Quality of life changes over time and predictors in a large head and neck patients' cohort: secondary analysis from an Italian multi-center longitudinal, prospective, observational study-a study of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) head and neck working group

Purpose: The present study examined the longitudinal trajectories, through hierarchical modeling, of quality of life among patients with head and neck cancer, specifically symptoms burden, during radiotherapy, and in the follow-up period (1, 3, 6, and 12 months after completion of radiotherapy), through the M.D. Anderson Symptom Inventory Head and Neck questionnaire, formed by three factors. Furthermore, analyses were conducted controlling for socio-demographic as well as clinical characteristics. Methods: Multi-level mixed-effects linear regression was used to estimate the association between quality of life and time, age, gender, household, educational level, employment status, ECOG performance status, human papilloma virus (HPV) status, surgery, chemotherapy, alcohol intake, and smoking. Results: Among the 166 participants, time resulted to be a predictor of all the three questionnaire factors, namely, general and specific related symptoms and interference with daily life. Moreover, regarding symptom interference with daily activities factor, HPV-positive status played a significant role. Considering only HPV-negative patients, only time predicted patients' quality of life. Differently, among HPV-positive patients, other variables, such as gender, educational level, alcohol use, surgery, age at diagnosis, employment status, and ECOG status, resulted significant. Conclusion: It was evident that quality of life of patients with head and neck cancer declined during RT, whereas it slowly improved after ending treatment. Our results clarified the role of some socio-demographic and clinical variables, for instance, HPV, which would allow to develop treatments tailored to each patient

Upper-neck irradiation versus standard whole-neck irradiation in nasopharyngeal carcinoma: A systematic review and meta-analysis

Purpose: To evaluate the role of upper-neck irradiation versus standard whole-neck irradiation in patients with N0-1 nasopharyngeal carcinoma. Methods: We conducted a PRISMA guideline based systematic review and meta-analysis. Randomized clinical trials assessing upper-neck irradiation versus whole-neck irradiation with or without chemotherapy in non-metastatic N0-1 nasopharyngeal carcinoma patients were identified. The studies were searched on the PubMed, Embase and Cochrane library up to March 2022. Survival outcomes, including overall survival, distant metastasis-free survival and relapse-free survival, and toxicities rate were evaluated. Results: There were two randomized clinical trials with 747 samples finally included. Upper-neck irradiation had similar overall survival (hazard ratio = 0.69, 95% confidence interval = 0.37-1.30), distant metastasis-free survival (hazard ratio = 0.92, 95% confidence interval = 0.53-1.60) and relapse-free survival (risk ratio = 1.03, 95% confidence interval = 0.69-1.55) compared to whole-neck irradiation. No differences in both acute and late toxicities were recorded between upper-neck irradiation and whole-neck irradiation. Conclusion: This meta-analysis supports the potential role of upper-neck irradiation in this population of patients. Further research is needed to confirm results

Particle Reirradiation of Malignant Epithelial and Neuroectodermal Sinonasal Tumors: A Case Series from CNAO

Sinonasal cancers (SNCs) are rare and heterogeneous in histology and biological behavior. The prognosis is generally unfavorable, especially in inoperable cases. In recent years, for some histologies, such as undifferentiated sinonasal carcinoma (SNUC), multimodal treatment with a combination of induction chemotherapy, surgery, and chemo/radiotherapy (RT) has improved the prognosis. Nevertheless, still about half of the patients treated incur a recurrence, in most of the cases at the local site. Surgery with and without RT is usually the treatment choice in cases of recurrence after previous RT in combination with systemic therapy or RT in a histology-driven fashion. In the case of inoperable disease or contraindications to surgery, RT is still a valid treatment option. In this context, hadron therapy with protons (PT) or carbon ions (CIRT) is often preferred due to the physical and biological characteristics of charged particles, allowing the administration of high doses to the tumor target while sparing the surrounding healthy tissues and potentially limiting the side effects due to the high cumulative dose. In the absence of a standard of care for the recurrent setting, we aimed to investigate the role of re-RT with PT or CIRT. We retrospectively analysed 15 patients with recurrent, previously irradiated, SNCs treated at our institution between 2013 and 2020. Local control (LC) and overall survival (OS) were estimated by the Kaplan–Meier method. Acute and late toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events CTCAE version 5.0. A total of 13 patients received CIRT and 2 patients received PT. The median re-RT dose was 54 GyRBE (range 45–64 GyRBE) delivered in 3 or 4 GyRBE/fr (fraction) for the CIRT, and 2 Gy RBE/fr for the PT schedule. LC was 44% at the 1-year follow-up and 35.2% at the 3-year follow-up. OS at 1 and 3 years were 92.9% and 38.2%, respectively. Fourteen patients developed G1–G2 acute toxicity (dermatitis and mucositis), and no patients developed G3–G5. Regarding late toxicity, 10 patients encountered at maximum G1–2 events, and 4 did not experience any toxicity. Only for one patient G3 late toxicity was reported (dysphagia requiring a percutaneous endoscopic gastrostomy)

Dosimetric and Clinical Risk Factors for the Development of Maxillary Osteoradionecrosis in Adenoid Cystic Carcinoma (ACC) Patients Treated With Carbon Ion Radiotherapy

Background: The present study aims to evaluate dosimetric and clinical risk factors for the development of maxillary osteoradionecrosis (ORN) in head and neck adenoid cystic carcinoma (ACC) patients treated with carbon ion radiotherapy (CIRT). Methods: Clinical data and treatment plans of ACC patients, consecutively treated from January 2013 to September 2016 within the phase II clinical trial CNAO S9/2012/C, were retrospectively reviewed. ORN and other treatment-related toxicity were graded according to the Common Terminology Criteria for Adverse Events (CTACE), version 4.0. The maxillary bone was contoured on the planning CT, and only patients receiving more than 10% of the prescription dose at their maxilla were considered for the analysis (67 patients). The volumes of maxilla receiving doses from 10 Gy (RBE) to 60 Gy (RBE) (VD), with an increment of 10 Gy (RBE), and additional clinical factors were correlated to the incidence of ORN with univariate analysis (Chi-square test). The logistic regression model was subsequently applied for multivariate analysis. Treatment plans calculated with a local effect model (LEM)-based optimization were recalculated with the modified microdosimetric kinetic model (MKM), and compared with literature data from the Japanese experience. Results: The median time interval from the start of CIRT to ORN appearance was 24 months (range, 8-54 months). Maxillary ORN was observed in 11 patients (16.4%). Grade 1 ORN was observed in 2 patients (18.1%), G2 in 4 (36.3%), G3 in 4 (36.3%) and G4 in 1 (9.3%). From univariate analysis, the site of the tumor, the presence of teeth within the PTV and acute mucositis correlated with the development of maxillary ORN. VD were significantly higher for all the dose levels tested in patients with maxillary ORN than patients without necrosis, according to both radiobiological models. The multivariate analysis showed that V60 significantly correlated with ORN risk. Conclusion: The volume of maxilla irradiated with high dose values was relevant for ORN development in our cohort of ACC patients. These results are in line with previously published data obtained with a different radiobiological model. Our findings might be helpful to prevent the risk of ORN in patients receiving CIRT

A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate the Efficacy of AqualiefTM Mucoadhesive Tablets in Head and Neck Cancer Patients Who Developed Radiation-Induced Xerostomia

Xerostomia, the subjective complaint of dry mouth, is caused by therapeutic interventions or diseases. Nowadays, radiotherapy (RT) in patients with head and neck cancer (HNC) stands out as one of the most important causes of xerostomia. Currently available therapies for the treatment of xerostomia are still less than optimal and xerostomia still represents an unmet clinical need. In this article, we present the results of a prospective clinical study with a new product, AqualiefTM, in patients treated with curative RT with or without chemotherapy for HNC. AqualiefTM is based on two main ingredients, carnosine and karkadé, which have acid buffering and antioxidant properties. The study was performed on 30 patients, with 4 of the patients being lost during the study period. Each patient received randomly one of the two treatments, AqualiefTM or placebo, for 8 days. After a 10-day wash-out period, each patient received the other treatment for a further 8 days. The results show that AqualiefTM stimulated salivation in these patients and reduced the pH drop that was observed in an equivalent placebo-treated population of patients. Moreover, no serious, treatment-related adverse events were observed. AqualiefTM has shown positive results, although with limitations due to unsuccessful trial accrual. Therefore, it may be further investigated as a tool for the treatment of RT-related xerostomia

A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients

(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the ΔNTCP and ΔDVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to ΔNTCP > 3% for at least one severe toxicity, 4 (18.2%) due to ΔNTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of ΔNTCP and ΔDVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing

A Prognostic and Carboplatin Response Predictive Model in Ovarian Cancer: A Mono-Institutional Retrospective Study Based on Clinics and Pharmacogenomics

Carboplatin is the cornerstone of ovarian cancer (OC) treatment, while platinum-response, dependent on interindividual variability, is the major prognostic factor for long-term outcomes. This retrospective study was focused on explorative search of genetic polymorphisms in the Absorption, Distribution, Metabolism, Excretion (ADME) genes for the identification of biomarkers prognostic/predictive of platinum-response in OC patients. Ninety-two advanced OC patients treated with carboplatin-based therapy were enrolled at our institution. Of these, we showed that 72% of patients were platinum-sensitive, with a significant benefit in terms of OS (p = 0.001). We identified an inflammatory-score with a longer OS in patients with lower scores as compared to patients with the maximum score (p = 0.001). Thirty-two patients were genotyped for 1931 single nucleotide polymorphisms (SNPs) and five copy number variations (CNVs) by the DMET Plus array platform. Among prognostic polymorphisms, we found a potential role of UGT2A1 both as a predictor of platinum-response (p = 0.01) and as prognostic of survival (p = 0.05). Finally, we identified 24 SNPs related to OS. UGT2A1 correlates to an “inflammatory-score” and retains a potential prognostic role in advanced OC. These data provide a proof of concept that warrants further validation in follow-up studies for the definition of novel biomarkers in this aggressive disease

Proton Radiation Therapy for Nasopharyngeal Cancer Patients: Dosimetric and NTCP Evaluation Supporting Clinical Decision

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (−12.5%), brain necrosis (−2.3%), mucositis (−3.2%), tinnitus (−8.6%), hypothyroidism (−9.3%), and trismus (−5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3–T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain

Modelling Radiation-Induced Salivary Dysfunction during IMRT and Chemotherapy for Nasopharyngeal Cancer Patients

Background: Radiation-induced xerostomia is one of the most prevalent adverse effects of head and neck cancer treatment, and it could seriously affect patients’ qualities of life. It results primarily from damage to the salivary glands, but its onset and severity may also be influenced by other patient-, tumour-, and treatment-related factors. We aimed to build and validate a predictive model for acute salivary dysfunction (aSD) for locally advanced nasopharyngeal carcinoma (NPC) patients by combining clinical and dosimetric factors. Methods: A cohort of consecutive NPC patients treated curatively with IMRT and chemotherapy at 70 Gy (2–2.12 Gy/fraction) were utilised. Parotid glands (cPG, considered as a single organ) and the oral cavity (OC) were selected as organs-at-risk. The aSD was assessed at baseline and weekly during RT, grade ≥ 2 aSD chosen as the endpoint. Dose-volume histograms were reduced to the Equivalent Uniform Dose (EUD). Dosimetric and clinical/treatment features selected via LASSO were inserted into a multivariable logistic model. Model validation was performed on two cohorts of patients with prospective aSD, and scored using the same schedule/scale: a cohort (NPC_V) of NPC patients (as in model training), and a cohort of mixed non-NPC head and neck cancer patients (HNC_V). Results: The model training cohort included 132 patients. Grade ≥ 2 aSD was reported in 90 patients (68.2%). Analyses resulted in a 4-variables model, including doses of up to 98% of cPG (cPG_D98%, OR = 1.04), EUD to OC with n = 0.05 (OR = 1.11), age (OR = 1.08, 5-year interval) and smoking history (OR = 1.37, yes vs. no). Calibration was good. The NPC_V cohort included 38 patients, with aSD scored in 34 patients (89.5%); the HNC_V cohort included 93 patients, 77 with aSD (92.8%). As a general observation, the incidence of aSD was significantly different in the training and validation populations (p = 0.01), thus impairing calibration-in-the-large. At the same time, the effect size for the two dosimetric factors was confirmed. Discrimination was also satisfactory in both cohorts: AUC was 0.73, and 0.68 in NPC_V and HNC_V cohorts, respectively. Conclusion: cPG D98% and the high doses received by small OC volumes were found to have the most impact on grade ≥ 2 acute xerostomia, with age and smoking history acting as a dose-modifying factor. Findings on the development population were confirmed in two prospectively collected validation populations