 41.6% respectively, p=0.974). The incidence of pain, dysphagia, body weight loss and quality of life were not different between the experimental and standard arm. CONCLUSION: Our study was not able to demonstrate the efficacy of L. brevis CD2 lozenges in preventing radiation-induced mucositis in patients with head and neck cancer. Although modulating homeostasis of the salivary microbiota in the oral cavity seems attractive, it clearly needs further study.

Set-up errors in head and neck cancer patients treated with intensity modulated radiation therapy: Quantitative comparison between three-dimensional cone-beam CT and two-dimensional kilovoltage images.

OBJECTIVES: To compare the patient set-up error detection capabilities of three-dimensional cone beam computed tomography (3D-CBCT) and two-dimensional orthogonal kilovoltage (2D-kV) techniques. METHODS: 3D-CBCT and 2D-kV projections were acquired on 29 head-and-neck (H&N) patients undergoing Intensity Modulated Radiotherapy (IMRT) on the first day of treatment (time 0) and after the delivery of 40 Gy and 50 Gy. Set-up correction vectors were analyzed after fully automatic image registration as well as after revision by radiation oncologists. The dosimetric effects of the different sensitivities of the two image guidance techniques were assessed. RESULTS: A statistically significant correlation among detected set-up deviations by the two techniques was found along anatomical axes (0.60 < ρ < 0.72, p < 0.0001); no correlation was found for table rotation (p = 0.41). No evidence of statistically significant differences between the indications provided along the course of the treatment was found; this was also the case when full automatic versus manually refined correction vectors were compared. The dosimetric effects analysis revealed slight statistically significant differences in the median values of the maximum relative dose to mandible, spinal cord and its 5 mm Planning Organ at Risk Volume (0.95%, 0.6% and 2.45%, respectively), with higher values (p < 0.01) observed when 2D-kV corrections were applied. CONCLUSION: A similar sensitivity to linear set-up errors was observed for 2D-kV and 3D-CBCT image guidance techniques in our H&N patient cohort. Higher rotational deviations around the table vertical axis were detected by the 3D-CBCT with respect to the 2D-kV method, leading to a consistent better sparing of organs at risk.

Automatic segmentation and online virtualCT in head-and-neck adaptive radiation therapy.

PURPOSE: The purpose of this work was to develop and validate an efficient and automatic strategy to generate online virtual computed tomography (CT) scans for adaptive radiation therapy (ART) in head-and-neck (HN) cancer treatment. METHOD: We retrospectively analyzed 20 patients, treated with intensity modulated radiation therapy (IMRT), for an HN malignancy. Different anatomical structures were considered: mandible, parotid glands, and nodal gross tumor volume (nGTV). We generated 28 virtualCT scans by means of nonrigid registration of simulation computed tomography (CTsim) and cone beam CT images (CBCTs), acquired for patient setup. We validated our approach by considering the real replanning CT (CTrepl) as ground truth. We computed the Dice coefficient (DSC), center of mass (COM) distance, and root mean square error (RMSE) between correspondent points located on the automatically segmented structures on CBCT and virtualCT. RESULTS: Residual deformation between CTrepl and CBCT was below one voxel. Median DSC was around 0.8 for mandible and parotid glands, but only 0.55 for nGTV, because of the fairly homogeneous surrounding soft tissues and of its small volume. Median COM distance and RMSE were comparable with image resolution. No significant correlation between RMSE and initial or final deformation was found. CONCLUSION: The analysis provides evidence that deformable image registration may contribute significantly in reducing the need of full CT-based replanning in HN radiation therapy by supporting swift and objective decision-making in clinical practice. Further work is needed to strengthen algorithm potential in nGTV localization.

Compartmental tongue surgery: Long term oncologic results in the treatment of tongue cancer.

Compartmental tongue surgery (CTS) is a surgical technique that removes the compartments (anatomo-functional units) containing the primary tumor, eliminating the disease and potential muscular, vascular, glandular and lymphatic pathways of spread and recurrence. Compartment boundaries are defined as each hemi-tongue bounded by the lingual septum, the stylohyoid ligament and muscle, and the mylohyoid muscle. In this non-randomized retrospective study we evaluated the oncologic efficacy of CTS in patients with squamous cell carcinoma (SCCA) of the tongue treated from 1995 to 2008. We evaluated 193 patients with primary, previously untreated cT2-4a, cN0, cN+, M0 SCCA with no contraindication to anesthesia and able to give informed consent. Fifty patients treated between October 1995 and July 1999 received standard surgery (resection margin >1cm); 143 patients treated between July 1999 and January 2008 received CTS. Study endpoints were: 5-year local disease-free, locoregional disease-free and overall survival. After 5years, local disease control was achieved in 88.4% of CTS patients (16.8% improvement on standard surgery); locoregional disease control in 83.5% (24.4% improvement) and overall survival was 70.7% (27.3% improvement). The markedly improved outcomes in CTS patients, compared to those treated by standard surgery, suggest CTS as an important new approach in the surgical management of tongue cancer.