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Use of salvage radiotherapy (SRT) after cancer surgery has a low disease control rate. Low prostate-specific antigen (PSA) levels in the blood pre-SRT seem to be the best predictor of success. Our study used PSA monitoring during and after treatment to investigate if PSA levels during SRT can give further information about its chances of success. In a retrospective cohort of 78 patients submitted to salvage radiotherapy (SRT) for biochemical relapse after cancer surgery, we assess PSA values at start of the treatment, 1 week before the end of treatment, and every 3 months for at least 2 years. Post-treatment PSA in our series and the systematic review of the literature aimed to investigate the prognostic value of PSA variation for biochemical disease-free survival. The results suggest that a decline in PSA levels after at least 45 Gy of radiation therapy dosage or a decrease of at least 0.2 ng/mL compared with the start value may be a favorable prognostic factors for biochemical disease-free survival. These results need confirmation using prospective data before being applied to clinical practice and could help physician to choose the correct therapeutic strategy.

Introduction The COVID-19 pandemic has challenged healthcare systems worldwide over the last few months, and it continues to do so. Although some restrictions are being removed, it is not certain when the pandemic is going to be definitively over. Pandemics can be seen as a highly complex logistic scenario. From this perspective, some of the indications provided for palliative radiotherapy (PRT) during the COVID-19 pandemic could be maintained in the future in settings that limit the possibility of patients achieving symptom relief by radiotherapy. This paper has two aims: (1) to provide a summary of the indications for PRT during the COVID-19 pandemic; since some indications can differ slightly, and to avoid any possible contradictions, an expert panel composed of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) and the Palliative Care and Supportive Therapies Working Group (AIRO-palliative) voted by consensus on the summary; (2) to introduce a clinical care model for PRT [endorsed by AIRO and by a spontaneous Italian collaborative network for PRT named “La Rete del Sollievo” (“The Net of Relief”)]. The proposed model, denoted “No cOmpRoMise on quality of life by pALliative radiotherapy” (NORMALITY), is based on an AIRO-palliative consensus-based list of clinical indications for PRT and on practical suggestions regarding the management of patients potentially suitable for PRT but dealing with highly complex logistics scenarios (similar to the ongoing logistics limits due to COVID-19). Material and Methods First, a summary of the available literature guidelines for PRT published during the COVID-19 pandemic was prepared. A systematic literature search based on the PRISMA approach was performed to retrieve the available literature reporting guideline indications fully or partially focused on PRT. Tables reporting each addressed clinical presentation and respective literature indications were prepared and distributed into two main groups: palliative emergencies and palliative non-emergencies. These summaries were voted in by consensus by selected members of the AIRO and AIRO-palliative panels. Second, based on the summary for palliative indications during the COVID-19 pandemic, a clinical care model to facilitate recruitment and delivery of PRT to patients in complex logistic scenarios was proposed. The summary tables were critically integrated and shuffled according to clinical presentations and then voted on in a second consensus round. Along with the adapted guideline indications, some methods of performing the first triage of patients and facilitating a teleconsultation preliminary to the first in-person visit were developed. Results After the revision of 161 documents, 13 papers were selected for analysis. From the papers, 19 clinical presentation items were collected; in total, 61 question items were extracted and voted on (i.e., for each presentation, more than one indication was provided from the literature). Two tables summarizing the PRT indications during the COVID-19 pandemic available from the literature (PRT COVID-19 summary tables) were developed: palliative emergencies and palliative non-emergencies. The consensus of the vote by the AIRO panel for the PRT COVID-19 summary was reached. The PRT COVID-19 summary tables for palliative emergencies and palliative non-emergencies were adapted for clinical presentations possibly associated with patients in complex clinical scenarios other than the COVID-19 pandemic. The two new indication tables (i.e., “Normality model of PRT indications”) for both palliative emergencies and palliative non-emergencies were voted on in a second consensus round. The consensus rate was reached and strong. Written forms facilitating two levels of teleconsultation (triage and remote visits) were also developed, both in English and in Italian, to evaluate the patients for possible indications for PRT before scheduling clinical visits. Conclusion We provide a comprehensive summary of the literature guideline indications for PRT during COVID-19 pandemic. We also propose a clinical care model including clinical indications and written forms facilitating two levels of teleconsultation (triage and remote visits) to evaluate the patients for indications of PRT before scheduling clinical visits. The normality model could facilitate the provision of PRT to patients in future complex logistic scenarios.

Clinicopathologic risk factors previously were a guide to the indication for adjuvant treatment in early-stage endometrial cancer until the European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology (ESGO/ESTRO/ESP) guidelines introduced

BACKGROUND This study analyzes patient health-related quality of life (QoL) 24-month after prostate cancer (PCa) diagnosis within the PROState cancer monitoring in ITaly from the National Research Council (Pros-IT CNR) study. METHODS Pros-IT CNR is an ongoing, longitudinal and observational study, considering a convenience sample of patients enrolled at PCa diagnosis and followed at 6, 12, 24, 36, 48 and 60 months from the diagnosis. Patients were grouped according to the treatment received: nerve sparing radical prostatectomy (NSRP), non-nerve sparing radical prostatectomy (NNSRP), radiotherapy (RT), radiotherapy plus androgen deprivation (RT plus ADT) and active surveillance (AS). QoL was measured through the Italian versions of SF-12 and UCLA-PCI questionnaires at diagnosis and at 6-12 and 24-month. The minimal clinically important difference (MCID) was defined as half a standard deviation of the baseline domain. RESULTS Overall, 1 537 patients were included in the study. The decline in urinary function exceeded the MCID at each timepoint only in the NSRP and NNSRP groups (at 24 months -14.7, p

Background About a third of patients who underwent radical prostatectomy for prostate cancer (Pca) develop a biochemical failure (BF) within 10 years from surgery, and about a half of them receive salvage radiation therapy (SRT). Factors to predict risk to relapse after SRT are still lacking. Dynamic models, based on the assessment of changes in Prostate Specific Antigen (PSA) postsurgery seem to show good reliability. Aims The goal of the study was to identify a simple analytical method for the postsalvage radiation therapy biochemical failure (post-SRTBF) prediction before the end of the SRT, regardless of the PSA value at the beginning of the treatment (PSA start), measuring the PSA values at the start and 1 week before the end of SRT. Methods In a series of 83 patients treated with SRT for BF of Pca we measured PSA values at the first day and 1 week before the end of SRT. These values were used to define an analytical method for the post-SRTBF prediction. Results PSA value in patients without post-SRTBF show a significant difference in term of difference during the SRT with respect to patients with post-SRTBF. Starting from this difference, we identified a simple and practical analytical method for the post-SRTBF prediction before the end of the SRT. The data corresponds with the model and the analytical method is highly predictive (Sensitivity = 81%, Specificity = 85%, Accuracy = 83%). Conclusion This study offers a new tool to early predict Pca relapse overtime and to select patients who can benefit from an early additional systemic treatment.

Over the past century, technologic advances have promoted the evolution of radiation therapy into a precise treatment modality allowing for the maximal administration of dose to tumors while sparing normal tissues. In parallel with this technological maturation, the rapid expansion in understanding the basic biology and heterogeneity of cancer has led to the development of several compounds that target specific pathways. Many of them are in advanced steps of clinical development for combination treatments with radiotherapy, and can be incorporated into radiation oncology practice for a personalized approach to maximize the therapeutic gain. This review describes the rationale for combining novel agents with radiation, and provides an overview of the current landscape focused on treatment efficacy.

The big data approach offers a powerful alternative to Evidence-based medicine. This approach could guide cancer management thanks to machine learning application to large-scale data. Aim of the Thyroid CoBRA (Consortium for Brachytherapy Data Analysis) project is to develop a standardized web data collection system, focused on thyroid cancer. The Metabolic Radiotherapy Working Group of Italian Association of Radiation Oncology (AIRO) endorsed the implementation of a consortium directed to thyroid cancer management and data collection. The agreement conditions, the ontology of the collected data and the related software services were defined by a multicentre ad hoc working-group (WG). Six Italian cancer centres were firstly started the project, defined and signed the Thyroid COBRA consortium agreement. Three data set tiers were identified: Registry, Procedures and Research. The COBRA-Storage System (C-SS) appeared to be not time-consuming and to be privacy respecting, as data can be extracted directly from the single centre's storage platforms through a secured connection that ensures reliable encryption of sensible data. Automatic data archiving could be directly performed from Image Hospital Storage System or the Radiotherapy Treatment Planning Systems. The C-SS architecture will allow "Cloud storage way" or "distributed learning" approaches for predictive model definition and further clinical decision support tools development. The development of the Thyroid COBRA data Storage System C-SS through a multicentre consortium approach appeared to be a feasible tool in the setup of complex and privacy saving data sharing system oriented to the management of thyroid cancer and in the near future every cancer type.

The management of patients with a cardiac implanted electronic device (CIED) receiving radiotherapy (RT) is challenging and requires a structured multidisciplinary approach. A consensus document is presented as a result of a multidisciplinary working group involving cardiac electrophysiologists, radiation oncologists and physicists in order to stratify the risk of patients with CIED requiring RT and approaching RT sessions appropriately. When high radiation doses and beam energy higher than 6MV are used, CIED malfunctions can occur during treatment. In our document, we reviewed the different types of RT and CIED behavior in the presence of ionizing radiations and electromagnetic interferences, from the cardiologist's, radiation oncologist's and medical physicist's point of view. We also reviewed in vitro and in vivo literature data and other national published guidelines on this issue so far. On the basis of literature data and consensus of experts, a detailed approach based on risk stratification and appropriate management of RT patients with CIEDs is suggested, with important implications for clinical practice.

To enhance the positive predictive value (PPV) of chest digital tomosynthesis (DTS) in the lung cancer detection with the analysis of radiomics features. The investigation was carried out within the SOS clinical trial (NCT03645018) for lung cancer screening with DTS. Lung nodules were identified by visual analysis and then classified using the diameter and the radiological aspect of the nodule following lung-RADS. Haralick texture features were extracted from the segmented nodules. Both semantic variables and radiomics features were used to build a predictive model using logistic regression on a subset of variables selected with backward feature selection and using two machine learning: a Random Forest and a neural network with the whole subset of variables. The methods were applied to a train set and validated on a test set where diagnostic accuracy metrics were calculated. Binary visual analysis had a good sensitivity (0.95) but a low PPV (0.14). Lung-RADS classification increased the PPV (0.19) but with an unacceptable low sensitivity (0.65). Logistic regression showed a mildly increased PPV (0.29) but a lower sensitivity (0.20). Random Forest demonstrated a moderate PPV (0.40) but with a low sensitivity (0.30). Neural network demonstrated to be the best predictor with a high PPV (0.95) and a high sensitivity (0.90). The neural network demonstrated the best PPV. The use of visual analysis along with neural network could help radiologists to reduce the number of false positive in DTS. • We investigated several approaches to enhance the positive predictive value of chest digital tomosynthesis in the lung cancer detection. • Neural network demonstrated to be the best predictor with a nearly perfect PPV. • Neural network could help radiologists to reduce the number of false positive in DTS.

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. Electronic supplementary material The online version of this article (10.1007/s12032-020-01409-2) contains supplementary material, which is available to authorized users.

Purpose Response assessment to definitive non-surgical treatment for head and neck squamous cell carcinoma (HNSCC) is centered on the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET-CT) 12 weeks after treatment. The 5-point Hopkins score is the only qualitative system available for standardized reporting, albeit limited by suboptimal positive predictive value (PPV). The aim of our study was to explore the feasibility and assess the diagnostic accuracy of an experimental 6-point scale (“Cuneo score”). Methods We performed a retrospective, multicenter study on HNSCC patients who received a curatively-intended, radiation-based treatment. A centralized, independent qualitative evaluation of post-treatment FDG-PET/CT scans was undertaken by 3 experienced nuclear medicine physicians who were blinded to patients’ information, clinical data, and all other imaging examinations. Response to treatment was evaluated according to Hopkins, Cuneo, and Deauville criteria. The primary endpoint of the study was to evaluate the PPV of Cuneo score in assessing locoregional control (LRC). We also correlated semi-quantitative metabolic factors as included in PERCIST and EORTC criteria with disease outcome. Results Out of a total sample of 350 patients from 11 centers, 119 subjects (oropharynx, 57.1%; HPV negative, 73.1%) had baseline and post-treatment FDG-PET/CT scans fully compliant with EANM 1.0 guidelines and were therefore included in our analysis. At a median follow-up of 42 months (range 5-98), the median locoregional control was 35 months (95% CI, 32-43), with a 74.5% 3-year rate. Cuneo score had the highest diagnostic accuracy (76.5%), with a positive predictive value for primary tumor (Tref), nodal disease (Nref), and composite TNref of 42.9%, 100%, and 50%, respectively. A Cuneo score of 5-6 (indicative of residual disease) was associated with poor overall survival at multivariate analysis (HR 6.0; 95% CI, 1.88-19.18; p = 0.002). In addition, nodal progressive disease according to PERCIST criteria was associated with worse LRC (OR for LR failure, 5.65; 95% CI, 1.26-25.46; p = 0.024) and overall survival (OR for death, 4.81; 1.07-21.53; p = 0.04). Conclusions In the frame of a strictly blinded methodology for response assessment, the feasibility of Cuneo score was preliminarily validated. Prospective investigations are warranted to further evaluate its reproducibility and diagnostic accuracy.

The aim of this review is to present the available radiobiological, technical and clinical data about extreme hypofractionation in primary prostate cancer radiotherapy. The interest in this technique is based on the favourable radiobiological characteristics of prostate cancer and supported by advantageous logistic aspects deriving from short overall treatment time. The clinical validity of short-term treatment schedule is proven by a body of non-randomised studies, using both isocentric (LINAC-based) or non-isocentric (CyberKnife®-based) stereotactic body irradiation techniques. Twenty clinical studies, each enrolling more than 40 patients for a total of 1874 treated patients, were revised in terms of technological setting, toxicity, outcome and quality of life assessment. The implemented strategies for the tracking of the prostate and the sparing of the rectal wall have been investigated with particular attention. The urinary toxicity after prostate stereotactic body irradiation seems slightly more pronounced as compared to rectal adverse events, and this is more evident for late occurring events, but no worse as respect to conventional fractionation schemes. As far as the rate of severe acute toxicity is concerned, in all the available studies the treatment was globally well tolerated. While awaiting long-term data on efficacy and toxicity, the analysed studies suggest that the outcome profile of this approach, alongside the patient convenience and reduced costs, is promising. Forty-eight ongoing clinical trials are also presented as a preview of the expectation from the near future.

Hadrontherapy has been in constant progress in the past decades. Due to the increasing interest in this field and the spreading of the technique in Italy and worldwide, the Italian Society of Radiation Oncology surveyed (by an online survey) its members regarding their perception of hadrontherapy. The survey outline addressed different items all related to hadrontherapy, such as: demographics (3 items), personal knowledge (5 items), actual use in clinical practice (5 items), and future perspectives and development (5 items). The survey was filled in by 224 radiation oncologists (RO). Among them, 74.6 % were RO with more than 5 years of clinical practice, and only 10.4 % RO in training. Median age was 46 years (range 27-77). 32.24 % admitted average knowledge about heavy particles radiobiology rationale and 32.42 % about the ongoing particle therapy clinical trials. Radioresistant tumors are perceived as-principal indications for carbon ions in 39.3 % of responders, and pediatric malignancies for protons in 37 %. Re-irradiation is highly recommended for 52.2 %. Strikingly, 38.8 % of participating ROs reported that, in the daily clinical practice, approximately less than 1 out of 10 patients asks to be referred for hadrontherapy. On the other side, 35.7 % claimed need for at least 3 up to 5 particle therapy centers in Italy. Overall, the results of the present survey highlight the interest of the Italian RO community for particle therapy among the other radiotherapy technique. Analysis of our results might picture the clinical attitude of the RO community towards hadrontherapy in Italy, and help in promoting targeted initiatives to spread clinical results and knowledge about technical innovations in this field.

Objectives Cetuximab was shown in phase III clinical trials to improve chemotherapy efficacy in patients with advanced colorectal and head-neck cancer. Appropriate management of skin reactions associated with epidermal growth factor receptor inhibitor therapy is necessary to allow adequate drug compliance and to improve patient quality of life and outcomes. Methods The RAND/UCLA Appropriateness Method was used by a group of experts to produce new Italian recommendations on the management of skin reactions in this setting. Statements were generated on the basis of an updated systematic review of the literature and rated twice by a panel of 38 expert physicians. A meeting of the panel was held after the first rating session. Results Skin reactions included acneiformic rash, skin dryness (xerosis), pruritus, paronychia, hair abnormalities, mucositis, and increased growth of eyelashes or facial hair. Updates of the previous recommendations on the prevention and treatment of each type of reaction were proposed. Conclusions This updated Expert Opinion focuses on how to assess and correctly grade skin reactions according to the latest National Cancer Institute Common Terminology Criteria for Adverse Events and on how to manage these adverse events in clinical practice.

Purpose HPV-related locally advanced head and neck cancers (LA-HNCs) show a good prognosis. This study aimed to investigate the HPV prevalence in LA-HNCs and compare the prognostic value of E1, E6 and L1 genomic viral fragments and p16, individually and in combination, in order to find the best prognosticator in terms of overall survival (OS) and progression-free survival (PFS). Patients and Methods HPV16 was searched in 255 LA-HNC formalin-fixed paraffin-embedded tumor tissues, 89 oropharyngeal cancers (OPCs), and 166 non-OPCs by DNA-PCR with 3 primer pairs. p16 was analyzed by immunohistochemistry in 235 patients. Results The prevalence of positive samples decreased constantly from E6 to L1 and E1 in both OPCs and non-OPCs. Each LA-HNC patient highlighted variable positivity for each fragment. OPCs showed a higher prevalence of positive samples compared to non-OPCs. Positive coexistence of all the fragments was more common in OPCs (31.5%) than non-OPCs (4.2%), and E1 detection was always associated with E6 and L1. E1-positive OPCs showed improved OS (p = 0.012) and PFS (p = 0.036), while L1- or E6-positive ones did not. p16-positive patients were more prevalent in the OPC (29.8%) than the non-OPC group (7.3%) (pConclusions Though HPV16 positivity measured by DNA-PCR was higher for L1 and E6, they performed weakly as prognosticators; E1 might become a strong prognostic marker for OS and PFS in OPCs.

Purpose Adequate biomarkers are still required to optimize therapy in patients with locally advanced head and neck squamous carcinomas (HNSCC) treated with chemoradiotherapy (CRT). Methods We updated the follow-up of 66 HNSCC patients treated with CRT we described more than 10 years ago, focusing on SNP Arg/Pro (R/P) at codon 72 and somatic mutations in TP53 and on SNP309 in the MDM2 gene. Results In wild-type TP53 cases, overall survival (OS) was longer in 72RR and less favorable in 72PP (p = 0.005); when TP53 was mutated, OS was longest in 72PP and less favorable in 72RR and 72RP (p = 0.058). Median OS was significantly shorter in patients with MDM2 SNP309 GG or GT genotypes compared with the TT genotype (p = 0.002). Conclusions TP53 SNP72 may be useful in selecting patients for CRT, but has to be related to somatic TP53 mutations. The MDM2 SNP309, easily determined in peripheral blood, might be more convenient as a predictive biomarker.

Background: Oral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17-18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper. Material and methods: The Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise. Results: This paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus. Conclusions: OM represents a very stressful) situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold-standard protocol that is prominently better than others. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction:Stereotactic body radiation therapy is increasingly used in the treatment of early-stage lung cancers. Guidelines provide indications regarding the constraints to the organs at risk (OARs) and the minimum coverage of the planning target volume but do not suggest optimal dose distribution. Data on dose distribution from the different published series are not comparable due to different prescription modalities and reported dose parameters.Methods:We conducted a review of the published data on dose prescription, focusing on the role of homogeneity on local tumor control, and present suggestions on how to specify and report the prescriptions to permit comparisons between studies or between cases from different centers.Conclusions:To identify the dose-prescription modality that better correlates with oncologic outcomes, future studies should guarantee a close uniformity of dose distribution between cases and complete dose parameters reporting for treatment volumes and OARs.

Clinical development and use of novel systemic agents in combination with radiotherapy (RT) is at nowadays most advanced in the field of treatment of solid tumors. Although for many of these substances preclinical studies provide sufficient evidences on their principal capability to enhance radiation effects, the majority of them have not been investigated in even phase I clinical trials for safety in the context of RT. In clinical practice, unexpected acute and late side effects may emerge especially in combination with RT. As a matter of fact, despite combined modality treatment holds potential for enhancing the therapeutic ratio, some concerns are raised from the lack of high-quality clinical data to guide the care of patients who are treated with novel compounds in conjunction with RT. The aim of this review is to provide, from a radio-oncological point of view, an overview of the most advanced combined treatment concepts for solid tumors focusing on treatment toxicity.

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

The therapeutic approach to thyroid carcinoma usually involves surgery as initial treatment. The use of external beam radiotherapy (EBRT) is limited to high-risk patients and depends on clinical stage and histologic type. Different behavior patterns and degrees of aggressiveness of thyroid carcinomas require different management for differentiated, medullary, and anaplastic carcinoma. However, the role of EBRT is an issue of debate. Most clinical studies are retrospective and based on single-institution experiences. In this article, we review the main literature and give recommendations for the use of EBRT in thyroid carcinoma on behalf of the “Radioterapia Metabolica” Group of the Italian Radiation Oncology Association.

The TNM classification is a worldwide standard staging system used to define the extent of cancer and is a major prognostic factor in predicting the outcome of patients. The TNM Classification of Malignant Tumours, 8th edition, has been used since January 1, 2018. In the area of head and neck cancer major modifications were produced: important updated T and N modification for oral cavity and nasopharyngeal cancer, the introduction of clinical and pathological stages for neck disease, and a new HPV-16-positive HNSCC classification. While until a few years ago the TNM staging system classified prognostic risk groups based on tumour size, the 8th edition responds to the need to categorize the prognosis of patients with similarly sized tumours but with very different clinical and biological behaviour. This review details TNM changes and the clinical need for these modifications, valuating possible limits in daily applicability.

Highlights • Treatment of relapsed/metastatic head and neck cancer is unclear. • Cyclophosphamide, avelumab, and radiotherapy may be effective for R/M-HNC. • Combined treatment may improve avelumab activity without increasing its toxicity. • Ongoing trials will clarify the potential of immunotherapy in RM-HNC patients., Introduction and background Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited. This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors. Methods/design In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8. Discussion The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1–PD-L1 axis by avelumab. The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile. Finally, an ancillary translational study will be extended to all the patients’ population. Trial registration EudraCT n. 2017-000353-39.

PurposeDermatologic adverse events (dAEs) in cancer treatment are frequent with the use of targeted therapies. These dAEs have been shown to have significant impact on health-related quality of life (HRQoL). While standardized assessment tools have been developed for physicians to assess severity of dAEs, there is a discord between objective and subjective measures. The identification of patient-reported outcome (PRO) instruments useful in the context of targeted cancer therapies is therefore important in both the clinical and research settings for the overall evaluation of dAEs and their impact on HRQoL.MethodsA comprehensive, systematic literature search of published articles was conducted by two independent reviewers in order to identify PRO instruments previously utilized in patient populations with dAEs from targeted cancer therapies. The identified PRO instruments were studied to determine which HRQoL issues relevant to dAEs were addressed, as well as the process of development and validation of these instruments.ResultsThirteen articles identifying six PRO instruments met the inclusion criteria. Four instruments were general dermatology (Skindex-16©, Skindex-29©, Dermatology Life Quality Index (DLQI), and DIELH-24) and two were symptom-specific (functional assessment of cancer therapy-epidermal growth factor receptor inhibitor-18 (FACT-EGFRI-18) and hand-foot syndrome 14 (HFS-14)).ConclusionsWhile there are several PRO instruments that have been tested in the context of targeted cancer therapy, additional work is needed to develop new instruments and to further validate the instruments identified in this study in patients receiving targeted therapies.

When using an electronic portal imaging device (EPID) for dosimetric verifications, the calibration of the sensitive area is of paramount importance. Two calibration methods are generally adopted: one, empirical, based on an external reference dosimeter or on multiple narrow beam irradiations, and one based on the EPID response simulation. In this paper we present an alternative approach based on an intercalibration procedure, independent from external dosimeters and from simulations, and is quick and easy to perform. Each element of a detector matrix is characterized by a different gain; the aim of the calibration procedure is to relate the gain of each element to a reference one. The method that we used to compute the relative gains is based on recursive acquisitions with the EPID placed in different positions, assuming a constant fluence of the beam for subsequent deliveries. By applying an established procedure and analysis algorithm, the EPID calibration was repeated in several working conditions. Data show that both the photons energy and the presence of a medium between the source and the detector affect the calibration coefficients less than 1%. The calibration coefficients were then applied to the acquired images, comparing the EPID dose images with films. Measurements were performed with open field, placing the film at the level of the EPID. The standard deviation of the distribution of the point‐to‐point difference is 0.6%. An approach of this type for the EPID calibration has many advantages with respect to the standard methods — it does not need an external dosimeter, it is not related to the irradiation techniques, and it is easy to implement in the clinical practice. Moreover, it can be applied in case of transit or nontransit dosimetry, solving the problem of the EPID calibration independently from the dose reconstruction method. PACS number: 87.56.‐v

Introduction Uveal melanoma (UM) is a highly vascularised tumour generally treated with radiotherapy (RT). A recent preclinical study from our group [1] demonstrated that RT-associated anti-angiogenic therapy has more than additive effects on cell growth, by modulating vascular endothelial growth factor (VEGF) levels. The pro-angiogenic interleukin-8 (IL-8) is highly expressed in both tumour and endothelial cells and is associated with resistance to VEGF-targeted therapies in various tumour types. The aim of this study is to investigate IL-8 release in response to the anti-angiogenic drug bevacizumab (AV) and RT given alone and in combination. Material and methods The human ocular melanoma cells (OCM-1) and human umbilical vein endothelial cells (HUVEC) were grown in transwell plates. AV was administered at a 2,500 μg/ml dose and cells were irradiated with a 6 Gy dose. IL-8 concentrations were determined by ELISA assay. Protein expression was detected by western blot. Results AV alone or in combination with RT reduces VEGF levels in both cell lines when co-cultured; unexpectedly, RT alone did not increase VEGF levels. In transwell plate AV alone lowered IL-8 secretion in both cell lines. This inhibitory effect was reduced when co-cultured cells are treated with AV + RT, suggesting that RT-induced VEGF may reactivate IL-8 secretion, enhancing an alternative pathway to sustain tumour angiogenesis. Conclusions These data indicate that the UM microenvironment, beside VEGF, can activate IL-8 signalling as an alternative pro-angiogenic pathway.

Dysphagia is one of the most important treatment-related side effects in head and neck cancer (HNC), as it can lead to severe life-threating complications such as aspiration pneumonia and malnutrition. Intensity-modulated radiotherapy (IMRT) could reduce swallowing dysfunction by producing a concave dose distribution and reducing doses to the swallowing-related organs at risk (SWOARs). The aim of this study was to review the current literature in order to compare swallowing outcomes between IMRT and three-dimensional conformal radiotherapy (3DCRT). A search was conducted in the PubMed and Embase databases to identify studies on swallowing outcomes, both clinically and/or instrumentally assessed, after 3DCRT and IMRT. Dysphagia-specific quality of life and objective instrumental data are summarized and discussed. A total of 262 papers were retrieved from the searched databases. An additional 23 papers were retrieved by hand-searching the reference lists. Ultimately, 22 papers were identified which discussed swallowing outcomes after 3DCRT and IMRT for HNC. No outcomes from randomized trials were identified. Despite several methodological limitations, reports from the current literature seem to suggest better swallowing outcomes with IMRT compared to 3DCRT. Further improvements are likely to result from the increased use of IMRT plans optimized for SWOAR sparing.

Re-irradiation has been increasingly offered as a potential effective treatment for head and neck squamous cell carcinoma (HNSCC) loco-regional recurrence as well as second primary tumor in previously irradiated area. This review focused on the role of postoperative re-irradiation (POreRT) in terms of feasibility, toxicity and long-term outcomes in HNSCC patients. The key issue for the research was formulated in two questions according to the PICO (population, intervention, control, and outcomes) criteria. A total of 16 publications met the inclusion criteria for a total of 919 patients; in 522 patients POreRT was performed. POreRT in recurrent and second primary HNSCC seems to be feasible in highly selected patients with the intent to guarantee an acceptable LC compared to surgery alone. The optimal RT schedule remains unclear due to the heterogeneity of literature data.

Until a few decades ago neck dissection (ND) was the standard surgical approach for node-positive tumours. Nowadays patients with locally advanced head and neck cancer can be treated with definitive chemoradiation (CRT), which includes the treatment of the neck; however, results on residual viable tumour after conservative treatment are heterogeneous and depend on initial node stage and primary treatment. Many authors accept adjuvant surgery in patients with N2–3 disease. Regardless of the results of upfront CRT, even if there is no evidence of lymph node metastases, when the risk for persistent positive neck nodes exceeds 15–20%, elective ND might be indicated. However, despite the diffusion of innovative technologies and therapies, there are controversies about both response evaluation and surgical management of initially involved neck nodes after definitive CRT and organ preservation treatment. In this paper we will analyse state of art of neck evaluation after CRT and discuss the role of ND.

Chemoradiotherapy is the treatment mostly used as organ preservation (OP) strategy worldwide in advanced laryngo-hypopharyngeal cancer. Due to the not homogeneous results of the literature data regarding the pre-treatment assessment and treatment schedule in this setting of patients, the Italian societies of radiation oncology and medical oncology surveyed (by an online survey) their memberships regarding the Italian attitude on larynx preservation in clinical practice. The survey outline addressed different items such as: demographics (11 items), pre-treatment evaluation (12 items), treatment schedules (10 items) and outcomes (3 items). The survey was filled in by 116 clinical oncologists (64 % radiation and 36 % medical oncologists). Results highlighted that pretreatment evaluation was not homogeneous among the respondents. The treatment of choice for the OP program resulted the concurrent chemoradiotherapy (66 %). Induction chemotherapy was proposed mostly in case of aggressive tumors such as advanced stage (T4 or N3) and/or unfavorable primary sites (hypopharynx). Moreover, after induction chemotherapy, for responders patients most participants (46 %) proposed concurrent chemoradiotherapy, while 18 and 19 % proposed radiotherapy alone or radiotherapy and cetuximab, respectively. For patients with stable disease after induction chemotherapy, the respondents declared to suggest surgery, radiotherapy and cetuximab or radiotherapy alone in 38, 32 and 15 % of cases, respectively. Results of the present survey highlighted the variability of therapeutic approaches offered in clinical practice for patients candidate to a larynx OP program. Analysis of abovementioned results may give the chance to modify some clinical attitudes and create the background for future clinical investigation in this field.

Background Radiotherapy (RT) is the standard treatment for uveal melanoma. However it can cause damage to the retina and optic nerve. This study examined the in vitro and in vivo effects of the anti-VEGF monoclonal antibody bevacizumab associated with radiotherapy (RT) on tumor growth and tumor proliferation and vasculature on OCM-1 human uveal melanoma cell line. Methods The anti-proliferative effects of bevacizumab, RT and their combination were tested both in vitro (OCM-1 cells co-cultured with HUVEC cells in Transwell plates) and in vivo (OCM-1 tumor xenografts in nude mice). In addition, treatment effects in vitro on VEGF secretion, as well as treatment effects in vivo on tumor proliferation (Ki67 labelling), tumor vasculature (VEGFR2 labelling) and VEGF tumoral concentration were analyzed. Results Bevacizumab given alone had a significant impact on tumor growth in vivo (and moderate effects in vitro). The bevacizumab-RT combination had additive effects in vitro (tumor cell proliferation) and in vivo (tumor growth), which translated into a significant decrease in Ki67 expression, VEGFR2 labelling and VEGF tumoral content. Conclusions The bevacizumab-RT combination could be a promising clinical option to explore for the management of human uveal melanoma, since it may allow RT dose reduction without loss of antitumor efficacy.

Survival prediction is useful in selecting patients for palliative care or active anticancer therapy. The palliative and prognostic (PaP) score was shown to predict 1-month survival in terminally ill patients. Its application to patients with less advanced disease is a subject of debate. We assessed the value of the PaP score and of other clinical parameters in predicting survival in patients admitted in an oncological ward due to acute conditions. We also evaluated the frequency of active anticancer treatment in the last weeks of life. All the 208 patients, consecutively admitted in a department of medical oncology and radiotherapy in a 9-month period, were included. Patients and disease features together with the PaP score were assessed and included in a multivariable model for survival prediction. Overall, median survival was 19 weeks and 12-week survival was 59.6%. The PaP score accurately predicted 4-week survival. Among the 39 patients who died within 4 weeks, 36% were on active treatment. The reason of admission, disease control, treatment, and PaP score were independently related to 12-week survival in the multivariate analysis; however patients with a 12-week survival lower than 30% were a minority. Although the PaP score accurately predicts life expectancy, its use in the setting of acute conditions seems not straightforward, due to the overall good prognosis of these patients. Active treatment in the last period of life is common. The potential reversibility of acute conditions makes prognostic measures inadequate for the purpose of treatment choices.

Background. Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes. Methods. A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists. Results. Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. Conclusions. Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified.

Initial research showed that EGFR targeting through known single agents, both monoclonal antibodies and small-molecule tyrosine-kinase inhibitors, applied to patients with refractory head and neck cancer, resulted in low response rates and short median survival times. However, the combination of Cetuximab with radiotherapy in patients with locally advanced disease and with a combination of platinum and fluorouracil in the setting of relapsed and/or metastatic disease resulted in a sharp improvement compared to standard therapy. Cetuximab entered clinical practice in both indications. Other anti-EGFR drugs, although showing activity, have not demonstrated an improvement of the results of standard therapy. Unfortunately, no molecular parameter emerged as a useful tool in predicting activity, thus impairing clinical applications. Only skin rash was repeatedly shown to be related with drug activity. Although generally well tolerated, class and drug specific toxicities can be troublesome and require knowledge and expertise for an optimal management. Further research is needed in order to find the best ways of integrating the anti-EGFR strategy with current standards of care.

LDL-apheresis (LDLa) efficacy in the treatment of symptomatic HyperLp(a)lipoproteinemia -HyperLp(a)- has been studied in a multicentre trial. After 3.1+/-2.7 years of weekly and biweekly treatment, the data from 19 patients (males:12; females:7; aged 53.8+/-9.3 years; mean body mass index: 24.6+/-2.3 Kg/m²) were evaluated. Data were collected using the same questionnaire shared by 5 participating centres. A total of 2331 procedures were performed. A mean of 3593.7+/-800.3 ml of plasma or 8115.3+/-2150.1 ml of blood, depending upon the technique used (H.E.L.P., D.A.LI., Dextransulphate, Lipocollect 200), was regularly treated on average every 10.1+/-2.6 days. Baseline mean Lp(a) levels were 172.3+/-153.8 mg/dL. The mean pre-/post-apheresis Lp(a) levels decreased from 124.5+/-107.2 mg/dL (p0.001 vs baseline) to 34.2+/-40.6 mg/dL (p0.001 vs pre-). Baseline mean LDL-cholesterol (LDLC) levels were 152.3+/-74.6 mg/dL. The mean pre-/post-apheresis LDLC levels decreased from 130.4+/-61.1 mg/dL (p0.004 vs baseline) to 41.2+/-25.1 mg/dL (p0.001 vs pre-). The hypolipidemic drugs given to the patients during LDLa were: ezetimibe+simvastatin, atorvastatin, rosuvastatin, pravastatin, acipimox, and omega-3 fatty acids. 58% of the patients had arterial hypertension. Cigarette smokers were 5.3%. Alcohol intake was present in 21%. 52.6% were physically active. Patients with coronary artery disease (CAD) submitted to coronary catheterization before LDLa were 95%. In 5.5% (#1) CAD recurred despite treatment with LDLa. 79% were submitted to coronary revascularization before LDLa. CAD was: monovasal in 8 patients (42.1%), bivasal in 5 (26.4%), trivasal in 4 (21%), plurivasal in 2 (10.5%). In 94.5% of the sample the lesions were stable (0% deviation) over 3.1+/-2.7 years. 37% had both CAD and extra-coronary artery disease. This multicentre study confirmed that long-term treatment with LDLa was at least able to stabilize CAD in the majority of the individuals with symptomatic HyperLp(a).

Surveys carried out in Mediterranean countries demonstrated very low rates of awareness of both diagnosis and prognosis among cancer patients. In our institution, a long-term training program aimed at improving communication skills among all physicians interacting with cancer patients was conducted. We report here the results of an extensive assessment of patients' awareness conducted after the first training period.In a 2-year period, after every first visit of patients with a histological diagnosis of cancer, oncologists elicited perception of the patients and completed a structured questionnaire focusing on the understanding of the diagnosis and prognosis. Our data are thus a photograph of the results of the informative process conducted during the diagnostic phase.Among the enrolled 649 patients, 79.3% were aware of their diagnosis; factors significantly associated with higher levels of awareness were age younger than 70 and referral from surgery (versus internal medicine). Knowledge about the palliative or curative aims of future treatments (a surrogate sign of prognostic consciousness) was evident in 55.2%.Compared with historical data, our results show a high level of comprehension of the diagnosis of malignancy, probably due to the extensive training effort together with the method chosen for assessment.

Radiotherapy alone or in combination with chemotherapy and/or surgery is a well-known radical treatment for head and neck cancer patients. Nevertheless acute side effects (such as moist desquamation, skin erythema, loss of taste, mucositis etc.) and in particular late toxicities (osteoradionecrosis, xerostomia, trismus, radiation caries etc.) are often debilitating and underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met in Milan with the aim of reaching a consensus on a clinical definition and management of these toxicities. The Delphi Appropriateness method was used for this consensus and external experts evaluated the conclusions. The paper contains 20 clusters of statements about the clinical definition and management of stomatological issues that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecrosis (10 clusters of statements), whereas this second part deals with trismus and xerostomia (10 clusters of statements).

Pain in head and neck cancer represents a major issue, before, during and after the oncological treatments. The most frequent cause of pain is chemo/radiation related oral mucositis, which involves 80% of the patients and worsens their quality of life inhibiting speaking, eating, drinking or swallowing and sometimes reducing the treatment compliance, the maximum dose intensity and thus the potential efficacy of treatment. Nevertheless pain is still often under estimated and undertreated. An Italian multidisciplinary group of head and neck cancer specialists met with the aim of reaching a consensus on pain management in this setting. The Delphi Appropriateness method was used for the consensus. External expert reviewers evaluated the final statements. The paper contains 30 consensus-reached statements about pain management in HNC patients and offers a review of recent literature in these topics.