Sodium-hyaluronate mouthwash on radiotherapy-induced xerostomia: a randomised clinical trial.

INTRODUCTION: Radiotherapy-induced xerostomia (RIX) is one of the most common adverse effects of radiotherapy (RT) in head and neck cancer patients (HNC) and a major determinant of survivors' quality of life. The primary objective was to evaluate the reduction of patients' xerostomia symptoms after the utilisation of a sodium-hyaluronate mouthwash compared to a placebo solution. The secondary objectives were to evaluate the improvement of quality of life and to evaluate the patients' satisfaction. METHODS: The protocol was approved by the ethical committee (Ref. 50,053/19) and registered at ClinicalTrials.gov (ID: NCT05103124). The study was a double-blind randomised clinical trial (RCT) with a crossover design and was conducted at the Fondazione Policlinico Universitario A. Gemelli, Rome. RESULTS: Thirty-two patients completed the study protocol. Lower values of the modified Xerostomia Questionnaire (XQ) were retrieved when comparing the baseline scores to the ones after the treatment, when compared with placebo (Mann-Whitney U test = 0.01); higher values of patients' satisfaction (Likert scale) and modified XQ were retrieved for the sodium-hyaluronate mouthwash (Mann-Whitney U test = 0.001). CONCLUSIONS: This RCT highlights the advantages of treating RIX with the sodium-hyaluronate mouthwash since it seems to be clinically effective in reducing its symptoms, without any reported adverse events. CLINICALTRIALS: gov: NCT05103124 in 17/10/2021.

Role of radiomics in predicting lymph node metastasis in gastric cancer: a systematic review.

Introduction: Gastric cancer (GC) is an aggressive and clinically heterogeneous tumor, and better risk stratification of lymph node metastasis (LNM) could lead to personalized treatments. The role of radiomics in the prediction of nodal involvement in GC has not yet been systematically assessed. This study aims to assess the role of radiomics in the prediction of LNM in GC. Methods: A PubMed/MEDLINE systematic review was conducted to assess the role of radiomics in LNM. The inclusion criteria were as follows: i. original articles, ii. articles on radiomics, and iii. articles on LNM prediction in GC. All articles were selected and analyzed by a multidisciplinary board of two radiation oncologists and one surgeon, under the supervision of one radiation oncologist, one surgeon, and one medical oncologist. Results: A total of 171 studies were obtained using the search strategy mentioned on PubMed. After the complete selection process, a total of 20 papers were considered eligible for the analysis of the results. Radiomics methods were applied in GC to assess the LNM risk. The number of patients, imaging modalities, type of predictive models, number of radiomics features, TRIPOD classification, and performances of the models were reported. Conclusions: Radiomics seems to be a promising approach for evaluating the risk of LNM in GC. Further and larger studies are required to evaluate the clinical impact of the inclusion of radiomics in a comprehensive decision support system (DSS) for GC.

Management of Esophago-Gastric Junction Carcinoma: A Narrative Multidisciplinary Review.

Esophagogastric junction (EGJ) carcinoma represents a specific site of disease, given the opportunities for multimodal clinical care and management and the possibilities of combined treatments. It encompasses various clinical subgroups of disease that are heterogeneous and deserve different treatments; therefore, the guidelines have progressively evolved over time, considering the evidence provided by clinical trials. The aim of this narrative review was to summarize the main evidence, which orientates the current guidelines, and to collect the main ongoing studies to address existing gray areas.

Prognostic Score in Radiotherapy Practice for Palliative Treatments (PROPHET) Study for Bone Metastases: An Investigation Into the Clinical Effect on Treatment Prescription.

Purpose: Bone metastases frequently occur during malignant disease. Palliative radiation therapy (PRT) is a crucial part of palliative care because it can relieve pain and improve patients' quality of life. Often, a clinician's survival estimation is too optimistic. Prognostic scores (PSs) can help clinicians tailor PRT indications to avoid over- or undertreatment. Although the PS is supposed to aid radiation oncologists (ROs) in palliative-care scenarios, it is unclear what type of support, and to what extent, could impact daily clinical practice. Methods and Materials: A national-based investigation of the prescriptive decisions on simulated clinical cases was performed in Italy. Nine clinical cases from real-world clinical practice were selected for this study. Each case description contained complete information regarding the parameters defining the prognosis class according to the PS (in particular, the Mizumoto Prognostic Score, a validated PS available in literature and already applied in some clinical trials). Each case description contained complete information regarding the parameters defining the prognosis class according to the PS. ROs were interviewed through questionnaires, each comprising the same 3 questions per clinical case, asking (1) the prescription after detailing the clinical case features but not the PS prognostic class definition; (2) whether the RO wanted to change the prescription once the PS prognostic class definition was revealed; and (3) in case of a change of the prescription, a new prescriptive option. Three RO categories were defined: dedicated to PRT (RO-d), nondedicated to PRT (RO-nd), and resident in training (IT). Interviewed ROs were distributed among different regions of the country. Results: Conversion rates, agreements, and prescription trends were investigated. The PS determined a statistically significant 11.12% of prescription conversion among ROs. The conversion was higher for the residents and significantly higher for worse prognostic scenario subgroups, respectively. The PS improved prescriptive agreement among ROs (particularly for worse-prognostic-scenario subgroups). Moreover, PS significantly increased standard prescriptive approaches (particularly for worse-clinical-case presentations). Conclusions: To the best of our knowledge, the PROPHET study is the first to directly evaluate the potential clinical consequences of the regular application of any PS. According to the Prophet study, a prognostic score should be integrated into the clinical practice of palliative radiation therapy for bone metastasis and training programs in radiation oncology.

Oral Candida spp. Colonisation Is a Risk Factor for Severe Oral Mucositis in Patients Undergoing Radiotherapy for Head & Neck Cancer: Results from a Multidisciplinary Mono-Institutional Prospective Observational Study.

BACKGROUND: This study aims to find a correlation between Candida spp. oral colonisation prior to radiotherapy (RT) and (i) the development of severe oral mucositis (OM) (grade 3/4) and (ii) early development of severe OM (EOM). METHODS: The protocol was registered on ClinicalTrials.gov (ID: NCT04009161) and approved by the ethical committee of the 'Fondazione Policlinico Universitario Gemelli IRCCS' (22858/18). An oral swab was obtained before RT to assess the presence of Candida spp. Severe OM occurring before a dose of 40 Gy was defined as EOM. RESULTS: No patient developed G4 OM, and only 36/152 patients (23.7%) developed G3 OM. Tumour site and lymphocytopenia were risk factors for severe OM (OR for tumour site: 1.29, 95% CI: 1-1.67, p = 0.05; OR for lymphocytopenia: 8.2, 95% CI: 1.2-55.8, p = 0.03). We found a correlation between Candida spp. and EOM (OR: 5.13; 95% CI: 1.23-21.4 p = 0.04). Patients with oral colonisation of Candida spp. developed severe OM at a mean dose of 38.3 Gy (range: 28-58; SD: 7.6), while negative patients did so at a mean dose of 45.6 Gy (range: 30-66; SD: 11.1). CONCLUSIONS: Candida spp. in the oral cavity appears to be a predictive factor of EOM.

Clinical Validation of a Deep-Learning Segmentation Software in Head and Neck: An Early Analysis in a Developing Radiation Oncology Center.

BACKGROUND: Organs at risk (OARs) delineation is a crucial step of radiotherapy (RT) treatment planning workflow. Time-consuming and inter-observer variability are main issues in manual OAR delineation, mainly in the head and neck (H & N) district. Deep-learning based auto-segmentation is a promising strategy to improve OARs contouring in radiotherapy departments. A comparison of deep-learning-generated auto-contours (AC) with manual contours (MC) was performed by three expert radiation oncologists from a single center. METHODS: Planning computed tomography (CT) scans of patients undergoing RT treatments for H&N cancers were considered. CT scans were processed by Limbus Contour auto-segmentation software, a commercial deep-learning auto-segmentation based software to generate AC. H&N protocol was used to perform AC, with the structure set consisting of bilateral brachial plexus, brain, brainstem, bilateral cochlea, pharyngeal constrictors, eye globes, bilateral lens, mandible, optic chiasm, bilateral optic nerves, oral cavity, bilateral parotids, spinal cord, bilateral submandibular glands, lips and thyroid. Manual revision of OARs was performed according to international consensus guidelines. The AC and MC were compared using the Dice similarity coefficient (DSC) and 95% Hausdorff distance transform (DT). RESULTS: A total of 274 contours obtained by processing CT scans were included in the analysis. The highest values of DSC were obtained for the brain (DSC 1.00), left and right eye globes and the mandible (DSC 0.98). The structures with greater MC editing were optic chiasm, optic nerves and cochleae. CONCLUSIONS: In this preliminary analysis, deep-learning auto-segmentation seems to provide acceptable H&N OAR delineations. For less accurate organs, AC could be considered a starting point for review and manual adjustment. Our results suggest that AC could become a useful time-saving tool to optimize workload and resources in RT departments.

A predictive nomogram for trismus after radiotherapy for head and neck cancer.

BACKGROUND: The aim of this study is to develop a prediction model for trismus (maximal interincisal distance equal to or less than 35 mm) based on a multivariable analysis of dosimetric and clinical factors. METHODS: The maximum inter-incisal opening (MIO) of hean and neck cancer (HNC) patients who underwent radiotherapy (RT) ± concurrent chemotherapy with radical intent, was prospectively measured prior to RT (baseline) and 6 months post-RT. The outcome variable is trismus. The potential risk factors (clinical and dosimetric) were first screened by univariate analysis and then by multivariate analysis. At the end of this process, we used the features identified as relevant, to fit a logistic regression model and calculate the probability of observed trismus during the 6-month follow-up after RT. RESULTS: One hundred and four consecutive patients were included (mean age 63 years, range 25-87), 68 males, 36 females. In the univariate analysis, the MIO at baseline, as an independent variable, and several Vdoses of different masticatory structures were found as significant. Additionally, using a bivariate model, a feature selection process was performed. Finally, we considered as best performing model the MIO at baseline and V42 at masseter muscles. The area under curve (AUC) of Receiver Operating Characteristic (ROC) curve value was 0.8255 (95% CI 0.74-0.9). The Hosmer and Lemeshow goodness-of-fit test, used to calibrate our model, was not-significant. CONCLUSIONS: A prediction nomogram was developed to assess trismus risk in planning process. An external validation of the model is required to apply it for current clinical use.

Development of a prognostic model of overall survival in oropharyngeal cancer from real-world data: PRO.M.E.THE.O.

Objective: The PRO.M.E.THE.O. study (PredictiOn Models in Ent cancer for anti-EGFR based THErapy Optimization) aimed to develop a predictive model (PM) of overall survival (OS) for patients with locally advanced oropharyngeal cancer (LAOC) treated with radiotherapy (RT) and cetuximab (Cet) from an Italian dataset. Methods: We enrolled patients with LAOC from 6 centres treated with RT-Cet. Clinical and treatment variables were collected. Patients were randomly divided into training (TS) (80%) and validation (VS) (20%) sets. A binary logistic regression model was used on the TS with stepwise feature selection and then on VS. Timepoints of 2, 3 and 5 years were considered. The area under the curve (AUC) of receiver operating characteristic of 2, 3 and 5 year and confusion matrix statistics at 5-threshold were used as performance criteria. Results: Overall, 218 patients were enrolled and 174 (79.8%) were analysed. Age at diagnosis, gender, ECOG performance, clinical stage, dose to high-risk volume, overall treatment time and day of RT interruption were considered in the final PMs. The PMs were developed and represented by nomograms with AUC of 0.75, 0.73 and 0.73 for TS and 0.713, 0.713, 0.775 for VS at 2, 3 and 5 years, respectively. Conclusions: PRO.M.E.THE.O. allows the creation of a PM for OS in patients with LAOC treated with RT-Cet.

Oral Health Status in Patients with Head and Neck Cancer before Radiotherapy: Baseline Description of an Observational Prospective Study.

(1) Background: The general hypothesis that HNC patients show compromised oral health (OH) is generally accepted, but it is not evidence-based. The objective of this baseline report of a prospective observational study was to describe the oral health of a cohort of patients with HNC at the time of dental evaluation prior to radiotherapy (RT). (2) Materials and Methods: Two hundred and thirteen patients affected by HNC who had received an indication for RT were examined with the support of orthopantomography (OPT). The DMFt of all included subjects, their periodontal status and the grade of mouth opening were recorded. (3) Results: A total of 195 patients were ultimately included: 146/195 patients (74.9%) showed poor OH (defined as having a DMFt score ≥ 13 and severe periodontitis). The following clinical characteristics were correlated with poor oral health in the univariate analysis: tumor site, smoking habit and age of the patients (in decades); χ2 test, p < 0.05. (4) Conclusions: This study confirms that the OH of HNC patients is often compromised even before the beginning of cancer treatment and, consequently, highlights how important it is to promptly schedule a dental evaluation at the moment of diagnosis of the cancer.

Prevalence of HPV Infection and p16INK4a Overexpression in Surgically Treated Laryngeal Squamous Cell Carcinoma.

Background: The mucosal high-risk (HR) human papillomavirus (HPV) is associated with oropharyngeal carcinogenesis. Aims of this study were to evaluate the prevalence of HR-HPV infection in laryngeal squamous cell carcinoma (LSCC) from different subsites, and the clinico-biological meaning of p16 overexpression. Methods: Ninety-seven LSCCs submitted to primary surgery (n = 75) or to post-irradiation salvage laryngectomy (n = 22) were evaluated for HR-HPV DNA and RNA using Luminex-based assays. p16 immunohistochemistry was performed. Results: HR-HPV DNA from HPV16 was detected in seven cases (8.75%), without significant differences between supraglottic and glottic lesions. HPV RNA was never detected. p16 overexpression correlated with HR-HPV DNA, but the kappa agreement score was poor. HPV DNA showed no impact on prognosis. p16 overexpression was associated with a better survival (OS, RFS) in primarily operated cases, while an inverse association with OS was observed in the salvage surgery group. Conclusions: HR-HPV infection appears to have a marginal role in LSCC independent of the anatomical subsite. p16 expression is deregulated in LSCC independent of HPV but displays a prognostic role in patients submitted to primary surgery. The negative predictive role of p16 overexpression in patients undergoing salvage surgery deserves more investigations for validation and elucidation of its clinical relevance.

Osteoradionecrosis of the Jaws Due to Teeth Extractions during and after Radiotherapy: A Systematic Review.

Teeth extractions before or after radiotherapy (RT) could be procedures at high risk for osteoradionecrosis (ORN) onset. This systematic review was performed to investigate the ORN incidence following teeth extractions during and after RT for head and neck (H&N) cancer and to evaluate any other possible risk factor. METHODS: This systematic review was conducted according to PRISMA protocol, and the PROSPERO registration number was CRD42018079986. An electronic search was performed on the following search engines: PubMed, Scopus, and Web of Science. A cumulative meta-analysis was performed. RESULTS: Two thousand two hundred and eighty-one records were screened, and nine were finally included. This systematic review revealed an ORN incidence of 5.8% (41 patients out of 462, 95% CI = 2.3-9.4); 3 ORN developed in the maxilla. No other clinical risk factors were detected. CONCLUSION: Post-RT teeth extractions represent a major risk factor for ORN development, especially in the mandible, with a diminishing trend in the last years. Further research on other possible risk factors might improve this evidence.

Successful Treatment of Tumor-Induced Osteomalacia by Multidisciplinary Therapy with Radiation to Intracranial Fibromyxoid Tumor.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by protein fibroblast-growth-factor-23 (FGF-23) secreting tumors. Complete tumor resection is the current standard of care for TIO; however, some patients may develop tumor recurrence. Due to the rarity of this paraneoplastic syndrome, the role of radiotherapy is unclear. This case is worth reporting because it adds to our knowledge some insights about the potential role of radiotherapy in this rare condition. Case Presentation. After multidisciplinary consultation, in July 2015, postoperative adjuvant radiotherapy was offered to a 52-year-old man with a multiple recurrent ossifying fibromyxoid tumor in the right frontal sinus causing TIO. The patient had a history of multiple bone fractures and pain since more than 20 years. The tumor had been removed in 2003 for the first time. Subsequent endoscopic resections of the tumor had been performed for recurrences of TIO in May 2012, October 2013, and July 2015. Starting from October 2015, external beam radiotherapy was delivered with a volumetric modulated arc technique to the tumor bed with a daily dose of 2 Gy up to a total dose of 60 Gy. After five years from treatment, the patient is free from local tumor relapse, TIO progression, and radiation-induced side effects. CONCLUSIONS: Radiotherapy may provide long-term TIO remission and tumor control, thus being a treatment option in cases where surgery is unfeasible or unsuccessful.

miR-9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC.

Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains the aggressiveness of HNSCC cells and protects from RT-induced cell death. Mechanistically, by targeting KLF5, miR-9 regulates the expression of the transcription factor Sp1 that, in turn, stimulates tumor growth and confers resistance to RT+CTX in vitro and in vivo. Intriguingly, high miR-9 levels have no effect on the sensitivity of HNSCC cells to cisplatin. In primary HNSCC, miR-9 expression correlated with Sp1 mRNA levels and high miR-9 expression predicted poor prognosis in patients treated with RT+CTX. Overall, we have discovered a new signaling axis linking EGFR activation to Sp1 expression that dictates the response to combination treatments in HNSCC. We propose that miR-9 may represent a valuable biomarker to select which HNSCC patients might benefit from RT+CTX therapy.

A snapshot on radiotherapy for head and neck cancer patients during the COVID-19 pandemic: a survey of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) head and neck working group.

OBJECTIVES: The objective of the paper was to assess real-life experience in the management of head and neck cancer (HNC) patients during the COVID-19 pandemic in radiotherapy departments and to evaluate the variability in terms of adherence to American Society of Radiation Oncology (ASTRO) and European Society for Radiotherapy and Oncology (ESTRO) recommendations. MATERIALS AND METHODS: In May 2020, an anonymous 30-question online survey, comparing acute phase of outbreak and pre-COVID-19 period, was conducted. Two sections exploited changes in general management of HNC patients and different HNC primary tumors, addressing specific statements from ASTRO ESTRO consensus statement as well. RESULTS: Eighty-eight questionnaires were included in the demographic/clinical workflow analysis, and 64 were analyzed for treatment management. Forty-eight percent of radiotherapy departments became part of oncologic hubs. First consultations reduced, and patients were addressed to other centers in 33.8 and 18.3% of cases, respectively. Telematic consultations were used in 50% of follow-up visits and 73.9% of multidisciplinary tumor board discussions. There were no practical changes in the management of patients affected by different primitive HNCs. Hypofractionation was not favored over conventional schedules. CONCLUSIONS: Compared to pre-COVID era, the clinical workflow was highly re-organized, whereas there were no consistent changes in RT indications and schedules.

Head and neck radiotherapy amid the COVID-19 pandemic: practice recommendations of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Management of patients with head and neck cancers (HNCs) is challenging for the Radiation Oncologist, especially in the COVID-19 era. The Italian Society of Radiotherapy and Clinical Oncology (AIRO) identified the need of practice recommendations on logistic issues, treatment delivery and healthcare personnel's protection in a time of limited resources. A panel of 15 national experts on HNCs completed a modified Delphi process. A five-point Likert scale was used; the chosen cut-offs for strong agreement and agreement were 75% and 66%, respectively. Items were organized into two sections: (1) general recommendations (10 items) and (2) special recommendations (45 items), detailing a set of procedures to be applied to all specific phases of the Radiation Oncology workflow. The distribution of facilities across the country was as follows: 47% Northern, 33% Central and 20% Southern regions. There was agreement or strong agreement across the majority (93%) of proposed items including treatment strategies, use of personal protection devices, set-up modifications and follow-up re-scheduling. Guaranteeing treatment delivery for HNC patients is well-recognized in Radiation Oncology. Our recommendations provide a flexible tool for management both in the pandemic and post-pandemic phase of the COVID-19 outbreak.

Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines.

PURPOSE: Few studies have reported large inter-observer variations in target volume selection and delineation in patients treated with radiotherapy for head and neck squamous cell carcinoma. Consensus guidelines have been published for the neck nodes (see Grégoire et al., 2003, 2014), but such recommendations are lacking for primary tumour delineation. For the latter, two main schools of thoughts are prevailing, one based on geometric expansion of the Gross Tumour Volume (GTV) as promoted by DAHANCA, and the other one based on anatomical expansion of the GTV using compartmentalization of head and neck anatomy. METHOD: For each anatomic location within the larynx, hypopharynx, oropharynx and oral cavity, and for each T-stage, the DAHANCA proposal has been comprehensively reviewed and edited to include anatomic knowledge into the geometric Clinical Target Volume (CTV) delineation concept. A first proposal was put forward by the leading authors of this publication (VG and CG) and discussed with opinion leaders in head and neck radiation oncology from Europe, Asia, Australia/New Zealand, North America and South America to reach a worldwide consensus. RESULTS: This consensus proposes two CTVs for the primary tumour, the so called CTV-P1 and CVT-P2, corresponding to a high and lower tumour burden, and which should be associated with a high and a lower dose prescription, respectively. CONCLUSION: Implementation of these guidelines in the daily practice of radiation oncology should contribute to reduce treatment variations from clinicians to clinicians, facilitate the conduct of multi-institutional clinical trials, and contribute to improved care of patients with head and neck carcinoma.

The vicious circle of treatment-induced toxicities in locally advanced head and neck cancer and the impact on treatment intensity.

The intensity of the available treatment approaches for locally-advanced head and neck cancer (HNC) is at the upper limit of tolerance of acute toxicities. Several factors including breakthrough cancer pain, mucositis, dysphagia, local and systemic infections, and nutritional problems are related to treatment intensity. Particularly, pain, as symptom directly associated with the disease or combined with other treatment-related factors, has a major impact on quality of life of HNC patients and ultimately can influence the efficacy of treatments in HNC. Here, a Multidisciplinary Board of Italian Experts has addressed these issues, with the aim to identify the unmet need and appropriate strategies for the maintenance of optimal treatment intensity in HNC.

Perioperative HDR brachytherapy for reirradiation in head and neck recurrences: single-institution experience and systematic review.

AIM: The aim of our study was to evaluate the outcomes of patients reirradiated with high-dose-rate (HDR) intensity-modulated brachytherapy (IMBT) for recurrent head and neck cancer and to perform a systematic review of the literature. MATERIALS AND METHODS: Patients treated with prior radiation doses >65 Gy were considered. After resection of macroscopic disease, catheters were fixed to the tumor bed. The total dose was 30 Gy in 12 fractions of 2.5 Gy twice daily for 5 days a week. A systematic literature search was conducted through several electronic databases including Medline/PubMed, Scopus, Embase and the Cochrane library. RESULTS: Seventeen patients were included; median overall survival was 19 months with a median local control interval of 15 months. Median follow-up was 36 months. Seven papers were considered for the review. CONCLUSIONS: IMBT could play an important role in the retreatment of recurrent head and neck cancer.