The SINTART 1 study. A phase II non-randomised controlled trial of induction chemotherapy, surgery, photon-, proton- and carbon ion-based radiotherapy integration in patients with locally advanced resectable sinonasal tumours.

PURPOSE: Sinonasal tumours are rare diseases with poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. METHODS: Patients with untreated, operable sinonasal tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enrolled in a single-arm, phase II, multicenter clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype, followed either by curative chemo-RT for pts with ≥80% reduction of initial tumour diameter or surgery and adjuvant (chemo)RT. Photon and/or proton/carbon ion-based RT was employed according to the disease site and stage. Primary end-point was 5-year progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate (ORR) per RECIST 1.1 and safety. RESULTS: Thirty-five patients were evaluable for primary end-point. Fourteen patients (40%) were treated with definitive (CT)RT and 20 (57%) underwent surgery. Five-year PFS was 38% (95% confidence interval [CI], 21-69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28-75), with a median OS of 36 months. Three-year PFS-OS for pts achieving PR/CR versus stable disease (SD)/PD to ICT were 49.8-57% versus 43.2-53%, respectively. Three-year PFS for patients achieving major volumetric partial response (≥80% reduction of initial tumour volume, major partial volumetric response [mPRv]) versus non-mPRv were 82% versus 28% and 3-year OS were 92% versus 36% (p value 0.010 and 0.029, respectively). The ORR to ICT was 54% and 60% across all histotypes and in the sinonasal undifferentiated carcinoma (SNUC) subpopulation, respectively, with 6/15 SNUCs (40%) achieving mPRv. CONCLUSION: Treatment of advanced sinonasal cancer with histology-driven ICT followed by (CT)RT in responsive patients was feasible. Overall, these findings suggest a possible role of ICT as the primary approach in newly diagnosed, resectable sinonasal tumours-especially SNUC-to select patients with favourable prognosis. Histology heterogeneity limits generalisation of trial results.

The SINTART 2 Study. A phase II non-randomised controlled trial of induction chemotherapy, photon-, proton- and carbon-ion-based radiotherapy integration in patients with locally advanced unresectable sinonasal tumours.

PURPOSE: Unresectable, locally advanced sinonasal epithelial tumours are rare diseases with poor prognosis. Multimodal approach is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. METHODS: Patients with untreated, unresectable sinonasal epithelial tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enroled in a single-arm, open-label, phase II, multicentre clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon-ion-based RT was employed according to disease site, stage and ICT response. Primary end-point was 5-years progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate per RECIST 1.1 and safety. RESULTS: Twenty-five patients were evaluable for primary end-point. Five-year PFS was 26.8% (95% confidence interval [CI]: 12.6-57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI: 9.5-59.3), with a median OS of 27 months. The overall response rate to ICT was 40%. Three-year PFS for patients achieving major volumetric partial response (mPRv) versus non-mPRv was 40% (95% CI: 13.7-100%) versus 23.1% (95% CI: 8.3-64.7%) (P = 0.318) and 3-year OS was 53.3% (95% CI: 21.4-100%) versus 37.7% (95% CI: 20.0-71.0%) (P = 0.114). CONCLUSION: Multimodal combination of ICT and innovative RT did not provide a significant improvement in survival rates with respect to previous experiences. This finding underscores the need for future research in this rare disease, still characterised by a heavy burden and poor prognosis. We observed longer survival in subjects achieving response to ICT. The overall treatment safety is acceptable.

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.

Exploring the role of neutrophil-to-lymphocyte ratio and blood chemistry in head and neck adenoid cystic carcinomas treated with carbon ion radiotherapy.

BACKGROUND AND PURPOSE: In recent years, there is an emerging interest in the prognostic role of chemistry blood biomarkers in oncological patients but their role in adenoid cystic carcinomas (ACCs) is still unknown. This study aims to assess the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) and blood chemistry in a series of head and neck ACC patients treated with carbon ion radiotherapy (CIRT). MATERIAL AND METHODS: We retrospectively retrieved the data of 49 consecutive head and neck ACC patients treated with CIRT. Univariable and multivariable Cox proportional hazard regression (Cox-ph) analyses were performed to look for a potential association of NLR, and other blood biomarker values, with disease-free survival (DFS), Local Control (LC), Metastasis Free Survival (MFS) and overall survival (OS). RESULTS: No significant association between NLR > 2,5 and DFS, LC, MFS and OS was found with univariable analysis although a trend was reported for DFS (Hazard ratio [HR]: 2,10, 95 % CI: 0,85 - 5,08, p-value = 0,11). Patients with hemoglobin (hb) ≤ 14 g/dL showed significantly better DFS, MFS and OS. Multivariable regression Cox-ph analysis for DFS, adjusted for margin status, clinical target volume and Absolute Number of Monocytes, reported the following statistically significant HRs, for both NLR > 2,5 and hb > 14 g/dL respectively: 4,850 (95 % CI = 1,408 - 16,701, p = 0,012) and 3,032 (95 % CI = 1,095 - 8,393, p = 0,033). Moreover, hb > 14 with HR = 3,69 (95 % CI: 1,23 - 11,07, p-value = 0,02), was a negative independent prognostic predictor for MFS. CONCLUSIONS: Pre-treatment NLR and hb values seem to be independent prognostic predictor for clinical outcomes in head and neck ACC patients. If their role will be validated in a larger prospective cohort, they might be worthwhile for a pre-treatment risk stratification in patients treated with CIRT.

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.

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.

M. D. Anderson symptom inventory head neck (MDASI-HN) questionnaire: Italian language psychometric validation in head and neck cancer patients treated with radiotherapy ± systemic therapy - A study of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

PURPOSE: Head and neck cancer (HNC) patients are likely to develop severe side effects, which may persist long after the end of treatment and may be responsible for decrease patient's quality of life. The M.D. Anderson Symptom Inventory- Head and Neck Module (MDASI-HN) is a questionnaire developed to detect patient's symptom burden. To conduct an Italian language psychometric validation of MDASI-HN among Italian HNC patients on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Head and Neck Working Group. METHOD AND MATERIALS: To assess construct validity, it was performed a confirmatory factor analysis (CFA) with both a five-factor solution and three-factor solution, which were compared by a chi-square difference test. The concurrent validity was evaluated by the correlation with EORTC QLQ-C30 and HN35, and it was also assessed known-group validity. The internal consistency was tested using Cronbach's alpha coefficient. RESULTS: In total 166 patients (71.7% male) were included in the study, most of patients (56.2%) had an oropharynx cancer and received definitive chemoradiotherapy (51.2%). The chi-square difference test was significant and indicated that the five-factor solution fits the data better than the other one. Regarding CFA, all items had a significant saturation with their respective factors; besides, significant and strong correlations were found among factors. Most of the correlations between MDASI-HN factors and EORTC QLQ-C30 and HN35 were significant. It was found a good internal consistency. CONCLUSION: The MDASI-HN is a valid, short, and easy patient-reported outcome questionnaire which would be useful and efficient in clinical setting.

Baseline MRI-Radiomics Can Predict Overall Survival in Non-Endemic EBV-Related Nasopharyngeal Carcinoma Patients.

Advanced stage nasopharyngeal cancer (NPC) shows highly variable treatment outcomes, suggesting the need for independent prognostic factors. This study aims at developing a magnetic resonance imaging (MRI)-based radiomic signature as a prognostic marker for different clinical endpoints in NPC patients from non-endemic areas. A total 136 patients with advanced NPC and available MRI imaging (T1-weighted and T2-weighted) were selected. For each patient, 2144 radiomic features were extracted from the main tumor and largest lymph node. A multivariate Cox regression model was trained on a subset of features to obtain a radiomic signature for overall survival (OS), which was also applied for the prognosis of other clinical endpoints. Validation was performed using 10-fold cross-validation. The added prognostic value of the radiomic features to clinical features and volume was also evaluated. The radiomics-based signature had good prognostic power for OS and loco-regional recurrence-free survival (LRFS), with C-index of 0.68 and 0.72, respectively. In all the cases, the addition of radiomics to clinical features improved the prognostic performance. Radiomic features can provide independent prognostic information in NPC patients from non-endemic areas.

Methodology and technology for the development of a prognostic MRI-based radiomic model for the outcome of head and neck cancer patients.

The purpose of this study was to establish a methodology and technology for the development of an MRI-based radiomic signature for prognosis of overall survival (OS) in nasopharyngeal cancer from non-endemic areas. The signature was trained using 1072 features extracted from the main tumor in T1-weighted and T2-weighted images of 142 patients. A model with 2 radiomic features was obtained (RAD model). Tumor volume and a signature obtained by training the model on permuted survival data (RADperm model) were used as a reference. A 10-fold cross-validation was used to validate the signature. Harrel's C-index was used as performance metric. A statistical comparison of the RAD, RADperm and volume was performed using Wilcoxon signed rank tests. The C-index for the RAD model was higher compared to the one of the RADperm model (0.69±0.08 vs 0.47±0.05), which ensures absence of overfitting. Also, the signature obtained with the RAD model had an improved C-index compared to tumor volume alone (0.69±0.08 vs 0.65±0.06), suggesting that the radiomic signature provides additional prognostic information.

A monocentric, open-label randomized standard-of-care controlled study of XONRID®, a medical device for the prevention and treatment of radiation-induced dermatitis in breast and head and neck cancer patients.

BACKGROUND: This study was an open-label, 2-arms, monocentric, randomized clinical trial comparing Xonrid®, a topical medical device, versus standard of care (SOC) in preventing and treating acute radiation dermatitis (ARD) in Head and Neck Cancer (HNC) and Breast Cancer (BC) patients undergoing radiotherapy (RT). METHODS: Eligible HNC and BC patients were randomized 1:1 to receive Xonrid® + SOC or SOC during RT. Patients were instructed to apply Xonrid® on the irradiated area three times daily, starting on the first day of RT and until 2 weeks after RT completion or until the development of grade ≥ 3 skin toxicity. The primary endpoint was to evaluate the proportion of patients who developed an ARD grade < 2 at the 5th week in both groups. Secondary endpoints were median time to grade 2 (G2) skin toxicity onset; changes in skin erythema and pigmentation and trans-epidermal water loss (TEWL); patient-reported skin symptoms. All patients were evaluated at baseline, weekly during RT and 2 weeks after treatment completion. The evaluation included: clinical toxicity assessment; reflectance spectrometry (RS) and TEWL examination; measurement of patients' quality of life (QoL) through Skindex-16 questionnaire. RESULTS: Eighty patients (40 for each cancer site) were enrolled between June 2017 and July 2018. Groups were well balanced for population characteristics. All BC patients underwent 3-Dimensional Conformal RT (3D-CRT) whereas HNC patients underwent Volumetric-Modulated Arc Therapy (VMAT). At week 5 the proportion of BC patients who did not exhibit G2 ARD was higher in Xonrid® + SOC group (p = 0.091). In the same group the onset time of G2 ARD was significantly longer than in SOC-alone group (p < 0.0491). For HNC groups there was a similar trend, but it did not reach statistical significance. For both cancer sites, patients' QoL, measured by the Skindex-16 score, was always lower in the Xonrid® + SOC group. CONCLUSION: Despite the failure to achieve the primary endpoint, this study suggests that Xonrid® may represent a valid medical device in the prevention and treatment of ARD at least in BC patients, delaying time to develop skin toxicity and reducing the proportion of patients who experienced G2 ARD during RT treatment and 2 weeks later. TRIAL REGISTRATION: The study was approved by the Ethical Committee of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT 52/14 - NCT02261181 ). Registered on ClinicalTrial.gov on 21st August 2017.

Prevention and treatment of radiation-induced acute dermatitis in head and neck cancer patients: a systematic review.

Acute dermatitis is the most common radio-induced side effect during treatment for head and neck cancer. The use of a wide variety of agents is reported to handle skin toxicity. Our aim was to review the literature and synthesize current available evidence. A comprehensive search was performed on multiple electronic databases until February 2017 and a systematic approach was carried out according to PRISMA guidelines. A total of 17 papers (950 patients on the whole) met the inclusion/exclusion criteria, with 12 randomized controlled trials and five nonrandomized observational and prospective studies. Generally speaking, there was no strong evidence to support the superiority of any specific intervention neither in prevention nor in therapeutic settings. Well-designed randomized studies including quality of life measurements are needed.

Non-intestinal type sinonasal cancers and exposure to occupational carcinogens: a case-control study. / Tumori nasosinusali diversi da adenocarcinoma di tipo intestinale ed esposizione a cancerogeni professionali: uno studio caso-controllo.

BACKGROUND: Sinonasal cancers are rare, often fatal, tumors with a very high proportion of cases attributable to occupational exposures. The relevance of different carcinogens deeply varies among histological subtypes, with intestinal type adenocarcinomas (ITAC) characterized by a very large proportion of workers exposed to wood dust. The role of occupation in the etiology of other histotypes is less clear and more disputed, with authors questioning the possible occupational origin of non-ITAC cancers. METHODS: We conducted a hospital-based case-control study on 50 consecutives non-ITAC cancers and 50 controls, in Varese, Italy. Relative risks for previous exposure to carcinogens (any or single agent, i.e. wood/leather dust, solvents, metals) were calculated by multivariate logistic regression models adjusted for age, gender, smoking habits and residence (within or outside the Lombardy region). RESULTS: Having been exposed to any occupational carcinogen carried an OR of 3.04 (95%CI: 0.91-10.21). Considering single carcinogens, we observed no increased risk for wood dust exposure (OR=1.02, 95%CI: 0.21-4.94), while a large effect associated with previous exposure to other recognized carcinogens (leather dust, solvents or metals) appeared: OR=7.01 (95%CI: 1.51-32.8). DISCUSSION: Our results highlighted the importance of properly considering sinonasal cancers histological subtypes when investigating the role of occupational carcinogens. Grouping together all sinonasal cancers may end up in underestimating the role of wood in ITAC etiology as well as the relevance of other occupational exposures for non-ITAC tumors. All sinonasal cancers deserve a thorough investigation of the occupational history.

[Looking for "lost occupational cancers": a systematic evaluation of occupational exposure in a case series of cutaneous squamous cell carcinomas in Italy]. / Alla ricerca dei "tumori professionali perduti": valutazione sistematica dell'esposizione professionale in una serie consecutiva di carcinomi cutanei spinocellulari.

BACKGROUND: Cutaneous carcinomas are tumors with a potential occupational etiology due to exposure to established carcinogens such as polycyclic aromatic hydrocarbons (PAH), ionizing radiation, ultraviolet (UV) radiation and arsenic. The occupational origin of such neoplasms is hugely underestimated in Italy. OBJECTIVES: To asses the proportion of Squamous Cell Carcinomas (SCC) cases with a previous occupational exposure to carcinogens. METHODS: We systematically evaluated occupational exposure in a series of consecutive cases, discharged in the period 2010-11 from the Dermatology Unit of Varese Hospital, Italy, with a histological diagnosis of SCC. Through a structured telephone interview we identified patients with a potential exposure to skin carcinogens. As a second-level step, an extensive evaluation by an occupational physician was performed to assess the occupational etiology in those selected cases. RESULTS: 105 patients were identified (65 men). 15 male cases out of a total of 85 patients who did the telephone interview, revealed a potential occupational exposure; 7 cases were confirmed as occupational cancers after second-level evaluation (proportion of male occupational cases = 13.2%). UV radiation and PAH were recognized as major causal agents. Applying those results to the national incidence data, we estimated a number of 700 annual occupational cases, 100-fold more than the cases currently evaluated by the Italian National Workers Compensation Authority. CONCLUSIONS: Our results revealed that occupational SCC is still at present a substantially "lost disease" in Italy. Greater attention and enhanced collaboration between specialists is thus needed to overcome this tendency.