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Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is a multifactorial disease involving genetic and environmental factors representing one of the most frequent cancer-related deaths worldwide. Tobacco and alcohol use account for most SCCHN, while a growing subset of oropharyngeal cancers is causally associated with human papillomavirus (HPV) infection. Despite improvements in overall survival, patients with HPV-negative locally advanced (LA) SCCHN continue to have a poor prognosis. For these patients, the standard of care is radiotherapy with concurrent chemotherapy (RCT). Methods: This retrospective, multicenter, and observational study analyzed the treatment compliance of 326 patients with LA-SCCHN who underwent RCT between January 1st, 2014, and June 30th, 2017. This study also evaluated the potential factors associated with treatment compliance, the compliance impact on clinical response, and the main toxicities experienced by patients. Results: A total of 274 (84%) patients were compliant and received the planned dose of cisplatin. Overall, 957 adverse events were reported in 98.2% of patients during the study. The overall response rate was 80.2%, with 60.4% of patients achieving a complete response. Discussion: Despite the high treatment compliance, 62.6% of adverse events reported were related to cisplatin. Identifying risk factors associated with non-compliance could enable physicians to identify ineligible patients for cisplatinbased RCT and prevent patients from receiving inadequate treatment leading to severe adverse events.. [ABSTRACT FROM AUTHOR]

IntroductionSquamous cell carcinoma of the head and neck (SCCHN) is a multifactorial disease involving genetic and environmental factors representing one of the most frequent cancer-related deaths worldwide. Tobacco and alcohol use account for most SCCHN, while a growing subset of oropharyngeal cancers is causally associated with human papillomavirus (HPV) infection. Despite improvements in overall survival, patients with HPV-negative locally advanced (LA) SCCHN continue to have a poor prognosis. For these patients, the standard of care is radiotherapy with concurrent chemotherapy (RCT).MethodsThis retrospective, multicenter, and observational study analyzed the treatment compliance of 326 patients with LA-SCCHN who underwent RCT between January 1st, 2014, and June 30th, 2017. This study also evaluated the potential factors associated with treatment compliance, the compliance impact on clinical response, and the main toxicities experienced by patients.ResultsA total of 274 (84%) patients were compliant and received the planned dose of cisplatin. Overall, 957 adverse events were reported in 98.2% of patients during the study. The overall response rate was 80.2%, with 60.4% of patients achieving a complete response.DiscussionDespite the high treatment compliance, 62.6% of adverse events reported were related to cisplatin. Identifying risk factors associated with non-compliance could enable physicians to identify ineligible patients for cisplatin-based RCT and prevent patients from receiving inadequate treatment leading to severe adverse events..

Background and objective: To evaluate the rates of immediate locoregional response and acute toxicities associated with the reirradiation and oral capecitabine treatment of locoregionally recurring, unresectable squamous cell carcinomas of the head and neck. Method: Forty patients met the study's inclusion criteria and were randomly assigned to receive reirradiation for previously treated inoperable and/or irresectable tumours using conventional fractionation (2GY per fraction, 5 days a week, up to a total cumulative dose of 120GY, including the prior RT dose) and Capecitabine (500 mg once daily) during treatment. Result: The average time between the first and second radiation treatment sessions was 20 months. Our experiment showed an overall 90% response rate, with 20 patients showing a complete response, 16 showing a partial response, and 4 showing stable disease. Fifteen patients experienced grade 2 toxicity, and thirteen individuals experienced grade 3 toxicity in the pharynx. A median cumulative lifetime dosage of 116 GY was found. Conclusion: In this prospective single institutional trial, reirradiation and chemotherapy are being combined for the first time to treat recurrent SCCHN. We conclude that chemotherapy-assisted reirradiation up to a total dose of 60GY is feasible and efficient in carefully selected patients with manageable initial toxicities. [ABSTRACT FROM AUTHOR]

In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.

Simple Summary: In 2020, there were 880,000 new cases and 440,000 deaths attributed to head and neck cancer worldwide. Nivolumab was approved in 2016 in the United States, and 2017 in the European Union and Canada, for use in patients with recurrent/metastatic squamous cell carcinoma of the head and neck with progressive disease at or within 6 months after platinum-based therapy. This study was conducted to capture the real-world utilization of nivolumab and to assess the impact of treatment on quality of life among affected patients. The retrospective protocol (VOLUME) described the effectiveness of treatment with nivolumab in terms of survival times and response on imaging, while the prospective protocol (VOLUME-PRO) described the health-related quality of life (HRQoL) among patients treated with nivolumab. This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as 'partial response', with 3.9% reporting 'complete response'. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients. [ABSTRACT FROM AUTHOR]

Abstract Background Squamous cell carcinoma of the head and neck (SCCHN) is globally the sixth most common cancer. TGF-β1 is a key regulator of cell proliferation and differentiation, and it induces the epithelial-mesenchymal transition (EMT) by activating Smad2 signaling in SCCHN cells. Previous studies have revealed that oleuropein (OL) can inhibit the EMT alterations and migration of cancer cells. The aim of this study was to examine the involvement of TGF-β1 signaling pathway in SCCHN and the effect of OL on it. Methods Through in vitro experiments at cellular level and in vivo evaluation in mouse xenograft tumor model, with morphological and Western blotting assays, we examined the effects of OL on TGF-β1-mediated signaling pathway in Tu686, CAL-27 and 686LN-M2 tumor cell lines. Results We found that OL reversed the TGF-β1-induced EMT, and changed the morphology of cells and the expression levels of epithelial and interstitial markers. Wound-healing and transwell invasion assays indicated that OL reversed the TGF-β1-promoted cell migration and invasion dramatically. The effects of OL were also verified in xenograft tumor model of mice, and the findings were identical to the in vitro assays. Conclusion This study demonstrated that OL inhibits the growth and metastasis of SCCHN by interfering with the TGF-β1 signaling pathway, and the findings are beneficial for the development of prevention and treatment strategy of SCCHN. Due to the low toxicity and less side effects, OL may be of potential value in the inhibition of metastasis of SCCHN and improve survival.

Background: Squamous cell carcinoma of the head and neck (SCCHN) is globally the sixth most common cancer. TGF-β1 is a key regulator of cell proliferation and differentiation, and it induces the epithelial-mesenchymal transition (EMT) by activating Smad2 signaling in SCCHN cells. Previous studies have revealed that oleuropein (OL) can inhibit the EMT alterations and migration of cancer cells. The aim of this study was to examine the involvement of TGF-β1 signaling pathway in SCCHN and the effect of OL on it.Methods: Through in vitro experiments at cellular level and in vivo evaluation in mouse xenograft tumor model, with morphological and Western blotting assays, we examined the effects of OL on TGF-β1-mediated signaling pathway in Tu686, CAL-27 and 686LN-M2 tumor cell lines.Results: We found that OL reversed the TGF-β1-induced EMT, and changed the morphology of cells and the expression levels of epithelial and interstitial markers. Wound-healing and transwell invasion assays indicated that OL reversed the TGF-β1-promoted cell migration and invasion dramatically. The effects of OL were also verified in xenograft tumor model of mice, and the findings were identical to the in vitro assays.Conclusion: This study demonstrated that OL inhibits the growth and metastasis of SCCHN by interfering with the TGF-β1 signaling pathway, and the findings are beneficial for the development of prevention and treatment strategy of SCCHN. Due to the low toxicity and less side effects, OL may be of potential value in the inhibition of metastasis of SCCHN and improve survival. [ABSTRACT FROM AUTHOR]

Abstract Background Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT. Methods EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20–30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry. Results Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3−/CD56+, CD3−/CD94+, CD3−/NKG2D+, CD3−/NKp30+, CD3−/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5). Conclusion Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed. Trial registration Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668 .

Abstract Background Although current therapy for patients with early-stage squamous cell carcinoma of the head and neck (SCCHN) is potentially curative, the recurrence rate is high. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis and substantial disease burden, including impaired health-related quality of life (HRQoL), productivity loss and indirect costs, such as need for caregiver support. The aim of this study was to characterize the impact of R/M SCCHN and its first-line treatment on patient and caregiver quality of life, daily activities and work productivity using real-world evidence from Europe. Methods This was a multicentre retrospective study of patients with R/M SCCHN in France, Germany, Italy, Spain and the United Kingdom incorporating patient and caregiver surveys, and a physician-reported medical chart review, conducted between January and May 2019. Patients aged 18 or over with a physician confirmed diagnosis R/M SCCHN completed four validated measures of disease activity and its impact on quality of life and work productivity, while caregivers also completed questionnaire to assess the burden of providing care. Physicians provided data for clinical characteristics, patient management, testing history and treatment patterns. Results A total of 195 medical/clinical oncologists provided data for 937, predominantly male (72%) patients, with almost half of patients aged over 65 years. The most frequently reported symptoms were fatigue (43%), weight loss (40%), pain (35%) and difficulty swallowing (32%). The EXTREME regimen was the most common first line therapy in over half of patients, who reported moderate or extreme pain/discomfort, and anxiety/depression, and problems with self-care resulting in a diminished health status compared with the general population. Only 14% were employed with high absenteeism or presenteeism, and over half of patients had a caregiver for whom the burden of care was substantial. Conclusion Our results provide real-world insight into the multi-faceted burden associated with R/M SCCHN. The combination of poor HRQoL and the impairment in daily activities, social life and employment illustrates the wider impact of R/M SCCHN on patients and their caregivers, and highlights a need for novel 1 L treatment regimens to improve the humanistic and productivity burdens of this cancer.

Purpose: To determine if there was a higher percentage of patients treated surgically and with advanced radiotherapy in 2016 (N = 897) versus 2009 (N = 1136), the patient and tumor characteristics associated with surgical care and advanced radiotherapy, and if chemotherapy or targeted agent use varied over time for squamous cell carcinoma of the head and neck. Methods: We utilized Surveillance Epidemiology and End Results Patterns of Care datasets. Rao-Scott Chi-square tests and logistic regressions were applied to determine differences in surgery, advanced radiotherapy (RT), and chemotherapy by year. Results: There was a lower prevalence of surgery only treatment in 2016 versus 2009 with exception of oral cavity stages IVB/IVC and unknown, and larynx stage unknown. Advanced RT was more common in 2016 for patients receiving definitive RT among all sites, excluding stages I/II glottic larynx. Among each site (oral cavity, oropharynx, and larynx) lower stage was associated with increased odds of surgery. Among each site, advanced RT was more common in patients receiving definitive versus postoperative RT. For the larynx site, 2016 versus 2009 was associated with greater odds of advanced RT. Systemic treatment with fluorouracil, taxanes, or cetuximab was less prevalent in 2016. Conclusion: In 2016 versus 2009, there was largely not a higher percentage of patients treated surgically. There was a higher prevalence of advanced RT for definitive care. Further investigations of these patterns are needed, including trend analysis. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer (HNC) and its treatment are associated with muscle weakness and considerable long-term comorbidity. The goal of this study was to determine whether skeletal muscle density (SMD) as quantified from pretreatment computed tomography (CT) scans will correlate with measures of function and strength prior to treatment in physical function in HNC patients. Patients and methods: A cross-sectional analysis was conducted on 90 HNC patients. SMD (myosteatosis vs. normal) was calculated from pretreatment CT scans using SliceOmatic software. Pretreatment physical function was assessed via handgrip strength (HGS), the timed up and go test (TUG), and the short physical performance battery (SPPB). Demographic, cancer, and social characteristics were also collected as confounders. Linear regression models assessed the association between myosteatosis and measures of physical function. Results: The 90 patients were predominately White, male, former smokers with an average BMI of 28.7 ± 5.7 kg/m2. Among men, adjusted models indicate, as compared to those with normal muscle density, the total SPPB score of those with myosteatosis was 1.57 points lower (p = 0.0008), HGS was 0.85 kg lower (p = 0.73), and TUG took 1.34 s longer (p = 0.03). There were no differences in women. Conclusion: Myosteatosis is associated with physical function prior to treatment in HNC patients. Larger studies are needed to examine the importance of exercise programs prior to and during treatment to build lean mass and improve long-term prognosis in HNC. [ABSTRACT FROM AUTHOR]

To explore the clinical significance and mechanisms of altered miRNAs in squamous cell carcinoma of head and neck (SCCHN) and provide references for SCCHN diagnosis and prognosis.

Peng Li,1 Liyan Sun,2 Luyan Sun3 1Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Orthodontics, SATH Hospital of Stomatology, Henan University , Zhengzhou, People’s Republic of China; 3Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Peng LiDepartment of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Jinshui District, Zhengzhou, Henan 450008, People’s Republic of ChinaEmail zlyylipeng2383@zzu.edu.cnObjective: Differences in body mass index (BMI) were used to analyze the survival and prognosis of SCCHN patients.Patients and Methods: A retrospective cohort study was conducted to select 323 patients who underwent surgical treatment for SCCHN from June 2013 to June 2016. The patients were divided into a healthy BMI group (BMI< 24kg/m2), an overweight group (24kg/m2≤BMI< 28kg/m2) and an obese group (BMI≥ 28 kg/m2). Various statistical methods were used to summarize and analyze clinical data, complications, disease specific survival (DSS), the overall survival (OS), and recurrence-free survival (RFS) within the last 3 y.Results: At 3 y, OS (54.40%) and DSS (51.94%) were slightly lower in the obese group compared with the overweight (64.62%, 61.92%) and healthy BMI groups (64.66%, 65.02%), but no statistical significance was found in DSS (P=0.178), OS (P=0.123) and RFS (P=0.362). The difference in operation duration (P=0.008) and bleeding volume (P=0.001) in obese patients was consistent with those in diabetes mellitus (P=0.002) and coronary heart disease (P=0.000). A high incidence of pharyngeal fistula was observed in obese (P=0.014) and overweight patients (P=0.025), but mouth floor fistula (P=0.038), lung infection (P=0.047), fat liquefaction (P=0.003) and lower extremities deep venous thrombosis (P=0.020) were only found in the obese group. Cox univariatable and multivariatable analysis showed that clinical stage, T stage, and N stage were independent prognostic factors for patients with SCCHN, which was not related to BMI.Conclusion: BMI was associated with a higher probability of complications. However, BMI had no significant correlation with 3-year OS, RFS and DSS, and was not a prognostic indicator for patients with SCCHN.Keywords: body mass index, SCCHN, DSS, OS, RFS, prognosis

Background: In the Phase‐III clinical trial, CheckMate 141, nivolumab significantly improved survival versus standard of care in patients with platinum‐refractory recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Methods: This pooled analysis investigated the real‐world effectiveness of nivolumab, following prior platinum‐based therapy, in patients with R/M SCCHN from the United States (US) Flatiron Health database and German HANNA prospective observational study. Results: Overall, 782 patients (56% US; 44% Germany) were included. Median overall survival (OS) was 8.71 months, and progression‐free survival was 4.11 months. Eastern Cooperative Oncology Group Performance Status 0 or 1, platinum sensitivity, and older age were associated with longer OS, in which number of prior lines of therapy had no significant effect. Conclusion: These findings demonstrate survival benefits of nivolumab in patients with R/M SCCHN in the real‐world setting. The observed real‐world effectiveness of nivolumab aligns with the efficacy of nivolumab in CheckMate 141. [ABSTRACT FROM AUTHOR]

Introduction: Squamous cell carcinomas of the head and neck (SCCHN) account for approximately 4% of all malignancies and are associated with high morbidity and poor prognosis. For patients who are not eligible for surgery or radiotherapy, treatment options are limited, especially for those with recurrent or metastatic (R/M) disease. Current European guidelines recommend first-line (1L) treatment with palliative chemotherapy, using biologic or platinum-based regimens. In the absence of new clinical trials in SCCHN, the use of real-world data has facilitated the assessment of treatment patterns and outcomes in different healthcare systems. This study reports on the 1L treatment of platinum-eligible patients with R/M SCCHN in Italy and Spain. Methods: A point-in-time survey of the management of patients with R/M SCCHN was completed by clinical oncologists in Italy and Spain between October 2018 and February 2019. Patient demographics and clinical characteristics were obtained by retrospective chart review, whilst participating patients self-reported the impact of their disease on their quality of life (QoL) and well-being. Results: A total of 436 patients were recruited from Italy (216) and Spain (220). Patient demographics for both countries comprised mostly male patients, aged 65 years in Italy and 63 in Spain on average. The primary site for the SCCHN was the pharynx and 36% of patients had metastatic disease overall. EXTREME or cetuximab-based regimens were the most common treatments administered at 1L (52% in Italy and 78% in Spain). Scores on the FACT-G in both countries were substantially lower than those of the general and other advanced cancer populations, while scores on the EQ-5D were clinically meaningfully lower than local population norms. Conclusion: Despite 1L treatment of platinum-eligible patients with R/M SCCHN in Italy and Spain following current European guidelines, patients' QoL remains poor, which highlights the need for alternative treatments that could improve clinical outcomes. [ABSTRACT FROM AUTHOR]

• This multicenter phase 3 trial compared adaptive & FDG-PET-guided radiotherapy (rRT) to conventional radiotherapy in LAHNSCC. • FDG-PET-guided dose escalation did not significantly improve locoregional control, progression-free or overall survival. • Dose escalation was successfully delivered with comparable toxicity using adaptive and dose redistribution strategies. • rRT improved locoregional control in patients with oropharynx (HPV+/-) and N0-1 disease, which warrants further evaluation. This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10th fraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2 cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74–89 %) vs. 74 % (66–83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43–1.31, P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %, P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05–0.93) and oropharyngeal cancer (0.31, 0.10–0.95), regardless of HPV. Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT. [ABSTRACT FROM AUTHOR]

Background: Radiochemotherapy (RCT) has been shown to induce changes in immune cell homeostasis which might affect antitumor immune responses. In the present study, we aimed to compare the composition and kinetics of major lymphocyte subsets in the periphery of patients with non-locoregional recurrent (n = 23) and locoregional recurrent (n = 9) squamous cell carcinoma of the head and neck (SCCHN) upon primary RCT.Methods: EDTA-blood of non-locoregional recurrent SCCHN patients was collected before (t0), after application of 20-30 Gy (t1), in the follow-up period 3 (t2) and 6 months (t3) after RCT. In patients with locoregional recurrence blood samples were taken at t0, t1, t2 and at the time of recurrence (t5). EDTA-blood of age-related, healthy volunteers (n = 22) served as a control (Ctrl). Major lymphocyte subpopulations were phenotyped by multiparameter flow cytometry.Results: Patients with non-recurrent SCCHN had significantly lower proportions of CD19+ B cells compared to healthy individuals before start of any therapy (t0) that dropped further until 3 months after RCT (t2), but reached initial levels 6 months after RCT (t3). The proportion of CD3+ T and CD3+/CD4+ T helper cells continuously decreased between t0 and t3, whereas that of CD8+ cytotoxic T cells and CD3+/CD56+ NK-like T cells (NKT) gradually increased in the same period of time in non-recurrent patients. The percentage of CD4+/CD25+/FoxP3+ regulatory T cells (Tregs) decreased directly after RCT, but increased above initial levels in the follow-up period 3 (t2) and 6 (t3) months after RCT. Patients with locoregional recurrence showed similar trends with respect to B, T cells and Tregs between t0 and t5. CD4+ T helper cells remained stably low between t0 and t5 in patients with locoregional recurrence compared to Ctrl. NKT/NK cell subsets (CD56+/CD69+, CD3-/CD56+, CD3-/CD94+, CD3-/NKG2D+, CD3-/NKp30+, CD3-/NKp46+) increased continuously up to 6 months after RCT (t0-t3) in patients without locoregional recurrence, whereas in patients with locoregional recurrence, these subsets remained stably low until time of recurrence (t5).Conclusion: Monitoring the kinetics of lymphocyte subpopulations especially activatory NK cells before and after RCT might provide a clue with respect to the development of an early locoregional recurrence in patients with SCCHN. However, studies with larger patient cohorts are needed.Trial Registration: Observational Study on Biomarkers in Head and Neck Cancer (HNprädBio), NCT02059668. Registered on 11 February 2014, https://clinicaltrials.gov/ct2/show/NCT02059668 . [ABSTRACT FROM AUTHOR]

Background: Although current therapy for patients with early-stage squamous cell carcinoma of the head and neck (SCCHN) is potentially curative, the recurrence rate is high. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis and substantial disease burden, including impaired health-related quality of life (HRQoL), productivity loss and indirect costs, such as need for caregiver support. The aim of this study was to characterize the impact of R/M SCCHN and its first-line treatment on patient and caregiver quality of life, daily activities and work productivity using real-world evidence from Europe.Methods: This was a multicentre retrospective study of patients with R/M SCCHN in France, Germany, Italy, Spain and the United Kingdom incorporating patient and caregiver surveys, and a physician-reported medical chart review, conducted between January and May 2019. Patients aged 18 or over with a physician confirmed diagnosis R/M SCCHN completed four validated measures of disease activity and its impact on quality of life and work productivity, while caregivers also completed questionnaire to assess the burden of providing care. Physicians provided data for clinical characteristics, patient management, testing history and treatment patterns.Results: A total of 195 medical/clinical oncologists provided data for 937, predominantly male (72%) patients, with almost half of patients aged over 65 years. The most frequently reported symptoms were fatigue (43%), weight loss (40%), pain (35%) and difficulty swallowing (32%). The EXTREME regimen was the most common first line therapy in over half of patients, who reported moderate or extreme pain/discomfort, and anxiety/depression, and problems with self-care resulting in a diminished health status compared with the general population. Only 14% were employed with high absenteeism or presenteeism, and over half of patients had a caregiver for whom the burden of care was substantial.Conclusion: Our results provide real-world insight into the multi-faceted burden associated with R/M SCCHN. The combination of poor HRQoL and the impairment in daily activities, social life and employment illustrates the wider impact of R/M SCCHN on patients and their caregivers, and highlights a need for novel 1 L treatment regimens to improve the humanistic and productivity burdens of this cancer. [ABSTRACT FROM AUTHOR]

• This EHNS–ESMO–ESTRO Clinical Practice Guideline provides key recommendations for managing SCCHN. • It covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up. • Opportunities for personalised medicine in SCCHN are also discussed. • All recommendations were compiled by a multidisciplinary group of experts from different institutions and countries. • Recommendations are based on available clinical evidence and the collective expert opinion of the authors. [ABSTRACT FROM AUTHOR]

Abstract Background NLRP3 inflammasome acts as a danger signal sensor that triggers and coordinates the inflammatory response. However, the roles of NLRP3 inflammasome in the tumorigenesis and development of cancer stem cells (CSCs) of squamous cell carcinoma of the head and neck (SCCHN) remain ambiguous. Methods In our study, tissue microarrays, ELISA, sphere-forming assay, colony formation assay and Western blot analysis were performed to evaluate the effect of NLRP3 inflammasome on the development of CSCs in human SCCHN tissue specimen, cell lines, and transgenic mouse SCCHN model. Results The components of NLRP3 inflammasome, namely, NLRP3, ASC, Caspase-1, and IL-18 were correlated with CSCs markers BMI1, ALDH1 and CD44 in human SCCHN specimens. Moreover, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in SCCHN cell lines. NLRP3 inflammasome activated by LPS and ATP promoted sphere-forming and colony formation capacities along with an upregulation of BMI1, ALDH1 and CD44. In addition, NLRP3 inflammasome blockade by NLRP3 inhibitor MCC950 reduced sphere and colony number, also decreased the expression of BMI1, ALDH1 and CD44 in SCCHN cell lines. Expression of NLRP3, ASC, Caspase-1, IL-1β, IL-18, BMI1, ALDH1 and CD44 was upregulated in Tgfbr1/Pten 2cKO mouse SCCHN model, and NLRP3 inflammasome expression was closely related to those CSCs makers in mice SCCHN. However, MCC950 treatment reduced the expression of NLRP3 inflammasome, CSCs markers BMI1, ALDH1 and CD44 in Tgfbr1/Pten 2cKO mice SCCHN. In addition, blockade of NLRP3 inflammasome can also delayed the tumor-burdened speed in SCCHN mice. Conclusions Our study demonstrates that NLRP3 inflammasome was upregulated and associated with the carcinogenesis and CSCs self-renewal activation in SCCHN. NLRP3 inflammasome can be a potential target in the development of novel approaches for head and neck squamous cell carcinoma therapy.

Objective ‒ To explore the clinical significance and mechanisms of altered miRNAs in squamous cell carcinoma of head and neck (SCCHN) and provide references for SCCHN diagnosis and prognosis. Method ‒ Differential expressed miRNAs (DEMs) in SCCHN were screened through gene expression omnibus (GEO) DataSets and verified by the cancer genome atlas (TCGA) database. Next, the overall survival analysis, receiver operating characteristics, and clinical correlation analysis were adopted to filter the miRNAs with diagnostic and prognostic values. Finally, functional enrichment analyses were conducted for inquiring into the mechanisms of miRNAs. Results ‒ Total 103 DEMs (p < 0.05, fold change ≥ 2) in SCCHN were screened out from GSE124566. Partly, the expression levels of the selected (12/17) miRNAs were verified by TCGA. Followed, of the 12 miRNAs, two miRNA expression levels were associated with the overall survival, and five miRNAs showed diagnostic values (AUC ≥ 0.85). Besides, miR-223-3p and miR-204- 5p expression levels were correlated to certain clinical features. Epithelial–mesenchymal transition (EMT) related biological process and energy metabolism controlling related AMPK signaling pathway might mediate the roles of miR-223-3p and miR-204-5p, respectively. Conclusion ‒ With diagnostic and prognostic values, miR-223-3p and miR-204-5p may be involved in the progression of SCCHN through EMT-related biological process and energy balance related AMPK signaling pathway, respectively. [ABSTRACT FROM AUTHOR]

Background: We sought to evaluate intratumor heterogeneity in squamous cell carcinoma of the oral cavity (OCC) and specifically determine the effect of physical separation and histologic differentiation within the same tumor. Methods: We performed whole exome sequencing on five biopsy sites—two from well‐differentiated, two from poorly differentiated regions, and one from normal parenchyma—from five primary OCC specimens. Results: We found high levels of intratumor heterogeneity and, in four primary tumors, identified only 0 to 2 identical mutations in all subsites. We found that the heterogeneity inversely correlated with physical separation and that pairs of well‐differentiated samples were more similar to each other than analogous poorly differentiated specimens. Only TP53 mutations, but not other purported "driver mutations" in head and neck squamous cell carcinoma, were found in multiple biopsy sites. Conclusion: These data highlight the challenges to characterization of the mutational landscape of OCC with single site biopsy and have implications for personalized medicine. [ABSTRACT FROM AUTHOR]

Background In the present study, we examined real-world treatment patterns for squamous cell carcinoma of the head and neck (scchn) in Canada, which are largely unknown. Methods Oncologists across Canada provided data for disease history, characteristics, and treatment patterns during May-July 2016 for 6-8 consecutive patients receiving first-line or second-line drug treatment for scchn (including locally advanced and recurrent or metastatic disease). Results Information from 16 physicians for 109 patients receiving drug treatment for scchn was provided; 1 patient was excluded from the treatment-pattern analysis. Median age in the cohort was 63 years [interquartile range (iqr): 57-68 years], and 24% were current smokers, with a mean exposure of 26.2 ± 12.7 pack-years. The most common tumour site was the oropharynx (48%). Most patients (84%) received platinum-based regimens as first-line treatment (44% received cisplatin monotherapy). Use of cetuximab-based regimens as first-line treatment was limited (17%). Of 53 patients receiving second-line treatment, 87% received a first-line platinum-based regimen. Median time between first-line treatment with a platinum-based regimen and initiation of second-line treatment was 55 days (iqr: 20-146 days). The most common second-line regimen was cetuximab monotherapy (43%); platinum-based regimens were markedly infrequent (13%). Conclusions Our analysis provides real-world insight into scchn clinical practice patterns in Canada, which could inform reimbursement decision-making. High use of platinum-based regimens in first-line drug treatment was generally reflective of treatment guidelines; cetuximab use in the second-line was higher than anticipated. Additional real-world studies are needed to understand the effect of novel therapies such as immuno-oncology agents on clinical practice and outcomes, particularly for recurrent or metastatic scchn. [ABSTRACT FROM AUTHOR]

Metastasis is one of the primary causes for high mortality in patients with squamous cell carcinoma of the head and neck (SCCHN). Our previous study showed that chemokine (C‐C motif) ligand 18 (CCL18), derived from tumour‐associated macrophages (TAMs), regulates SCCHN metastasis by promoting epithelial‐mesenchymal transition (EMT) and preserving stemness. However, the underlying mechanism needs to be further investigation. Interestingly, metadherin (MTDH) expression was induced when SCCHN cells were stimulated with recombinant CCL18 protein in this study. Suppressing MTDH expression reversed CCL18‐induced migration, invasion and EMT in SCCHN cells. Furthermore, the NF‐κB signalling pathway was involved in the MTDH knock‐down cells with CCL18 stimulation. We performed ELISA to evaluate the CCL18 levels in the serums of 132 treatment‐naive SCCHN patients, 25 patients with precancerous lesion and 32 healthy donors. Our results demonstrated that serum CCL18 levels were significantly higher in SCCHN patients than patients with precancerous lesion and healthy individuals. CCL18 levels were found to be significantly correlated with tumour classification, clinical stage, lymph node metastasis and histological grade in SCCHN patients. Thus, our findings suggest that CCL18 may serve as a potential biomarker for diagnosis of SCCHN and promote SCCHN invasion, migration and EMT by MTDH‐NF‐κB signalling pathway. [ABSTRACT FROM AUTHOR]

Circulating lipoproteins as risk factors or prognostic indicators for various cancers have been investigated previously; however, no clear consensus has been reached. In this study, we aimed at evaluating the impact of serum lipoproteins on the prognosis of patients with squamous cell carcinoma of the head and neck (SCCHN). Levels of total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and lipoprotein(a) were measured in serum samples from 106 patients and 28 healthy controls. We found that HDL was the only lipoprotein exhibiting a significant difference in concentration between healthy controls and patients (p = 0.012). Kaplan–Meier survival curves indicated that patients with high levels of total cholesterol or LDL had better overall survival than patients with normal levels (p = 0.028 and p = 0.007, respectively). Looking at patients without lipid medication (n = 89) and adjusting for the effects of TNM stage and weight change, multivariate Cox regression models indicated that LDL was an independent prognostic factor for both overall (p = 0.005) and disease-free survival (p = 0.013). In summary, our study revealed that high LDL level is beneficial for survival outcome in patients with SCCHN. Use of cholesterol-lowering medicines for prevention or management of SCCHN needs to be evaluated carefully.

OBJECTIVE: This study aims to investigate the effect of miR-26a on the epithelial- mesenchymal transition (EMT) and invasion of Tu686 cell line through SMAD1. MATERIALS AND METHODS: Tu686 Squamous cell carcinoma of head and neck (SCCHN) cell strains were divided into the miR-26a group, miR-NC group, co-transfection group and blank control group. Among them, the miR-26a group only transfected miR-26a mimics, the miR-NC group only transfected miR-26a negative control, the co-transfection group transfected miR- 26a mimics and pcDNA3.1-SMAD1 plasmid. The qRT-PCR method was used for the detection of the expressions of miR-26a and SMAD1 in each group of cells, transwell assay for the detection of the invasion ability of each group of cells and Western blot for detecting the expression level of SMAD1 and the expressions of EMT-related proteins E-cadherin and N-cadherin. RESULTS: The relative expression of miR- 26a in the miR-26a group was significantly higher than that in the miR-NC group and blank control group, and the relative expression in the co-transfection group was significantly higher than that in the miR-NC and blank control groups. The relative expression of SMAD1 in the miR-26a group was significantly lower than that in the miR-NC and blank control groups, and the relative expression in the co-transfection group was lower than that in the miR-NC and blank control groups, and higher than that in the miR- 26a group (all p<0.05). There was no significant difference between the miR-NC group and the blank control group (p>0.05). CONCLUSIONS: miR-26a may reduce the expression level of SMAD1, affect the expression of EMT-related proteins, inhibit the EMT function of Tu686 cells of squamous cell carcinoma of head and neck, and inhibit the invasion of them. [ABSTRACT FROM AUTHOR]

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials. [ABSTRACT FROM AUTHOR]

Background Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8–45.8 months). Median progression-free survival was 2.6 months (range 0.5–48.4 months), and median overall survival was 6.0 months (range 0.5–51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842. [ABSTRACT FROM AUTHOR]

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre‐activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor‐infiltrating CD56+ NK cells in formalin‐fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin‐based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3–4) showed significantly decreased overall survival (OS; p = 0.008), local progression‐free survival (LPFS; p = 0.034) and distant metastases‐free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0–2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16‐ (p = 0.001), p53‐ (p = 0.0003) and HPV16 DNA‐negative (p = 0.001) tumors. The absence or low numbers of tumor‐infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor‐infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor‐infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers. [ABSTRACT FROM AUTHOR]

Abstract: Epithelial–mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor‐associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N‐cadherin was down‐regulated and that of E‐cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF‐β1) and CAL27 similar to mesenchymal cells formed after TGF‐β1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor‐dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1‐positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN. [ABSTRACT FROM AUTHOR]

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA ( p < 0.001 and p = 0.008, respectively) and high infiltration by CD8+ TILs ( p < 0.001 for both markers). High PD-L1 expression correlated with superior OS ( p = 0.025), LPFS ( p = 0.047) and DMFS ( p = 0.048) in multivariable analysis, whereas no significance could be demonstrated for PD-1. Patients with CD8high/PD-L1high expression had favorable outcome ( p < 0.001 for all endpoints) compared to other groups. We validated the superior OS data on CD8high/PD-L1high using the Cancer Genome Atlas TCGA dataset ( n = 518; p = 0.032). High PD-L1 expression was a favorable prognostic marker in HPV16-negative but not HPV16-positive patients. In conclusion, HPV-positive tumors showed higher expression of immune markers. PD-L1 expression constitutes an independent prognostic marker in SCCHN patients post-adjuvant CRT. In conjunction with CD8 status, these data provide an important insight on the immune contexture of SCCHN and are directly relevant for future treatment stratification with PD-1/PD-L1 immune checkpoint inhibitors to complement CRT. [ABSTRACT FROM AUTHOR]

Background: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to EGFR and HER3, inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody dependent cell mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Methods: This multicenter, open-label, randomized phase II study (MEGHAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy, and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers (NRG1, ERBB3, and HPV status).Results: Patients (N =121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 y; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival (4.2 vs. 4.0 months; HR: 1.23 [90% CI: 0.89-1.70]), overall survival (7.2 vs. 8.7 months; HR 1.15 [90% CI: 0.81-1.63], and objective response rate (12% vs. 14.5%), with no difference between patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (duligotuzumab vs. cetuximab, respectively) included infections (22% vs. 11.5%) and GI disorders (17% vs. 7%) contributing to higher rates of serious adverse events (41% vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10% vs. 16%); any grade rash-related events were less with duligotuzumab (49% vs. 67%).Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab.

Immune system deregulation and evasion play a key role in cancers' evolution and progression, including squamous cell carcinoma of the head and neck (SCCHN). Development of basic research proposed a whole new vision of cancer treatment, based on a strong biological rational, and targeting intrinsic deregulations. Immunotherapies provide an encouraging strategy for patients' improved outcomes. Immune-based therapies could act on cancer growth and/or development throughout many pathways. If cetuximab is for now the only monoclonal antibody approved for SCCHN management, other strategies, e.g. immune checkpoints openers, are arousing enthusiasm. Clinical trials are multiplying in patients with recurrent/metastatic SCCHN and primary results offer promising outcomes. Prospects of combining various immunotherapies with more established treatments, such as chemotherapy and radiotherapy, seem very encouraging and could provide synergistic benefits. Ongoing phase III clinical trials should soon enlighten us on the next "standard of care" for SCCHN. In the present review we summarized the different immunotherapy strategies that are currently under clinical investigation for SCCHN' medical care. [ABSTRACT FROM AUTHOR]

Background: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Methods: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m² load, 250 mg/m² IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status]. Results: Patients (N = 121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (CI): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% CI: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash-related events were less with duligotuzumab (49 vs. 67%). Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab. [ABSTRACT FROM AUTHOR]

Background Mucositis and dysphagia are common adverse effects of radiotherapy (RT) treatment of locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Chemotherapy added to RT increases survival rates but causes worse mucositis and dysphagia. The aim of this analysis was to assess the impact of p16 status on mucositis, dysphagia, and feeding tube use in LA-SCCHN among patients treated with RT ± cetuximab in the phase 3 IMCL-9815 trial. Methods Patients received RT plus weekly cetuximab or RT alone. Subgroup analyses were conducted on patients with p16-positive (n = 75) or p16-negative (n = 106) oropharyngeal cancer (OPC), as determined by immunohistochemical analysis. The onset and duration of mucositis and dysphagia by treatment arm and p16 status were displayed using Kaplan–Meier curves and the log-rank test. P values for the incidence of mucositis and dysphagia were calculated using the Fisher exact test. Feeding tube use was assessed as the percent of patients reporting use. Results The baseline characteristics of patients treated with RT ± cetuximab were similar in both the p16-positive and p16-negative OPC subgroups. Patients within the p16-positive OPC subgroup had higher Karnofsky scores and were more likely to have stage T1–T3 cancer and be from the United States. Regardless of p16 status, there was no difference in the onset or duration of grade 3/4 mucositis or dysphagia in patients receiving RT plus cetuximab compared with those receiving RT alone. In the overall population, and the p16-positive and p16-negative OPC subpopulations, feeding tube use was not different for patients receiving RT plus cetuximab compared with RT alone. Conclusion Regardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use. [ABSTRACT FROM AUTHOR]