BACKGROUND AND PURPOSE:The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS:Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS:For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION:The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.

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.

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.

Italy experienced one of the world’s severest COVID-19 outbreak, with Lombardy being the most afflicted region. However, the imposed safety measures allowed to flatten the epidemic curve and hence to ease the restrictions and inaugurate, on the 4th of May 2020, the Italian phase (P) 2 of the pandemic. The present survey study, endorsed by CODRAL and AIRO-L, aimed to assess how radiotherapy (RT) departments in Lombardy have dealt with the recovery. A questionnaire dealing with the management of pandemic was developed online and sent to all CODRAL Directors on the 10th of June 2020. Answers were collected in full anonymity one week after. All the 33 contacted RT facilities (100%) responded to the survey. Despite the scale of the pandemic, during P1 14 (42.4%) centres managed to safely continue the activity (≤ 10% reduction). During P2, 10 (30.3%) centres fully recovered and 14 (42.4%) reported an increase. Nonetheless, 6 (18.2%) declared no changes and, interestingly, 3 (9.1%) reduced activities. Overall, 21 centres (63.6%) reported suspected or positive cases within healthcare workforce since the beginning of the pandemic. Staff units were quarantined in 19 (57.6%) and 6 (18.2%) centres throughout P1 and P2, respectively. In the two phases, about two thirds centres registered positive or suspected cases amongst patients. The study revealed a particular attention to anti-contagion measures and a return to normal or even higher clinical workload in most RT centres in Lombardy, necessary to carry out current and previously deferred treatments.

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.

Objective: This study aimed to look into the relationship between intensity-modulated-radiotherapy (IMRT)- or volumetric-modulated-arc-therapy (VMAT)-based dose-volume parameters and 5-year outcome for a consecutive series of non-metastatic nasopharyngeal cancer (NPC) patients (pts) treated in a single institution in a non-endemic area in order to identify potential prognostic factors. Materials and methods: A retrospective analysis of consecutive non-metastatic NPC pts treated curatively with IMRT or VMAT and chemotherapy (CHT) between 2004 and 2014 was conducted. One patient was in stage I (0.7%), and 24 pts (17.5%) were in stage II, 38 pts (27.7%) in stage III, 29 pts (21.2%) in stage IVA, and 45 pts (32.8%) in stage IVB. Five pts (3.6%) received radiotherapy (RT) alone. Of the remaining 132 pts (96.4%), 30 pts (21.9%) received CHT concomitant to RT, and 102 pts (74.4%) were treated with induction CHT followed by RT-CHT. IMRT was given with standard fractionation at a total dose of 70 Gy. Clinical outcomes investigated in the study were local control (LC), disease-free survival (DFS), and overall survival (OS). Kaplan-Meier (KM) analysis was performed for the outcomes considering dose and coverage parameters, staging, and RT technique. Results: Overall, 137 pts were eligible for this retrospective analysis. With a median follow-up of 70 months (range 12-143), actuarial rates at 5 years were LC 90.4, DFS 77.2, and OS 82.8%. For this preliminary study, T stage was dichotomized as T1, T2, T3 vs. T4. At 5 years, the group T1-T2-T3 reported an LC of 93%, a DFS of 79%, and an OS of 88%, whereas T4 pts reported LC, DFS, and OS, respectively, of 56, 50, and 78%. Pts with V95% > 95.5% had better LC (p = 0.006). Pts with D99% > 63.8 Gy had better LC (p = 0.034) and OS (p = 0.005). The threshold value of 43.2 cm3 of GTVT was prognostic for LC (p = 0.016). To predict the risk of local recurrence at 5 years, we constructed a nomogram which combined GTVT with D99% relative to HRPTV. Conclusions: We demonstrated the prognostic value of some dose-volume parameters, although in a retrospective series, this is potentially useful to improve planning procedure. In addition, for the first time in a non-endemic area, a threshold value of GTVT, prognostic for LC, has been confirmed.

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.

Madam — Italy has been experiencing one of the world's deadliest COVID-19 outbreaks, and all healthcare facilities, including radiotherapy departments, have faced the unprecedented emergency. In order to investigate how radiotherapy directors in Lombardy (northern Italy) have managed the crisis, an online questionnaire (27 questions) via Google Forms, based on the first published COVID-19 reports, was sent to 34 CODRAL (Board of Directors of Radiation Oncology Departments in Lombardy) directors. Thirty-one (91%) specialists anonymously completed the survey. Within a few days of the outbreak, more than 75% of hospitals became COVID-19 centres. Following institutional indications, more than 80% of directors decided to interrupt or modify radiotherapy for some pathologies, preferring short treatments and home assistance where possible. About a half of centres reduced their clinical activity by 10–50%. Most hospitals (84%) cancelled out-patient follow-up visits and some (68%) activated telematic consultations. Triage procedures were adopted in virtually all centres. Almost a half of centres registered COVID-19-positive or suspected patients, and for some of them treatment was suspended. Nearly all radiotherapy centres declared that they would provide healthcare staff with surgical masks and gloves, while only a few of them also made other personal protective equipment available, including class II and III filtering facepieces (FFP2 and FFP3). Working from home solutions were adopted in about 30% of facilities. More than a half of centres had personnel in quarantine (between one and 12 persons off service). A considerable proportion of hospitals activated psychological support for patients and/or personnel. Our report shows how Lombardy radiotherapy departments have rapidly coped with the COVID-19 disruption. Significant reorganisation has been carried out in a short time with conversion to COVID-19 activities (wards, physicians transfer) and changes in radiotherapy practice. The priority was a balance between cancer patient care and safety, while protecting the healthcare professionals and providing any possible support in COVID-19 activities. The authors declare no conflict of interest.

Purpose Due to the rarity of vaginal intraepithelial neoplasia (VAIN), it is impossible to define the best treatment approach or to assess vaginal morbidity. However, brachytherapy (BT) could be a valuable choice for VAIN grade 3 (VAIN3). The aim of this paper was to report a single-institution study of the application of high-dose-rate BT and to evaluate clinical outcomes as well as to investigate the dose-effect relationship for vaginal stenosis. Material and methods We retrospectively collected hospital records and treatment plans of 14 consecutive women treated in our department from August 2010 to August 2016, with HDR-BT delivered using iridium-192 by a remote after-loading system. Doses in 3D-planned treatment based on computed tomography (CT) were prescribed in high-risk clinical target volume (HR-CTV) at the vaginal wall. Vaginal stenosis was defined as vaginal shortening/narrowing according to CTCAE4.1. The International Commission on Radiation Units & Measurements (ICRU) bladder and rectal points were used for dose report analysis. The posterior-inferior border of the symphysis points was used to derive reference points. The median age of the enrolled women was 60 years, and the median total radiation dose delivered was 35 Gy. Results During a median period of 15 days, the treatment was well tolerated, and no interruption was necessary. Acute toxicity was minimal, whereas late toxicity appeared in 4 patients as G2 and in 3 patients as G3 vaginal stenosis. Patients with stenosis G ≥ 2 received a higher median dose to the rectal point and were mainly over 60 years old. Conclusions Patients with VAIN3 seemed to benefit from BT. It is generally assumed that the vagina is radio-resistant, and no constraints have yet been set, but sexual dysfunction after BT is an important cause of long-term distress. Finding applicable dose limits to the vagina could improve patients’ quality of life.

Salivary gland tumors (SGTs) are rare diseases, and their treatment depends on histology, stage, primary site, and location within the gland.

•No high-quality data clearly guide the indications for PORT in early stage OSCC•Patients with multiple mAPFs tend to have poorer outcomes and to benefit from PORT•A proper PNI classification may help in identifying high-risk patients needing PORT•In patients with pN1 and ENE, the recommended treatment is PORT plus Chemotherapy

A mono-institutional trial was set up to investigate the role of saliva/gut microbiota (MB) in toxicity (tox) after RT for head & neck (HNC) and prostate cancers. We here focus on introduction of information on saliva MB into a normal tissue complication probability model (NTCP) for acute oral mucositis (OM) in HNC. One hundred thirty consecutive HNC patients (pts) receiving either postoperative (60-66 Gy @2Gy/fr) or radical IMRT (70 Gy @2-2.12Gy/fr) with/without chemotherapy were enrolled. A detailed evaluation was done pre+during RT and at RT end, including saliva MB measurement. Saliva samples were collected using oral devices. DNA extraction was carried out using a stool mini kit. The bacterial 16S ribosomal-RNA reads were analyzed with the QIIME software and pooled in Operational Taxonomic Units (OTUs) with Uclust software. Grade≥3 CTCAE acute OM (OM3) was the primary endpoint. For this preliminary analysis 24 pts were selected: 11 with G0–G1 OM and 13 with OM3. Unsupervised clustering (fuzzy c-means) was used to separate the pts into 2 MB clusters, based on relative abundance of OTUs at bacterial class level before RT start. Information on MB clustering was introduced as a dose-modifying factor into a logistic NTCP model. Dosimetric variables were derived from a previous model for OM3, including dose to oral cavity (Equivalent Uniform Dose, EUD_OC, with n=0.05) and mean dose to parotid glands (PGmeanD). Unsupervised clustering identified 12 pts included in a first MB cluster (A) and 12 in a second cluster (B). 4/12 (33.3%) and 9/12 (75%) pts with OM3 were found in clusters A and B, respectively (p=0.05). MB clustering resulted in AUC=0.71 (95%CI=0.50-0.87) for OM3 discrimination. The following bacterial classes presented with significantly different abundances (p<0.01) in MB clusters A and B: Proteobacteria_Gammaproteobacteria and Acidobacteria-6 were more abundant in cluster A, while Bacteroidetes_Bacteroidia, Firmicutes_Clostridia and Actinobacteria_Coriobacteriia were more abundant in cluster B. NTCP model including only dosimetry had OR=1.19 (for 1 Gy increase) for PGmeanD and 1.03 for EUD_OC (AUC=0.80, 95%CI=0.59-0.94). When MB clustering was introduced resulted in OR=4.1 and AUC=0.85 (95%CI=0.64-0.96), with 10% decrease of both high and low residual patients. This preliminary study demonstrates the possibility of introducing patient-specific MB data into NTCP model, through use of unsupervised clustering to exploit the whole MB information (292 classes) without dramatically increasing the number of features to be included in the model. Results in a small sample of HNC pts seem promising, indicating that pts with/without acute OM3 have different constitutional saliva MB profiles. If confirmed in the whole population, this could represent an important finding for prediction of tox and for design of possible interventional trials to reduce tox by modification of saliva MB before RT start.

Background To report the long-term outcome of patients undergoing re-irradiation (re-RT) for a recurrent or second primary head and neck cancer (RSPHNCs) in seven Italian tertiary centers, while testing the Multi-Institution Reirradation (MIRI) recursive partitioning analysis (RPA) recently published. Methods We retrospectively analyzed 159 patients. Prognostic factors for overall survival (OS) selected by a random forest model were included in a multivariable Cox analysis. To externally validate MIRI RPA, we estimated the Kaplan-Meier group-stratified OS curves for the whole population. Results Five-year OS was 43.5% (median follow-up: 49.9 months). Nasopharyngeal site, no organ dysfunction, and re-RT volume <36 cm(3) were independent factors for better OS. By applying the MIRI RPA to our cohort, a Harrell C-Index of 0.526 was found indicating poor discriminative ability. Conclusion Our data reinforce the survival benefit of Re-RT for selected patients with RSPHNC. MIRI RPA was not validated in our population.

Background: Up to 40% of patients with metastatic melanoma (MM) develop brain metastases. Radiotherapy (RT) may potentiate the effects of immunotherapy (IO), even on distant sites (abscopal effect). Material and Methods: We retrospectively analyzed all our MM patients treated with IO within 6 months before/after brain RT between 2012 and 2016. Progression-free (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with those of controls treated with IO during the same period. Results: Thirty-six cases and 25 controls were identified. Among cases, 23 patients received an anti-CTLA4 agent and 13 an anti-PD1 agent. Eighteen cases were treated with stereotactic RT and 18 with whole-brain RT. Median PFS from the beginning of RT was 4 months in first-line and 2 months in second-line treatment. A third of the cases progressed at first evaluation after RT. Median OS from the beginning of RT was 7 months in first-line and 4 months in second-line treatment. Median PFS and OS of each treatment line showed a trend towards inferiority compared with those of controls. Conclusion: Synergism between RT and IO was not observed in our case series. No cases of abscopal effect were seen, and most patients underwent early systemic progression after RT.

High Dose Rate vaginal brachytherapy for endometrial cancer has evolved from simple single-channel (i.e. cylindrical applicator) deliveries to treatments involving several channels (i.e. multichannel applicator) for the radiotherapy source to dwell, increasing the complexity of the dose distribution, and allowing more space for potential errors. For this reason real-time treatment verification has gained a greater importance than ever before, and more methods need to be developed in order to provide assurance that the dose delivery has been carried out as intended by the hospital staff. P-type silicon epi diodes have been designed at the Centre for Medical Radiation Physics (CMRP) in Australia to suit the specific needs of HDR BT, and characterized in the clinical BT facility of the Fondazione IRCCS (INT) in Italy. They have shown great potential for BT treatment verification in real time due to their radiation hardness, dose rate independence, flexibility in physical design, and ability to monitor the treatment at a 1-kHz readout frequency. Their dynamic range has been determined as ±17 to ±20 mm and dwell time calculation accuracy of > 0.1 s has been shown. If placed on the same longitudinal plane of a treatment accessory, these detectors would enable coverage of about 40 mm for source position and dwell time tracking. Respective detector positioning at (0, +3, −3 mm) would extend this range to 45-50 mm, depending on the catheter location, proving to be sufficient for the majority of treatment cases. Further studies are encouraged to develop diodes with a wider dynamic range.