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Background: Radiotherapy has both immunostimulant and immunosuppressive effects, particularly in radiation-induced lymphopenia. Proton therapy has demonstrated potential in mitigating this lymphopenia, yet the mechanisms by which different types of radiation affect the immune system function are not fully characterized. The Circulating Immunes Cells, Cytokines and Brain Radiotherapy (CYRAD) trial aims to compare the effects of postoperative X-ray and proton radiotherapy on circulating leukocyte subpopulations and cytokine levels in patients with head and neck (CNS and ear nose throat) cancer., Methods: CYRAD is a prospective, non-randomized, single-center non interventional study assessing changes in the circulating leukocyte subpopulations and cytokine levels in head and neck cancer patients receiving X-ray or proton radiotherapy following tumor resection. Dosimetry parameters, including dose deposited to organs-at-risk such as the blood and cervical lymph nodes, are computed. Participants undergo 29 to 35 radiotherapy sessions over 40 to 50 days, followed by a 3-month follow-up. Blood samples are collected before starting radiotherapy (baseline), before the 11th (D15) and 30th sessions (D40), and three months after completing radiotherapy. The study will be conducted with 40 patients, in 2 groups of 20 patients per modality of radiotherapy (proton therapy and photon therapy). Statistical analyses will assess the absolute and relative relationship between variations (depletion, recovery) in immune cells, biomarkers, dosimetry parameters and early outcomes., Discussion: Previous research has primarily focused on radiation-induced lymphopenia, paying less attention to the specific impacts of radiation on different lymphoid and myeloid cell types. Early studies indicate that X-ray and proton irradiation may lead to divergent outcomes in leukocyte subpopulations within the bloodstream. Based on these preliminary findings, this study aims to refine our understanding of how proton therapy can better preserve immune function in postoperative (macroscopic tumor-free) head and neck cancer patients, potentially improving treatment outcomes., Protocol Version: Version 2.1 dated from January 18, 2023., Trial Registration: The CYRAD trial is registered from October 19, 2021, at the US National Library of Medicine, ClinicalTrials.gov ID NCT05082961., (© 2024. The Author(s).)

Purpose: Social eating (SE) is a corner stone of daily living activities, quality of life (QoL), and aging well. In addition to feeding functional disorders, patients with head and neck cancer (HNC) face individual and social psychological distress. In this aging population, we intended to better assess the influence of age on these challenges, and the role of self-stigmatization limiting SE in patients with and beyond HNC., Methods: This was an exploratory multicenter cross-sectional mixed method study. Eligibility criteria were adults diagnosed with various non-metastatic HNC, before, during, or until 5 years after treatment. SE disorders were explored with the Performance Status Scale Public Eating rate (PSS-HN PE). In the quantitative part of the study, SE habits, Functional Assessment of Cancer Therapy Body Image Scale (FACT-MBIS) and specific to HNC (FACT-HN35) were also filled in by the patients. In the qualitative study, the semi-structured interview guide was drawn out to explore stigma, especially different dimensions of self-stigmatization., Results: A total of 112 patients were included, mean age 64.7 years, 23.2% of female. One-third (n = 35) of patients had an abnormal PSS-HN PE rate < 100. Younger patients had more often an impaired Normalcy of Diet mean (70.4 vs 82.7, p = .0498) and PE rates (76 vs 86.9, p = .0622), but there was no difference between age subgroups in MBIS nor FACT-HN scores. Seventy patients (72.2%) found SE and drinking « important» to « extremely important» in their daily life. The qualitative study reported self-stigmatization in two older patients and strategies they have developed to cope with in their behaviors of SE., Conclusion: This study confirms that SE remains of high concern in patients with and beyond HNC. Even in older patients experiencing less often functional feeding disorders, body image changes and SE issues are as impaired as in younger patients and need to be addressed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details., Competing Interests: Declaration of interests AML reports uncompensated consultancy for Eisai; support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship, and institutional research funding support from Sanofi/Regeneron Pharmaceuticals. LM has participated in an advisory board for Merck Sharp & Dohme (MSD). CLT has participated in advisory boards for MSD, Roche, Merck Serono, ALX Oncology, Excientia, Seagen, Kumar Therapeutics, MaxiVax, BMS, PCI Biotech, Nanobiotix, Onxeo, MVX-ONCO, Seattle Genetics, Rakuten, GSK, Celgene, and AstraZeneca. AH has received grants and personal fees from ONO, Taiho, KYORIN, Eisai, and Mitsubishi Tanabe Pharma; grants from Otsuka Pharmaceutical Factory, Iwasakidenshi, and Torii; and personal fees from Bristol Myers Squibb, Bayer Yakuhin, Merck Biopharma, Eli Lilly, Sanofi, Rakuten Medical, Meiji Pharma, Demant, and MSD, outside the submitted work. DJT reports consulting fees from MSD; advisory board participation for Merck Serono; and research grants from Cancer Research UK. AM-P has participated in advisory boards for MSD and Norgine; and has received clinical trial research grants from MSD and Intuitive Surgical, outside the submitted work. CHu has participated in advisory boards for EMD Serono. PS has advisory relationships with Merck Serono, Servier, and MSD. ATD reports grants from the National Health Institute and the Cancer Prevention Institute of Texas. JEB has participated in advisory boards for Galera Therapeutics and Castle Biosciences. AP has participated in advisory boards for MSD, Roche, Merck Serono, BMS, Nanobiotics, GSK, and Seagen; reports honoraria for editorial work from Elsevier; research grants from KURA, BMS, and Ipsen; and received travel grants from Ipsen. HM reports grants from UK National Institute of Health research, Cancer Research UK, the UK Medical Research Council, and AstraZeneca; advisory board fees from AstraZeneca, MSD, Merck, Nanobiotix, and Seagen; and is Director of Warwickshire head and neck clinic and Docspert Health. SSY reports clinical trial research grants from Bristol Myers Squibb, EMD Serono, and Nanobiotix; honoraria for editorial work from Elsevier and ASTRO; and publishing royalties from Springer and Up To Date. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The management of head and neck cancers is multidisciplinary, often relying on the use of combined treatments to maximize the chances of cure. Combined treatments are however also responsible for cumulative side effects. The aim of reconstructive surgery with a flap is to restore a function lost with the loss of substance from the tumor resection. However, changes in reconstructive surgery have impact of postoperative radiotherapy planning. The optimization of imaging protocols for radiotherapy planning should make it possible to identify postoperative changes and to distinguish flaps from surrounding native tissues to delineate the flaps and document the spontaneous evolution of these flaps or dose-effect relationships in case of radiotherapy. Such changes include atrophy, fibrosis of soft tissue flaps and osteoradionecrosis of bone flaps. Radiotherapy optimization also involves standardization of the definition of target volumes in situations where a flap is present, a situation that is increasingly common in routine care. This evolution of practice, beyond the essential multidisciplinary consultation meetings defining treatment indications, requires a close radio surgical collaboration with respect to technical aspects of the two disciplines. Doing so, anticipation of relapse and toxicity profiles could possibly lead to propose strategies for personalized de-escalation of multimodal treatments through interdisciplinary trials., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HM is the director and a shareholder of Warwickshire Head and Neck Clinic; chair of the Head and Neck Cancer International Group (HNCIG); and past president of the British Association of Head and Neck Oncologists. HM also reports receiving honoraria from AstraZeneca; Speakers Bureau on MSD, Sanofi Pasteur, Merck; research Funding from GSK Biologicals, MSD, Sanofi Pasteur, GSK Plc, AstraZeneca; travel Accommodation Expenses from Sanofi, Pasteur, MSD, Merck. AP has the following disclosures: Advisory board member with honoraria: Merck Serono, Roche, MSD, Astrazeneca, BMS, Bayer, Pfizer& Medical Education with honoraria: Medscape, Prime Oncology, Funding for research support: KURA, BMS, Merck Serono, Roche, BI, Genesis. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: We performed a cost-effectiveness analysis (CEA) comparing an adaptive radiotherapy (ART) strategy, based on weekly replanning, aiming to correct the parotid gland overdose during treatment and expecting therefore to decrease xerostomia, when compared to a standard IMRT., Materials and Methods: We conducted the ARTIX trial, a randomized, parallel-group, multicentric study comparing a systematic weekly replanning ART to a standard IMRT. The primary endpoint was the frequency of xerostomia at 12 months, measured by stimulating salivary flow with paraffin. The CEA was designed alongside the ARTIX trial which was linked to the French national health data system (SNDS). For each patient, healthcare consumptions and costs were provided by the SNDS. The reference case analysis was based on the primary endpoint of the trial. Sensitivity and scenario analyses were performed., Results: Of the 129 patients randomly assigned between 2013 and 2018, only 2 records were not linked to the SNDS, which provides a linkage proportion of 98.4%. All of the other 127 records were linked with good to very good robustness. On the intent-to-treat population at 12 months, mean total costs per patient were €41,564 (SD 23,624) and €33,063 (SD 16,886) for ART and standard IMRT arms, respectively (p = 0.033). Incremental cost effectiveness ratio (ICER) was €162,444 per xerostomia avoided. At 24 months, ICER was €194,521 per xerostomia avoided. For both progression-free and overall survival, ART was dominated by standard IMRT., Conclusion: The ART strategy was deemed to be not cost-effective compared with standard IMRT for patients with locally advanced oropharyngeal cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Rare cancers constitute less than 10% of head and neck cancers and lack sufficient evidence for standardized care. The French Rare Head and Neck Cancer Expert Network (REFCOR) as established a national database to collect data on these rare cancers. This study aims to describe patient and tumour characteristics in this database., Methods: Prospective data collection was conducted across multiple centers. Survival analyses were performed using Kaplan Meier method and Log Rank test. Odds ratios were used for comparing proportions., Results: A total of 7208 patients were included over a period of 10 years. The most frequent histologies were: Not Otherwise Specified (NOS) adenocarcinoma 13 %, adenoid cystic carcinoma 12 %, squamous cell carcinoma of rare locations 10 %, mucoepidermoid carcinoma 9 %, intestinal-type adenocarcinoma (8 %). Tumours were located in sinonasal area (38 %); salivary glands (32 %); oral cavity / oropharynx / nasopharynx (16 %); larynx / hypopharynx (3 %); ears (1 %); others (3 %). Tumours were predominantly classified as T4 (23 %), N0 (54 %), and M0 (62 %). Primary treatment approach involved tumour resection (78 %) and / or radiotherapy (63 %). Patients with salivary gland cancers exhibited better 5-year overall survival (OS) rates (p < 0.05), and lower recurrence rates compared to patients with sinonasal, laryngeal/ hypopharyngeal cancers. No significant differences were observed in the other comparisons. Acinar cell carcinoma demonstrated the best OS while mucous melanoma had the poorest prognosis., Conclusion: Melanoma, carcinoma NOS, and sinonasal undifferenciated carcinoma still have poor prognoses. Efforts are being made, including training and guidelines, to expand network coverage (REFCOR, EURACAN), improve data collection and contribute to personalized therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21-28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy., (© 2023. The Author(s).)

Purpose: Sexual health (SH) is an emerging concern in the assessment of quality of life in patients surviving head and neck cancer (HNC). Using data from the French National Prospective VICAN Survey, this study aimed to assess SH deterioration five years after HNC diagnosis and related factors., Methods: Using univariate and multivariate analyses were performed in the 241 HNC survivors. We studied the factors associated between the sexuality and intimate life of these patients with demographic and medical data from the national epidemiological survey VICAN 5., Results: Sexuality and body image were altered in 78.8% for men and 79.2% for women. This alteration in sexual quality of life affects both men and women. Dissatisfaction with the frequency of sexual intercourse was associated with being treated with radiotherapy (p=0.024), as well as decrease of sexual desire in patients treated with chemotherapy (p=0.044). Fatigue (p=0.002), impaired physical health (p=0.049), and high disease stage (p=0.001) remained significantly associated, after multivariate analysis, with decreased sexual desire. Among these 3 factors negatively influencing sexual quality of life, two are treatable with appropriate management., Conclusion: Five years after the diagnosis of HNC, a decrease in sexuality and body image are frequent and significantly impact the quality of life of survivors. These observations imply an adaptation of the management of the professionals involved., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers., Objective: To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer., Design, Setting, and Participants: This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022., Interventions: The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning)., Main Outcomes and Measures: The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival., Results: A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms., Conclusions and Relevance: This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates., Trial Registration: ClinicalTrials.gov Identifier: NCT01874587.

Among the 16,000 new cases of malignant tumors of the head and neck diagnosed in France each year, 10% are not conventional squamous cell carcinomas. These so-called rare cancers are distinguished by their presentation and patterns of failure, which is important to recognize in order to offer specific adapted management and maximize the chances of tumor control. These cancers can be rare by their histology, which determines their local invasiveness, and their hematogenous/nodal spread. Their diagnosis can be difficult and often requires comprehensive immunohistochemistry and genomic techniques. Expert pathology review is recommended in the cases of undifferentiated tumors, sarcomas and at the slightest diagnostic doubt. These rare cancers can also be rare by their anatomical location when arising from the paranasal sinuses, salivary glands and ear. Their location requires knowledge of their specific extension routes, and may call for a specific surgical technique (skull base endoscopic sinus surgery, extended total parotidectomy, etc.) and adapted radiotherapy to spare healthy organs surrounding the tumor. This article (part 1) discusses the diagnostic and therapeutic specificities of these rare cancers, and develops the recommendations of the French ENT Cancer Expertise Network (REFCOR) concerning rare epithelial tumors, i.e., salivary tumors, sinonasal tumors, variants of conventional squamous cell carcinomas, neuroendocrine carcinomas, malignant odontogenic tumors, and ear tumors. A second article (part 2) is focused on non-epithelial tumors (sarcomas, mucosal melanomas, lymphomas, tumors of uncertain or undetermined malignancy) and describes the organization and missions of the REFCOR., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Among the 16,000 new cases of malignant tumors of the head and neck diagnosed in France each year, 10% are not conventional squamous cell carcinomas. These so-called rare cancers are distinguished by their presentation and patterns of failure, which is important to recognize in order to offer specific adapted management and maximize the chances of tumor control. These cancers can be rare by their histology as well as their anatomical location when arising from the paranasal sinuses, salivary glands and ear. The management of these heterogeneous rare diseases of complex treatment has considerably been structured over the last 15 years, in particular via the French ENT Cancer Expertise Network (REFCOR) and international networks and registries (EURACAN, etc.). Structuration also favors research with identification of new entities and setting up of specific therapeutic trials. A first article (part 1) discusses the diagnostic and therapeutic specificities of these rare cancers, and develops the recommendations of the REFCOR concerning rare epithelial tumors, i.e., salivary tumors, sinonasal tumors, variants of conventional squamous cell carcinomas, neuroendocrine carcinomas, malignant odontogenic tumors, and ear tumors. This second article (part 2) is focused on non-epithelial tumors (sarcomas, mucosal melanomas, lymphomas, tumors of uncertain or undetermined malignancy) and describes the organization and missions of the REFCOR., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Radiotherapy induces significant and prolonged lymphopenia in head and neck cancer patients with poorer outcomes and reduced survival. Irradiated volumes may be correlated with lymphopenia with a potential impact on immunotherapy efficacy. We assessed associations between volumes treated with radiotherapy and the nadir of the lymphocyte count in patients with head and neck cancer., Materials and Methods: We conducted a monocentric retrospective study in patients with head and neck cancer treated with radiation. Univariate analysis used regression analysis to model nadir lymphocyte count and radiotherapy volumes; multivariate analysis then modelled factors associated with nadir lymphocyte count., Results: Of the 77 included patients, 97% presented lymphopenia during radiotherapy with an average nadir of 431 cells/mm 3 at a median of 40 days after the beginning of treatment. The volume of high-risk radiotherapy and gross tumour volume were correlated with nadir lymphocyte count with a Spearman coefficient of -0.267 (P=0.019) and -0.387 (P=0.001), respectively. After multivariate linear regression, high-risk radiotherapy was significantly associated with nadir lymphocyte count with a regression coefficient of -0.32 (per cubic centimetre) [95% CI=-0.60; -0.03] (P=0.028)., Conclusion: High-risk radiotherapy was significantly associated with nadir lymphocyte count in patients with head and neck cancer treated with radiation. Sparing lymphoid volumes from irradiation by elective nodal irradiation or proton therapy may limit lymphopenia and needs to be investigated in combination with immunotherapy., (Copyright © 2023 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: OsteoRadioNecrosis (ORN) is a late complication of radiation for head and neck cancer. Predicting ORN is a major challenge. We developed DERO (Dosimetric Evaluation of Risk of ORN), a semi-automatic tool which reports doses delivered to tooth-bearing sectors, to guide post-therapeutic dental care. We present the method and the first results of a 125-patient prospective cohort., Material and Methods: Dosimetric data of patients treated with IMRT for head and neck cancer were prospectively segmented to the DERO algorithm. Four arches corresponding to 8-tooth sectors were semi-automatically generated. Thirty-two cylindrical Regions Of Interest (ROI) corresponding to each tooth and surrounding periodontium were created by linear interpolation. Mean doses (Dmean) of ROI were extracted and included in a database, along with data about primary tumor site, laterality and dose values from organs at risk. Dmean to tooth sectors were computed for molar sectors, (teeth X5 to X8) and anterior sectors (teeth X1 to X4). An individual dose map was generated and delivered to patients and dentists., Results: Dosimetric data from 125 patients treated with Tomotherapy® were prospectively collected and analyzed: 9 parotid tumors (PA), 41 Sub-Hyoid tumors (larynx, hypopharynx) (SH), 43 Oropharynx tumors (OR), 32 Oral Cavity tumors (OC). Irradiation was unilateral for 100% of PA tumors (9), 12% of OR tumors (5) and 47% of OC tumors (15). For unilateral cervical irradiation, Dmean in ipsilateral molar sectors was 54Gy for OC tumors, 45Gy for OR tumors, 20Gy for PA tumors. For Oral Cavity bilateral irradiation, Dmean was high in all tooth sectors, 49 to 55Gy. For SH tumors, Dmean in molar sectors was 27Gy. A dose gradient of 10 to 20Gy was observed between molar and anterior sectors whether radiation was uni or bilateral., Conclusion: Mandibular molar sectors of Oropharynx and Oral Cavity tumors were exposed to high Dmean of 40 to 50Gy. On the other hand, tooth sectors received lower doses for SH radiation. The DERO tool guide post-radiation dental care with a personalized dosimetric cartography to patient. With data update and patient follow-up, we will be able to determine ORN risk after head and neck radiation., (Copyright © 2023 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: The purpose of our study was to investigate the impact of HPV status in oncologic outcomes in patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, and to determine progression prognosis factors aiming to define the best therapeutic strategies for these patients., Methods: This multicenter retrospective study included patients with T1-2 oropharyngeal SCC with N3 nodes treated between 2010 and 2015 in 8 French comprehensive cancer centers. HPV status was determined with P16 hyperexpression in immunohistochemistry. HPV-positive patients were separated into 2 groups according to the associated smoking history (HPV + T +) or not (HPV + T-). We compared the oncological outcomes of patients according to HPV-status and smoking history., Results: Of 67 patients with T1-2 N3 oropharyngeal SCC, 36 patients (53.7%) were HPV negative and 31 patients (46.3%) HPV positive. 2-year PFS was significantly better in HPV + T- group (p = 0.036). The risk of death or progression was significantly reduced in HPV + T- comparatively to HPV- (HR 0.25 95%CI [0.07; 0.89]). 2-year OS was significantly better in HPV + T- group than in the other two groups (p = 0.017)., Conclusion: In patients with T1-2 oropharyngeal SCC associated with bulky N3 nodes, HPV positive patients without smoking history had better OS and PFS than HPV positive patients with smoking history and HPV negative patients. Thus, HPV status is a significant prognostic factor for survival but this benefit is altered when smoking history is associated. N3 HPV positive patients with smoking history have to be classified as high-risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT)., Methods: This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%)., Results: Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48-0.72) in the afatinib group and 64% (95% CI 0.51-0.74) in the placebo group (HR 1.12, 95% CI 0.70-1.80)., Conclusion: Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials., Clinicaltrials: gov identifier NCT01427478., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Evidence on the efficacy of postoperative radiotherapy (PORT) in low-intermediate risk squamous cell carcinoma of the oral cavity (OSCC) remains inconclusive. Members of a task force from two national radio-oncology Associations (AIRO and GORTEC) defined 14 clinically relevant questions to identify "gray areas" pertinent to the indication for PORT in this clinical setting. Consequently, a literature review was performed on the topic. The resulting statements were then rated by an Expert Panel (EP) using a modified Delphi method. Only radiation oncologists were part of the discussion and voting on the scenarios. There was agreement on the 14 statements at the first round of voting. The task force then decided to propose clinical cases for the two more controversial statements that had received a lower agreement to better capture the Experts' attitudes. The clinical cases highlighted a more significant decisional heterogeneity. However, the good level of consensus reached among the two Associations gives relevant support in informing clinical choices while acknowledging general indications cannot fit all clinical situations and do not replace multidisciplinary discussion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Despite reduction of xerostomia with intensity-modulated compared to conformal X-ray radiotherapy, radiation-induced dental complications continue to occur. Proton therapy is promising in head and neck cancers to further reduce radiation-induced side-effects, but the optimal dental management has not been defined., Material and Methods: Dental management before proton therapy was assessed compared to intensity-modulated radiotherapy based on a bicentric experience, a literature review and illustrative cases., Results: Preserved teeth frequently contain metallic dental restorations (amalgams, crowns, implants). Metals blur CT images, introducing errors in tumour and organ contour during radiotherapy planning. Due to their physical interactions with matter, protons are more sensitive than photons to tissue composition. The composition of restorative materials is rarely documented during radiotherapy planning, introducing dose errors. Manual artefact recontouring, metal artefact-reduction CT algorithms, dual or multi-energy CT and appropriate dose calculation algorithms insufficiently compensate for contour and dose errors during proton therapy. Physical uncertainties may be associated with lower tumour control probability and more side-effects after proton therapy. Metal-induced errors should be quantified and removal of metal restorations discussed on a case by case basis between dental care specialists, radiation oncologists and physicists. Metallic amalgams can be replaced with water-equivalent materials and crowns temporarily removed depending on rehabilitation potential, dental condition and cost. Implants might contraindicate proton therapy if they are in the proton beam path., Conclusion: Metallic restorations may more severely affect proton than photon radiotherapy quality. Personalized dental care prior to proton therapy requires multidisciplinary assessment of metal-induced errors before choice of conservation/removal of dental metals and optimal radiotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To assess the impact of a global pretherapeutic comprehensive supportive care assessment performed in an outpatient supportive care clinic (OSCC) and early supportive care interventions on oncological treatment choice in patients with chemoradiation (CRT) indication for head and neck cancer (HNC)., Methods: In this monocentric prospective observational study, we included all patients considered for CRT (exclusive or post-operative) for HNC from February 2019 to March 2020. The following frailty indicators were assessed: comorbidities (Charlson index), nutritional status, altered functional ability (ADL and IADL), social precarity (EPICES score), cognitive impairment (MoCA score), addictive habits and pain., Results: OSCC led to a change in treatment for 13.7% of patients, mainly de-escalations. Ninety-three percent of patients had at least one altered domain, including 50% with three or more altered domains. Cognitive function was the most frequently altered domain (66.7%). Altered functional ability was significantly associated with treatment de-escalation after OSCC. Treatment interruptions were significantly associated with treatment de-escalation and social precarity. De-escalation was also associated with a significantly poorer PFS (median of 23.2 mos. vs 8.8 mos., HR = 2.18 95%IC[1.02-4.63] p = 0.037)) and a non-significant trend towards worse OS (median 23.3mos. vs not reached (HR = 2.16 95%CI[0.88-5.31] p = 0.0836)., Conclusion: We strongly encourage the creation of OSCC for patients treated with chemoradiation for HNC. This practice, through an exhaustive assessment, favours therapeutic adaptation, personalized follow-up and optimization of supportive care., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Several reports have suggested that radiotherapy after reconstructive surgery for head and neck cancer (HNC), could have deleterious effects on the flaps with respect to functional outcomes. To predict and prevent toxicities, flap delineation should be accurate and reproducible. The objective of the present study was to evaluate the interobserver variability of frequent types of flaps used in HNC, based on the recent GORTEC atlas. Materials and methods: Each member of an international working group (WG) consisting of 14 experts delineated the flaps on a CT set from six patients. Each patient had one of the five most commonly used flaps in HNC: a regional pedicled pectoralis major myocutaneous flap, a local pedicled rotational soft tissue facial artery musculo-mucosal (FAMM) (2 patients), a fasciocutaneous radial forearm free flap, a soft tissue anterolateral thigh (ALT) free flap, or a fibular free flap. The WG's contours were compared to a reference contour, validated by a surgeon and a radiologist specializing in HNC. Contours were considered as reproducible if the median Dice Similarity Coefficient (DSC) was > 0.7. Results: The median volumes of the six flaps delineated by the WG were close to the reference contour value, with approximately 50 cc for the pectoral, fibula, and ALT flaps, 20 cc for the radial forearm, and up to 10 cc for the FAMM. The volumetric ratio was thus close to the optimal value of 100% for all flaps. The median DSC obtained by the WG compared to the reference for the pectoralis flap, the FAMM, the radial forearm flap, ALT flap, and the fibular flap were 0.82, 0.40, 0.76, 0.81, and 0.76, respectively. Conclusions: This study showed that the delineation of four main flaps used for HNC was reproducible. The delineation of the FAMM, however, requires close cooperation between radiologist, surgeon and radiation oncologist because of the poor visibility of this flap on CT and its small size.

Intensity-modulated radiotherapy has been widely used routinely in recent past years for post-operative radiotherapy of salivary gland cancers Because of the sharp dose fall off outside of target volumes with IMRT, each volume must be strictly and rigorously defined, as the areas not specifically included in the target volume will not be treated to a therapeutic dose. The selection and delineation of these volumes is complex and requires extensive knowledge of parotid and submandibular gland cancer radiographic-anatomy, natural history and extension pathways (including local tumor spread, PNI risks and regional spread), which are detailed in the present article., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Pain is an increasing concern in the growing number of head and neck cancer survivors. This study aimed to analyze the 5-year prevalence of pain in French survivors of head and neck cancer and to identify associated factors., Methods: Analyses were performed among 296 5-year cancer survivors diagnosed in 2010. Using multivariable logistic regressions, we studied the associations between pain and factors collected in the French representative national "vie après le cancer" (VICAN) survey. Eligible participants were aged from 18 to 82 years; patients' living conditions, socioeconomic characteristics, and medical data were collected., Results: Pain was reported by 72.6% of the participants. In the multivariable analyses, decreasing level of physical activity was the only determinant of increased overall pain (OR= 2.77, CI= 1.48-5.17). The chronic pain prevalence was 62.3%. The main risk factors found were tumor localization in the oropharynx (OR= 2.49, CI= 1.27-4.88), education (at least a high school's degree) (OR= 0.33, CI= 0.13-0.9), and decreased physical activity (OR= 2.20, CI= 1.24-3.9)., Conclusions: Five years after diagnosis, pain is a very frequent sequelae that has a significant impact on quality of life in head and neck cancer survivors. Reduced physical activity, a low level of education, and tumor localization in the oropharynx are factors associated with pain., Implications for Cancer Survivors: Pain frequency and its impact on patients' lives imply that an adaptation must be made in terms of both pain diagnosis and management and the training of healthcare professionals., Clinical Trial Registration: This is not a clinical trial. ISP number: INSERM C11-63., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Purpose: A Benchmark Case (BC) was performed as part of the quality assurance process of the randomized phase 2 GORTEC 2014-14 OMET study, testing the possibility of multisite stereotactic radiation therapy (SBRT) alone in oligometastatic head and neck squamous cell carcinoma (HNSCC) as an alternative to systemic treatment and SBRT., Material and Methods: Compliance of the investigating centers with the prescription, delineation, planning and evaluation recommendations available in the research protocol was assessed. In addition, classical dosimetric analysis was supplemented by quantitative geometric analysis using conformation indices., Results: Twenty centers participated in the BC analysis. Among them, four major deviations (MaD) were reported in two centers. Two (10%) centers in MaD had omitted the satellite tumor nodule and secondarily validated after revision. Their respective DICE indexes were 0.37 and 0 and use of extracranial SBRT devices suboptimal There were significant residual heterogeneities between participating centers, including those with a similar SBRT equipment, with impact of plan quality using standard indicators and geometric indices., Conclusion: A priori QA using a BC conditioning the participation of the clinical investigation centers showed deviations from good SBRT practice and led to the exclusion of one out of the twenty participating centers. The majority of centers have demonstrated rigorous compliance with the research protocol. The use of quality indexes adds a complementary approach to improve assessment of plan quality., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Following major advances of the best of photon-techniques such as intensity-modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT) and, to arrive soon, magnetic resonance (MR)-linac radiotherapy, there are still substantial opportunities in the treatment of head and neck cancers to further reduce the toxicity burden. Proton therapy represents another attractive option in this high-quality and highly competitive precision radiotherapy landscape. Proton therapy holds promises to reduce toxicities and to escalate the dose in radioresistant cases or cases where dose distribution is not satisfactory with photons. However, the selection of patients for proton therapy needs to be done using evidence-based medicine to build arguments in favor of personalized precision radiation therapy. Referral to proton therapy versus IMRT or SBRT should be registered (ProtonShare® platform) and envisioned in a formalized clinical research perspective through randomized trials. The use of an enrichment process using a model-based approach should be done to only randomize patients doomed to benefit from proton. To tackle such great opportunities, the French proton therapy challenge is to collaborate at the national and international levels, and to demonstrate that the extra-costs of treatment are worth clinically and economically in the short, mid, and long-term. In parallel to the clinical developments, there are still preclinical issues to be tackled (e.g., proton FLASH, mini-beams, combination with immunotherapy), for which the French Radiotransnet network offers a unique platform. The current article provides a personal view of the challenges and opportunities with a focus on clinical research and randomized trial requirements as well as the needs for strong collaborations at the national and international levels for PT in squamous cell carcinomas of the head and neck to date., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Head and neck reconstructive surgery using a flap is increasingly common. Best practices and outcomes for postoperative radiotherapy (poRT) with flaps have not been specified. We aimed to provide consensus recommendations to assist clinical decision-making highlighting areas of uncertainty in the presence of flaps., Material and Methods: Radiation, medical, and surgical oncologists were assembled from GORTEC and internationally with the Head and Neck Cancer International Group (HNCIG). The consensus-building approach covered 59 topics across four domains: (1) identification of postoperative tissue changes on imaging for flap delineation, (2) understanding of tumor relapse risks and target volume definitions, (3) functional radiation-induced deterioration, (4) feasibility of flap avoidance., Results: Across the 4 domains, international consensus (median score ≥ 7/9) was achieved only for functional deterioration (73.3%); other consensus rates were 55.6% for poRT avoidance of flap structures, 41.2% for flap definition and 11.1% for tumor spread patterns. Radiation-induced flap fibrosis or atrophy and their functional impact was well recognized while flap necrosis was not, suggesting dose-volume adaptation for the former. Flap avoidance was recommended to minimize bone flap osteoradionecrosis but not soft-tissue toxicity. The need for identification (CT planning, fiducials, accurate operative report) and targeting of the junction area at risk between native tissues and flap was well recognized. Experts variably considered flaps as prone to tumor dissemination or not. Discrepancies in rating of 11 items among international reviewing participants are shown., Conclusion: International GORTEC and HNCIG-endorsed recommendations were generated for the management of flaps in head and neck radiotherapy. Considerable knowledge gaps hinder further consensus, in particular with respect to tumor spread patterns., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Swallowing difficulties in patients with advanced head and neck cancer (HNC) represent an obstacle to adequate antiemetic prophylaxis before chemotherapy. We aim to assess chemotherapy-induced nausea and vomiting (CINV) risk in HNC patients in our center, with a specific focus among patients who could not receive appropriate NK1 receptor antagonist (NK1-RA) prophylaxis., Materials and Methods: Prospective observational monocentric study. CINV were evaluated with the MASCC Antiemesis Tool self-questionnaire (MAT) for all patients treated by platinum-based chemotherapy for advanced HNC (January-April 2019), thereafter, only for patients without NK1-RA prophylaxis due to swallowing difficulties were included (May-October 2019)., Results: Sixty-one patients were included (82% male, 49.2% reccurent/metastatic disease), 18 did not received NK1-RA prophylaxis due to swallowing difficulties. Among 52 patients included from January to April 2019, 17.3% reported swallowing difficulties. The chemotherapy regimen was highly and moderately emetic for 40 (65.6%) and 21 patients (34.4%), respectively. CINV was associated with both cisplatin-based chemotherapy (OR 10.66, 95% CI [2.17-52.08]) and exclusive chemotherapy (OR 7.76, 95% CI [1.79-33.78]). Patients who did not receive anti-NK1 prophylaxis had no more CINV than patients with adequate CINV prophylaxis., Discussion: CINV remains frequent in patients treated by platinum-based chemotherapy for HNC. Oral NK1-RA prophylaxis can be unavailable because of swallowing difficulties, without an increased risk of CINV., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To assess the feasibility in routine practice of postoperative chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC) at high risk of recurrence., Method: A single-center retrospective study recruited all patients receiving postoperative cisplatin chemoradiotherapy for HNSCC at high risk of recurrence. The main endpoints were the rate of complete postoperative chemoradiotherapy and the impact of various clinical factors. Secondary endpoints comprised the impact of completion of therapy on survival and on acute and late toxicity., Results: One hundred and six patients were included. 24.5% showed severe comorbidity. Chemoradiotherapy was complete in 61 patients (57.5%). Radiation therapy was interrupted for >3 days in 16 patients (15.1%). The 3 rd concomitant cisplatin course could not be implemented in 34 patients (32.1%). Low pre-treatment glomerular filtration rate was significantly associated (p=0.003) with treatment interruption; >5% weight-loss during treatment showed suggestive association (p=0.026). Completion of treatment was not associated with any significant difference in overall survival (p=0.441) or progression-free survival (p=0.81). 14.9% of patients showed post-treatment kidney failure; there were 10 cases of osteoradionecrosis (9.4%)., Conclusion: The rate of complete postoperative chemoradiotherapy was comparable to that reported in clinical trials, despite frequent comorbidity and poor nutritional status. Early nutritional support is a key factor for treatment under optimal conditions., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: Reconstructive surgery in head and neck cancers frequently involves the use of autologous flaps to improve functional outcomes. However, the literature suggests that postoperative radiotherapy deteriorates functional outcomes due to flap atrophy and fibrosis. Data on patterns of relapse after postoperative radiotherapy with a flap are lacking, resulting in heterogenous delineation of postoperative clinical target volumes (CTV). Flap delineation is unusual in routine practice and there are no guidelines on how to delineate flaps. Therefore, we aim to propose a guideline for flap delineation in head and neck cancers to assess dose-effects more accurately with respect to flaps., Material and Methods: Common flaps were selected. They were delineated by radiation oncologists and head and neck surgeons based on operative reports, on contrast-enhanced planning CTs and checked by a radiologist. Each flap was divided into its vascular pedicle and its soft tissue components (fat, fascia/ muscle, skin, bone)., Results: Delineation (body and pedicle) of Facial Artery Musculo-Mucosal, pectoralis, radial forearm, anterolateral thigh, fibula and scapula flaps was performed. Based on information provided in operative reports, i.e. tissue components, size and location, flaps can be identified. The various tissue components of each flap can be individualized to facilitate the delineation., Conclusion: This atlas could serve as a guide for the delineation of flaps and may serve to conduct studies evaluating dose-effects, geometric patterns of failure or functional outcomes after reconstructive surgery. Changes in postoperative CTV definitions might be needed to improve risk/benefit ratio in the future based on surgery-induced changes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Advances in the reconstructive surgery and minimally invasive endonasal endoscopic surgery of head and neck is poorly evaluated in terms of their impact on radiotherapy planning and outcomes. These surgical advances have resulted in reduced morbidity with equivalent or better tumor control. In the absence of a recommendation on how to delineate target volumes in patients with flaps or to consider margins after endoscopic endonasal surgery, radiotherapy practices are inevitably heterogeneous. Efforts are needed to increase the therapeutic index of postoperative radiotherapy in these situations. We analysed the rare existing literature and outlined a preliminary basis for a recommendation. Strengthening of multidisciplinarity to accurately define target volumes in these complex and relatively new situations, and "delineation concertation meetings" between radiologists, surgeons and radiation oncologists could probably contribute to improved outcomes., (Copyright © 2020 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff., Methods and Materials: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (≥80%) and agreement (≥66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases., Results: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care., Conclusions: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Minimal invasive surgery and reconstructive surgery tend to become the standard in France in the management of head and neck tumors. The use of endoscopic approaches (through endoscopic endonasal/transoral approaches±robot-assisted) instead of open surgery and the use of reconstructive surgery using autologous (flaps) or heterologous materials aim to reduce surgical morbidity by making-up for the loss of substance to restore the function. The impact of these substantial changes in surgical techniques has not been assessed with respect to postoperative radiotherapy practice. Endoscopic endonasal approaches result, however, in piecemeal resection, which, along the analysis of resection margins (a key prognostic factor), make the interpretation of the quality of resection more complex for radiation oncologists. The definition of tumour sub-volumes to be irradiated and doses to these sub-volumes then requires accurate histosurgical mapping and close multidisciplinary consultation between surgeons, pathologists, radiologists and radiation oncologists. Similarly, the increasing use of various types of flaps (of soft tissue or bone flaps), adapted to the patient and tumor anatomy, is associated with substantial modifications to the operating bed. The delineation of tumour volumes in postoperative radiotherapy is made more complex. Tremendous multidisciplinary efforts should now be initiated to fully take advantage of surgical advances and to further optimize the therapeutic index by making radiotherapy also less toxic, i.e. "mini-morbid"., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The quality of radiation therapy has been shown to significantly influence the outcomes for head and neck squamous cell carcinoma (HNSCC) patients. The results of dosimetric studies suggest that intensity-modulated proton therapy (IMPT) could be of added value for HNSCC by being more effective than intensity-modulated (photon) radiation therapy (IMRT) for reducing side effects of radiation therapy. However, the physical properties of protons make IMPT more sensitive than photons to planning uncertainties. This could potentially have a negative effect on the quality of IMPT planning and delivery. For this review, the three French proton therapy centers collaborated to evaluate the differences between IMRT and IMPT. The review explored the effects of these uncertainties and their management for developing a robust and optimized IMPT treatment delivery plan to achieve clinical outcomes that are superior to those for IMRT. We also provide practical suggestions for the management of HNSCC carcinoma with IMPT. Because metallic dental implants can increase range uncertainties (3-10%), patient preparation for IMPT may require more systematic removal of in-field alien material than is done for IMRT. Multi-energy CT may be an alternative to calculate more accurately the dose distribution. The practical aspects that we describe are essential to guarantee optimal quality in radiation therapy in both model-based and randomized clinical trials., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The prognosis of advanced nodal (N3) squamous cell carcinoma of the head and neck (HNSCC) is poor. We investigated whether surgery or radiotherapy of early (T1-2) primary stage HSNCC is preferable to limit the overall morbidity after upfront neck dissection (uND) for N3 disease., Methods: This retrospective multicentric Groupe d'Étude des Tumeurs de la Tête Et du Cou study included patients undergoing uND and surgery or radiotherapy of their primary. Prognostic factors were evaluated using propensity score matching to account for biases in performing surgery depending on primary site and stage., Results: Of 189 T1-2, N3 HNSCC patients, 70 (37.0%) underwent uND: 42 with surgery of their primary and 28 with radiotherapy only. Radiotherapy alone was more frequent in patients with hypopharyngeal primaries. All local (N = 3) and regional (N = 10) relapses (included 2 locoregional relapses) occurred within the first 2 years. There were 16 distant metastatic failures. Five-year locoregional relapse and survival incidences were 15.7% and 66.5% and were similar regardless of the treatment of the primary. The overall morbidity rate was 65.2% and was similar after weighting by the inverse propensity score (p = 0.148). The only prognostic factor for morbidity was the radicality of the uND. Prolonged parenteral feeding was not more frequent in patients only irradiated to their primary (p = 0.118). Prolonged tracheostomy was more frequent after surgery of the primary., Conclusions: In patients with T1-2, N3 HNSCC undergoing uND, radiotherapy and surgery of the primary yield similar oncological outcomes. Morbidity was related to the extent of neck dissection.

Background: The incidence of cancer during pregnancy is low but is slightly increasing. Data on incidence and etiology of head and neck (HN) cancers in pregnant women are rare. We evaluated the frequency, tumor type, associated factors, and specific biomarkers in HN cancers occurring in pregnant (and peripartum) women., Methods: A systematic literature search was performed on PubMed, for any HN tumor site occurring in pregnant women., Results: Sixty cases of HN cancers occurring during pregnancy were identified. Most of them were oral cavity cancers. Relationships with oncogenic viruses, hormonal disturbance, and shift in maternal immunity profile were identified., Conclusion: Carcinogenesis of HN cancers in pregnant women may be led by different cancer type-specific hallmarks. Relevance of these etiological factors with respect to treatments and birth control recommendations is being investigated by the REFCOR in an ambispective study., (© 2019 Wiley Periodicals, Inc.)

Post-therapeutic follow-up of patients with head and neck cancer involves numerous professionals. The radiation oncologist should play an active role in this process. His oncological knowledge and technical expertise position him as a cornerstone for the detection of recurrences from the treated tumor, the research of second primary cancers and the screening of potential side-effects induced by the different treatments administered. To improve the benefits/costs ratio and allow good patient-compliance, follow-up programs should be built through close collaboration between the different contributors and planned according to a feasible schedule. Paraclinical exams must be arranged to respond to accurate objectives. Patient-education is essential to ensure the patient's full understanding and active participation. Finally, the transfer of the long-term follow-up of cancer survivors from specialists to primary care physicians is relevant but would require a prospective evaluation of its efficiency for this specific population., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate platinum rechallenge efficacy and tolerance in patients presenting recurrent head and neck squamous cell carcinoma (HNSCC) after platinum-based chemoradiation., Materials and Methods: We retrospectively included all patients treated from 2007 to 2016 by platinum-based polychemotherapy for recurrence of HNSCC previously treated by primary or postsurgical platinum-based chemoradiation. The primary end-point was disease control rate (DCR) on platinum rechallenge., Results: Forty-five patients were included. Median disease-free interval (DFI) after chemoradiation was 5.7 months. DCR on platinum rechallenge was 40%. Progression-free survival at recurrence was 3.7 months and overall survival 5.0 months. DCR in patients with recurrence within 6 months of chemoradiotherapy was 47.8%. DFI>4.5 months was associated with better DCR: 28.5% versus 54.8%; P=0.0311., Conclusion: Platinum rechallenge provided good DCR in recurrent HNSCC after chemoradiation., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Intensity-modulated radiation therapy (IMRT) is presently the recommended technique for the treatment of locally advanced head and neck carcinomas. Proton therapy would allow to reduce the volume of irradiated normal tissue and, thus, to decrease the risk of late dysphagia, xerostomia, dysgeusia and hypothyroidism. An exhaustive research was performed with the search engine PubMed by focusing on the papers about the physical difficulties that slow down use of proton therapy for head and neck carcinomas. Range uncertainties in proton therapy (±3 %) paradoxically limit the use of the steep dose gradient in distality. Calibration uncertainties can be important in the treatment of head and neck cancer in the presence of materials of uncertain stoichiometric composition (such as with metal implants, dental filling, etc.) and complex heterogeneities. Dental management for example may be different with IMRT or proton therapy. Some uncertainties can be somewhat minimized at the time of optimization. Inter- and intrafractional variations and uncertainties in Hounsfield units/stopping power can be integrated in a robust optimization process. Additional changes in patient's anatomy (tumour shrinkage, changes in skin folds in the beam patch, large weight loss or gain) require rescanning. Dosimetric and small clinical studies comparing photon and proton therapy have well shown the interest of proton therapy for head and neck cancers. Intensity-modulated proton therapy is a promising treatment as it can reduce the substantial toxicity burden of patients with head and neck squamous cell carcinoma compared to IMRT. Robust optimization will allow to perform an optimal treatment and to use proton therapy in current clinical practice., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate the frequency of use, modalities and potential interest of locoregional irradiation (LRT) in patients with upfront metastatic head and neck squamous cell carcinoma (HNSCC)., Methods: Retrospective multicentric study. Were included all patients presenting an upfront metastatic HNSCC treated by platin-5FU- cetuximab based regimen, from 2008 to 2016. Patients with past history of cervical irradiation or HNSCC within the 5 years before metastasis diagnosis were excluded., Results: 65 patients were included. 25 patients (38%) presented a response or stable disease with chemotherapy. Forty-one patients (63%) underwent a locoregional irradiation: 5 patients before chemotherapy (upfront RT), 13 patients with stable disease or response after chemotherapy (consolidation RT), and 23 patients with progressive disease. Median overall survival (OS) was 11.6 months, median progression free survival was 7.9 months. OS was significantly improved for patients who underwent LRT (median OS 16.1 vs 7.5 months, p < 0.01). Among patients who received LRT, OS trended to be better if LRT was performed as consolidation RT compared to upfront RT (median OS of 22.1 vs 15.5 months, p = 0.11). Among patients with stable disease or response after chemotherapy, there was a non-significant better OS for the 13 patients treated by LRT (median OS 22.1 vs 11.8 months, p = 0.21)). Radical dose was not associated with better locoregional control compared to palliative dose (p = 0.37)., Conclusion: LRT is frequently performed during management of upfront metastatic HNSCC and associated with better OS. Non-progressive disease after firs-line chemotherapy seems a good way to select patients who would benefit from radical LRT., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the benefit of cetuximab (Cx) addition to platinum-based and 5-fluorouracil chemotherapy (PFU) in unselected recurrent and/or metastatic head and neck cancer patients (R/MHNC) according to KRAS-LCS6 variant status., Methods: All patients who received at least two PFU ± Cx cycles from 2004 to 2014 were retrospectively included into to two distinct study periods according to Cx implementation: patients treated by PFU alone before 2009 and those treated by PFU + Cx from 2009. Primary objective was to evaluate the progression-free survival (PFS) between the two groups. Secondary objectives were to analyze the overall survival (OS) between the two groups and the prognostic impact of KRAS-LCS6 variant. Factors associated with survival were determined by a Cox multivariate analysis including age, WHO performance status (PS), type of treatment, KRAS-LCS6 variant, Charlson's score and p16 status., Results: Overall, 134 patients were included: 59 (44%) in PFU group and 75 (56%) in PFU + Cx group. Baseline characteristics were well balanced including 30% of patients with 2-3 PS. Median PFS was significantly improved in PFU + Cx group compared to PFU group (6.1 vs 4.4 months, respectively, HR 0.68, p = 0.02) and with a trend for better OS. A KRAS-LCS6 variant was found in 27 (25%) of samples without prognostic impact neither in whole population nor according to treatment. In multivariate analysis, addition of Cx to PFU was the only factor significantly associated with a better PFS (p = 0.01, HR 0.6)., Conclusion: Our results suggest that PFU + Cx combination may be effective in unselected population of R/MHNC regardless the KRAS-LCS6 variant status.

The definition of nodal and/or mucosal target volumes for radiation therapy for lymphadenopathies of unknown primary is controversial. Target volumes may include all nodal areas bilaterraly and be pan-mucosal or unilateral, selective, including the sole oropharyngeal mucosa. This review presents current recommendations in light of changes in the TNM classification, Human papillomavirus status and therapeutic advances. We conducted a systematic review of the literature with the following keywords: lymphadenopathy; head and neck; unknown primary and radiation therapy. There are no direct comparative studies between unilateral or bilateral nodal irradiation or pan-mucosal and selective mucosal irradiation. Contralateral lymph node failure rates range from 0 to 6% after unilateral nodal irradiation and 0 and 31% after bilateral irradiation. Occurrence of a mucosal primary varies between 0 and 19.2%. Initial clinical presentation and Human papillomavirus status are critical to define mucosal target volumes. Intensity-modulated radiotherapy is recommended (rather than three-dimensional irradiation) to avoid toxicities. Systemic treatments have similar indications as for identified primary head and neck cancers. Failures do not appear superior in case of unilateral nodal irradiation but comparative studies are warranted due to major biases hampering direct comparisons. Human papillomavirus status should be incorporated into the therapeutic strategy and practice-changing TNM staging changes will need to be evaluated., (Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Background: A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival., Patients and Methods: Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU - hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity)., Results: Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms., Conclusions: Twice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Squamous cell carcinomas are the most frequent subgroup among head and neck malignant tumors (HNSCC). Tobacco (±alcohol) and HPV infection, the two main risk factors, define two entities with distinct anatomo-clinical and genetic features. HPV-positive, non-tobacco-related HNSCCs are associated with a better prognosis, a rather simple genomic profile, frequent activating mutations of genes involved in pi3kinase-pathway, and the scarcity of mutations of tumor suppressor genes. HPV-negative, tobacco-related HNSCC are genetically more complex, are characterized by almost mandatory inactivating mutations/deletions of tumor suppressor genes (TP53, CDKN2A) and the possible, but less frequent, activating mutations or amplifications of some oncogenes that encode for cell cycle proteins or receptors with tyrosine kinase activity. This review describes the genetic features of HNSCC and discusses how these abnormalities could be incorporated into a therapeutic approach., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: To analyze trends in second primary cancer (SPC) incidence by using a case-mix approach to standardize on first cancer site distribution., Methods: Cases registered by 13 French cancer registries between 1989 and 2010 and followed-up until June 2013 were included. The person-year approach was used to compute standardized incidence ratios (SIRs) of metachronous SPC. Usual SIRs and cancer site-specific weighted SIRs called "case-mix SIRs" (cmSIRs) were estimated by sex and calendar period of first cancer diagnosis. Calendar trends in SIRs and cmSIRs were compared., Results: More than 2.9 million person-years at risk were included. Among males, SIRs dropped from 1.49 to 1.23 between 1989-1994 and 2005-2010, while cmSIRs decreased from 1.40 to 1.27. This difference seems mainly related to a stronger representation of prostate cancers (at lower risk of SPC) and a weaker contribution of bladder and head and neck cancers (at higher risk of SPC) in recent periods of diagnosis. Among females, both SIRs and cmSIRs have remained stable at around 1.22 and 1.21, respectively., Conclusions: The cmSIR is an indicator that is not influenced by changes in first cancer site distribution. Its use should be encouraged to assess second cancer incidence control., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To analyze the outcome of N3 patients treated with very accelerated radiotherapy (VART) or different schedules of concurrent chemoradiotherapy (CRT) within two phase III trials., Patients and Methods: Data of 179 patients with N3 HNSCC from two GORTEC randomized trials (96-01 and 99-02) were pooled. Patients received either VART: 64.8Gy/3.5weeks or one of the 3 following CRT regimens: Conventional CRT: 70Gy/7weeks+3 cycles carboplatin-5FU; Moderately accelerated CRT: 70Gy/6weeks+2 cycles carboplatin-5FU; Strongly intensified CRT: 64Gy/5weeks+cisplatin (days 2, 16, 30) and 5 FU (days 1-5, 29-33) followed by 2 cycles adjuvant cisplatin-5FU., Results: Median follow-up was 13.3 and 5.2years for GORTEC 96-01 and GORTEC 99-02, respectively. Five-year overall survival (OS) was 13.8%. No significant difference was observed between CRT versus VART in terms of OS (hazard ratio [HR]: 0.93, p=0.68), loco-regional progression (HR: 0.70, p=0.13), or distant progression (HR: 0.86, p=0.53). OS was worse for patients with T3-4 tumors versus early T stage (11.0% versus 25.7%, p=0.015). In multivariate analysis, the oropharyngeal subsite presented a higher risk of distant metastasis (as first event 46.5% vs 19.2%, p<0.001),). A significant interaction between treatment modalities and subsites has been observed concerning loco-regional and distant failures., Conclusion: The outcome of N3 HNSCC was extremely poor despite treatment intensification and no difference between CRT and VART. Both distant metastases and loco-regional failures remain important treatment challenge., (Copyright © 2017 Elsevier Ltd. All rights reserved.)