Therapy For Head And Neck Cancer Research Articles

Celecoxib and sulindac sulfide elicit anticancer effects on PIK3CA-mutated head and neck cancer cells through endoplasmic reticulum stress, reactive oxygen species, and mitochondrial dysfunction

Gain-of-function mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) is a significant factor in head and neck cancer (HNC). Patients with HNC harboring PIK3CA mutations receive therapeutic benefits from the use of non-steroidal anti-inflammatory drugs (NSAIDs). However, the molecular mechanisms underlying these effects remain unknown. Here, we examined the Detroit562 and FaDu cell lines as HNC models with and without a hyperactive PIK3CA mutation (H1047R), respectively, regarding their possible distinct responses to the NSAIDs celecoxib and sulindac sulfide (SUS). Detroit562 cells exhibited relatively high PI3K/Akt pathway-dependent cyclooxygenase-2 (COX-2) expression, associated with cell proliferation. Celecoxib treatment restricted cell proliferation and upregulated endoplasmic reticulum (ER) stress-related markers, including GRP78, C/EBP-homologous protein, activating transcription factor 4, death receptor 5, and reactive oxygen species (ROS). These effects were much stronger in Detroit562 cells than in FaDu cells and were largely COX-2-independent. SUS treatment yielded similar results. Salubrinal (an ER stress inhibitor) and N-acetyl-L-cysteine (a ROS scavenger) prevented NSAID-induced ROS generation and ER stress, respectively, indicating crosstalk between ER and oxidative stress. In addition, celecoxib and/or SUS elevated cleaved caspase-3 levels, Bcl-2-associated X protein/Bcl-2-interacting mediator of cell death expression, and mitochondrial damage, which was more pronounced in Detroit562 than in FaDu cells. Salubrinal and N-acetyl-L-cysteine attenuated celecoxib-induced mitochondrial dysfunction. Collectively, our results suggest that celecoxib and SUS efficiently suppress activating PIK3CA mutation-harboring HNC progression by inducing ER and oxidative stress and mitochondrial dysfunction, leading to apoptotic cell death, further supporting NSAID treatment as a useful strategy for oncogenic PIK3CA-mutated HNC therapy.

PPARα Agonism Enhances Immune Response to Radiotherapy While Dietary Oleic Acid Results in Counteraction.

Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will affect therapeutic efficacy. We performed in vivo and in vitro experiments using PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow-cytometric data to investigate these alterations. FF improved antitumor efficacy of high dose per fraction radiotherapy in HNC murine models, whereas the OAD reversed this effect. FF-treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36. Metabolic intervention with increased FA catabolism improves the efficacy of HNC therapy and enhances antitumoral immune response.

Effect of Sarcopenia on Swallowing in Patients With Head and Neck Cancer.

Sarcopenia, characterized by decreased skeletal muscle mass, is associated with poorer oncologic outcomes in head and neck cancer (HNC) patients. The effect of sarcopenia on swallowing following HNC treatment is unknown. This study aims to investigate the association of sarcopenia and swallowing dysfunction in patients treated for HNC. Retrospective cohort study. Academic medical center. Pretreatment sarcopenia was assessed using the skeletal muscle indexcalculated from cross-sectional imaging at the third cervical vertebra. Feeding tube dependence, patient-reported dysphagia, and swallowing safety were assessed before and after treatment with the Functional Oral Intake Scale, Eating Assessment Tool-10, and Penetration Aspiration Scale, respectively. The association between sarcopenia and swallowing dysfunction was evaluated. A total of 112 patients were included, 84 males (75%) and 28 females (25%). A total of 69 (61.6%) had sarcopenia prior to initiating HNC therapy. Sarcopenia was significantly associated with an elevated risk of patient-reported dysphagia (odds ratio [OR] = 2.71[95% confidence interval, CI, 1.12-6.79]; P < .05). Multivariate logistic regression demonstrated that sarcopenia (OR = 15.18[95% CI, 1.50-453.53]; P < .05) is an independent predictor for aspiration following treatment for HNC. Patients with pretreatment sarcopenia had higher rates of dysphagia before treatment and were more likely to develop aspiration after completion of HNC therapy. Sarcopenia is readily measured using cross-sectional imaging and may be useful for identifying patients at risk of swallowing dysfunction and those most likely to benefit from prehabilitation efforts.

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy.

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge.

Impact of photobiomodulation for prevention of oral mucositis on the quality of life of patients with head and neck cancer: a systematic review.

The aim of this study was to perform a systematic review to evaluate the impact of photobiomodulation therapy (PBMT) for the prevention of oral mucositis (OM) on the quality of life (QoL) of patients with head and neck cancer (HNC) undergoing radiation therapy. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The search strategy was performed in five electronic databases (Cochrane, Embase, PubMed, Scopus, and Web of Science). The included studies assessed the QoL of patients undergoing radiation therapy (RT) for HNC and undergoing PBMT for the management of OM. Seven articles met the eligibility criteria. Data extraction was performed in the selected studies including the PBMT parameters (active medium, application procedure, wavelength, fluence, power, irradiance, irradiation time, spot size, energy per point, schedule of irradiation, and total energy). The included studies were qualitatively analyzed, and descriptive analyses were performed. Also, summary results were evaluated for group comparison analysis. All included studies confirmed a decrease in the QoL of the patients that developed OM throughout the RT progress when compared to baseline. Of the informed cases, most of the patients who received PBMT showed grades 1 and 2 OM, while the control group showed more individuals with severe forms of OM (grades 3 and 4). In this sense, patients submitted to PBMT reported better QoL at the end of the treatment compared with the control group. PBMT used for the management of OM preserves the QoL of patients with head and neck cancer.

C-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer

Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.

Outcomes of Patients Treated with Re-Irradiation for Recurrent Head and Neck Cancer Using Pencil Beam Scanning Proton Therapy

Re-irradiation (re-RT) for recurrent head and neck cancer (HNC) after prior HNC radiation therapy (RT) is clinically challenging given prior radiation of nearby organs at risk (OARs). We describe clinical outcomes and toxicity of pencil beam scanning proton therapy (PBS-PT) for recurrent HNC. We performed a retrospective analysis of recurrent HNC patients treated at a single institution with PBS-PT. Baseline demographic, disease and treatment characteristics were recorded. Local control (LC), locoregional control (LRC), progression free survival (PFS), distant metastasis free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. UVA was completed using logistic regression, and MVA was performed using a backward elimination model. We also report acute and late grade 3+ toxicity outcomes, graded per CTCAE v5.0. A total of 89 patients treated with PBS-PT for recurrent HNC between 2016 and 2022 were included. Primary sites included oropharynx (30.0%), oral cavity (22.5%), sinonasal cavity (15.7%), larynx (12.4%) and nasopharynx (6.7%). The most common tumor histology was SCC (73.0%). Median time to re-RT was 47 months. Median dose of PBS-PT was 60 Gy (range: 40-72) with 50.6% receiving BID treatment. Median GTV volume was 30cc (range 4.8-1083cc). 24% of patients received concurrent systemic therapy (46% cytotoxic, 4.5% immunotherapy). Median follow-up after PBS-PT was 8 months (range: 0-71), and median OS was 13 months (95% CI: 9.3-16.7). The median PFS and DMFS were 7 months (95% CI 5.0-9.0) and 9 months (95% CI 5.3-12.7) respectively. The 1- and 2-year LC rates were 80.8% (95% CI: 70.8-90.8) and 66.2% (95% CI: 50.7-81.7). The 1- and 2-year DMFS were 41.0% (95% CI: 30.0-52.0) and 26.3% (95% CI: 15.7-36.9). On UVA and MVA, smaller GTV volume was associated with improved OS (HR 1.002, p = .004), DMFS (HR 1.002, p = 0.004) and PFS (HR 1.002, p = 0.014). In addition, shorter time to re-RT was associated with worse LRC (HR 1.003, p = 0.002), and higher KPS was associated with improved PFS (HR 0.57, p = 0.04). There were 31 acute grade 3 toxicity events (21 patients), the most common being odynophagia (9.0%) followed mucositis (5.6%), dehydration and dermatitis (both 4.5%). One patient had grade 4 toxicity, laryngeal edema requiring intubation 40 days after completion of re-RT. One patient had acute grade 5 toxicity, an oropharyngeal bleed 74 days after completion of re-RT. There were 35 late toxicity events (n = 27), the most common being dysphagia (n = 7, 7.9%). One patient suffered late grade 5 osteoradionecrosis, which resulted in sepsis. PBS-PT for recurrent HNC results in effective disease control and favorable toxicity. Patients with smaller GTV volume appear to have improved OS, PFS and DMFS, and may be better candidates. Those with shorter time to re-RT also have worse LRC. However, distant failure (DF) comprises a major failure pattern, and biomarkers to identify patients at risk for DF may improve clinical decision making.

Immunotherapy in Head and Neck Cancer: Where Do We Stand?

Head and neck cancer (HNC) comprises a group of malignancies, amongst which squamous cell carcinoma accounts for more than 90% of the cases. HNC has been related to tobacco use, alcohol consumption, human papillomavirus, Epstein-Barr virus, air pollution, and previous local radiotherapy. HNC has been associated with substantial morbidity and mortality. This review aims to summarize the recent findings regarding immunotherapy in HNC. The recent introduction of immunotherapy, with the use of programmed death 1 (PD-1) inhibitors pembrolizumab and nivolumab, which have been FDA approved for the treatment of metastatic or recurrent head and neck squamous cell carcinoma, has changed the field in metastatic or recurrent disease. There are many ongoing trials regarding the use of novel immunotherapeutic agents, such as durvalumab, atezolizumab, avelumab, tremelimumab, and monalizumab. In this review, we focus on the therapeutic potential of novel immunotherapy treatment modalities, such as combinations of newer immune-checkpoint inhibitors; the use of tumor vaccines such as human papillomavirus-targeted vaccines; the potential use of oncolytic viruses; as well as the latest advances regarding adoptive cellular immunotherapy. As novel treatment options are still emerging, a more personalized approach to metastatic or recurrent HNC therapy should be followed. Moreover, the role of the microbiome in immunotherapy, the limitations of immunotherapy, and the various diagnostic, prognostic, and predictive biomarkers based on genetics and the tumor microenvironment are synopsized.

CXCR3 isoform A promotes head and neck cancer progression by enhancing stem-like property and chemoresistance.

The chemokine network orchestrates the cancer stem-like property and consequently participates in cancer progression. CXCR3 contributes cancer progressive property and immunomodulation in the tumor microenvironment. The two major isoforms of CXCR3 are scrutinized and the divergence is showed that CXCR3A promotes cancer cell growth and motility while CXCR3B functions contrarily in many studies. However, rare studies illustrate the role of CXCR3 isoforms in cancer stem-like property and chemoresistance, especially in head and neck cancer (HNC). Levels of CXCR3, CXCR3B, and Sox2 were determined in HNC tissue microarray by immunohistochemistry staining to explore potential clinical relevance. Lentivirus-mediated CXCR3-isoform overexpression with MTS assay, clonogenic assay, transwell migration, sphere formation, and chemo-drug susceptibility were implemented to investigate the role of CXCR3-isofoms in HNC. High levels of CXCR3 were significantly associated with advanced stage (p < 0.01), regional lymph node metastasis (p < 0.05), and poor differentiation (p < 0.005) and further correlated with worse survival rate in oral cancer patients (p=0.036). Higher levels of CXCR3B were found in regional lymphatic invasion of HNC and progressive stage of squamous cell carcinoma. Elevated Sox2 expression was significantly associated with the advanced stage of HNC in the oral cavity, and demonstrated a co-expression pattern with CXCR3B. Furthermore, lentivirus-mediated overexpression of CXCR3A and CXCR3B in SAS human oral cancer cells promoted cell mobility. CXCR3A overexpression enhanced sphere-forming ability and chemoresistance of CSCs by upregulating stemness-related genes. This study first provides a novel insight of CXCR3 isoform A in HNC cancer progression via regulating cancer stem-like properties and chemoresistance, suggesting that CXCR3A may be a prognostic marker and novel target for HNC therapy.

Impact of RBE variations on risk estimates of temporal lobe necrosis in patients treated with intensity-modulated proton therapy for head and neck cancer

Background Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC. Material and Methods Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWDFix) and variable RBE-weighed doses (RWDVar) were calculated using RBE = 1.1 and two RBE models, respectively. RWDFix and RWDVar for temporal lobes were compared using Friedman’s test. Based on RWDFix, six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWDFix and RWDVar were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWDFix and RWDVar by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints. Results RWDVar were significantly higher than RWDFix (p < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWDFix and RWDVar ranged between 5.3% and 20.0% points (p < 0.01), with V60GyRBE and DMax at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWDFix (4.0%–13.1%) versus RWDVar (1.3%–5.3%). For V65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWDFix and RWDVar. Conclusion NTCP estimates were significantly influenced by RBE variations. Dmax as model predictor resulted in the largest deviations in risk estimates between RWDFix and RWDVar. V65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWDFix and RWDVar.

Proton Therapy for Head and Neck Cancer: Current Clinical Applications and Future Direction

Intensity-modulated radiation therapy (IMRT) using X-rays is a standard technique implemented for treating head and neck cancer (HNC). Compared to 3D conformal RT, IMRT can significantly reduce the radiation dose to surrounding normal tissues by using a highly conformal dose to the tumor. Proton therapy is a type of RT that uses positively charged particles named protons. Proton therapy has a unique energy deposit (i.e., Bragg peak) and greater biological effectiveness than that of therapy using X-rays. These inherent properties of proton therapy make the technique advantageous for HNC treatment. Recently, advanced techniques such as intensity-modulated proton therapy have further decreased the dose to normal organs with a higher conformal dose to the tumor. The usage of proton therapy for HNC is becoming widespread as the number of operational proton therapy centers has increased worldwide. This paper aims to present the current clinical evidence of proton therapy utility to HNC clinicians through a literature review. It also discusses the challenges associated with proton therapy and prospective development of the technique. Key Words: Proton therapy, Intensity-modulated proton therapy, Radiation therapy, Head and neck cancer

Endovascular Treatment of Carotid Blowout Syndrome

BackgroundCarotid blowout syndrome (CBS) is a life-threatening disease characterized by compromise of the carotid artery by head and neck cancer (HNC). Materials and methodsWe reviewed the characteristics and outcomes of all patients with carotid blowout syndrome who were treated between April 2010 and December 2019. Twelve patients with a history of HNC and radiation therapy were investigated. The balloon occlusion test (BOT) was performed in all patients to confirm collateral circulation. We placed a stent in patients who were intolerant to the BOT. ResultsThe patients’ ages ranged from 50 to 81 years (mean: 68.1 years). Therapeutic occlusion of the affected internal carotid artery was performed in nine patients, while stenting was performed in three patients. Immediate hemostasis was achieved in all patients. Patients treated using stents were administered perioperative DAPT. One patient experienced rebleeding after surgery. Two patients had procedure-related cerebral infarctions. One patient died, but the others survived without major neurological deficits. One patient had persistent aneurysm after surgery that resolved over time. ConclusionEndovascular treatment via occlusion or stent-based reconstruction of the internal carotid artery resulted in immediate hemostasis. Carotid occlusion and covered stent application are safe and efficient techniques to treat CBS secondary to HNC. Surgeons may obtain better outcomes if they perform BOT before occlusion and design treatment accordingly.

Change in Physical Performance Correlates with Decline in Quality of Life and Frailty Status in Head and Neck Cancer Patients Undergoing Radiation with and without Chemotherapy.

Simple SummaryQuality of life (QoL) scores and frailty status are becoming increasingly important criterion with implications on both how patients are treated and survival in head and neck cancer (HNC). Despite this, physicians lack tools to identify patients who are at risk of suffering declines in QoL and becoming frail following treatment. Therefore, we investigated whether functional decline, as measured by a series of physical tests called the Short Physical Performance Battery (SPPB), correlated with a reduction in QoL and increased risk of frailty. In the current study, patients who experienced a decline in SPPB scores were significantly more likely to have changes in physical functioning QoL measures as well as transition to frail status following treatment. In conclusion, the SPPB may be a useful tool to identify patients who may benefit from additional rehabilitation in future studies.Patient-reported quality of life (QoL) metrics, frailty status, and physical functioning are emerging concepts in head and neck cancer (HNC) with implications on both treatment decision-making and prognosis. The impact of treatment-related functional decline on QoL and frailty has not been well-characterized in HNC and was the focus of this investigation. Methods: Patients who underwent radiation therapy for HNC from 2018 to 2020 were evaluated as a prospective observational cohort. Functional decline, QoL, and the frailty phenotype were measured via the Short Physical Performance Battery (SPPB), European Organization for Research and Treatment of Cancer (EORTC) qlq-C30, and Fried Frailty index, respectively. Results: A total of 106 HNC patients were included, 75 of which received concurrent chemoradiation therapy (CCRT) and 31 received radiation alone, both with and without surgery. There was a decrease in SPPB overall (p < 0.001) from the beginning to the end of treatment in the CCRT group but not the radiation group (p = 0.43). Change in overall SPPB points following treatment correlated with the decline in physical QoL for both groups (p < 0.05) as well as transition frail status in the CCRT group (p < 0.001) with a trend in the radiation group (p = 0.08). Conclusions: Change in SPPB correlates with QoL and transition to frailty status in patients undergoing definitive CCRT for HNC with similar trends in those receiving radiation alone. Decline in SPPB could potentially be useful in identification of those who may benefit from rehabilitation in future studies.

Stimuli-responsive drug delivery systems for head and neck cancer therapy

Head and neck cancer (HNC) is among the most common malignancy that has a profound impact on human health and life quality. The treatment for HNC, especially for the advanced cancer is stage-dependent and in need of combined therapies. Various forms of adjuvant treatments such as chemotherapy, phototherapy, hyperthermia, gene therapy have been included in the HNC therapy. However, there are still restrictions with traditional administration such as limited in situ therapeutic effect, systemic toxicity, drug resistance, etc. In recent years, stimuli-responsive drug delivery systems (DDSs) have attracted the great attention in HNC therapy. These intelligent DDSs could respond to unique tumor microenvironment, external triggers or dual/multi stimulus with more specific drug delivery and release, leading to enhanced treatment efficiency and less reduced side effects. In this article, recent studies on stimuli-responsive DDSs for HNC therapy were summarized, which could respond to endogenous and exogenous triggers including pH, matrix metalloproteinases (MMPs), reactive oxygen species (ROS), redox condition, light, magnetic field and multi stimuli. Their therapeutic remarks, current limits and future prospect for these intelligent DDSs were discussed. Furthermore, multifunctional stimuli-responsive DDSs have also been reviewed. With the modification of drug carriers or co-loading with therapeutic agents. Those intelligent DDSs showed more biofunctions such as combined therapeutic effects or integration of diagnosis and treatment for HNC. It is believed that stimuli-responsive drug delivery systems showed great potential for future clinic translation and application for the treatment of HNC.

Nanoparticle-Based Chemotherapy Formulations for Head and Neck Cancer: A Systematic Review and Perspectives.

Head and neck cancer (HNC) is a complex and heterogeneous disease associated with high mortality and morbidity worldwide. Standard therapeutic management of advanced HNC, which is based on radiotherapy often combined with chemotherapy, has been hampered by severe long-term side effects. To overcome these side effects, tumor-selective nanoparticles have been exploited as a potential drug delivery system to improve HNC therapy. A combination of MEDLINE, EMBASE, Cochrane Oral Health Group’s Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception up to June 2020 was used for this systematic review. A total of 1747 published manuscripts were reviewed and nine relevant references were retrieved for analysis, while eight of them were eligible for meta-analysis. Based on these studies, the level of evidence about the efficacy of nanoformulation for HNC therapy on tumor response and adverse side effects (SAE) was low. Even though basic research studies have revealed a greater promise of nanomaterial to improve the outcome of cancer therapy, none of them were translated into clinical benefits for HNC patients. This systematic review summarized and discussed the recent progress in the development of targeted nanoparticle approaches for HNC management, and open-up new avenues for future perspectives.

Oral microbiota versus oral mucositis during cancer treatment: a review

Introduction: Oral microbiota has been implicated on oral mucositis (OM) that occurs during cancer therapy, however without consensus. Objective: This study, aimed to establish, through a review, the association between oral microbiota and OM at head and neck cancer therapy (HNCT). Material and methods: The search of PubMed was performed considering 2008-2018 period, and the descriptors “oral mucositis” and “oral microbiota” in subheadings etiology and microbiology into the Medical Subject Heading (MeSH) “Head and Neck Neoplasms”. The conducting question was “Is there an oral dysbiosis during HNCT associated with OM?”. Results: 22 articles were selected under two steps of data extraction: articles that evaluated de oral microbiota during HNCT (n=13), and articles that also focused in OM (n=9). Conclusion: The evidence presented in the literature suggests associations of oral microbiota dysbiosis with the progression and worsening of radiation-induced OM. However, to define a microbial core for the disease, future standardized studies are required.

Activation of memory/effector T cells and association between prognosis and OX40-positive T cells in advanced head and neck cancer patients treated with anti-programmed death-1 antibody.

35 Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.

Management Practices of Head and Neck Cancer in Chinese Tertiary Care Hospitals: A Multicenter Questionnaire-Based Survey Among Oncologists.

This survey was conducted to determine the head and neck cancer (HNC) treatment strategies followed by oncologists in Chinese hospitals. It was a questionnaire-based survey, conducted from October 2017 to January 2018 in 100 random tertiary hospitals in 21 cities of China to elicit information from oncologists on the management practices for treating HNC in China. A validated, structured questionnaire was used for formal investigation with oncologists. The questions regarding HNC types, treatment strategies used for locally advanced head and neck cancer (LA HNC) and recurrent/metastatic head and neck cancer (r/m HNC), diagnosis and prognostic factors were included. The results were presented as percentages. Among the 272 oncologists, 93.4% were from tertiary care hospitals, with 35.3% and 36.4% patients from radiotherapy (RT) and oncology department, respectively. Nasopharyngeal carcinoma was the most commonly treated type of HNC according to 65.1% oncologists. Patients aged >75 years have worse prognosis and 65% oncologists corroborated that age of the patients influences treatment decision. Most of the oncologists (77.6%) preferred chemotherapy (CT) + anti–epidermal growth factor receptor targeted therapy as the first-line therapy for r/m HNC. Approximately 95% of oncologists considered induction chemotherapy (ICT) to retain organ functions and tumor shrinkage and 43.4% preferred ICT followed by chemoradiotherapy or ICT combined with RT followed by targeted therapy for LA HNC. For the management of HNC, Chinese oncologists recommended ICT with RT and targeted therapy for LA HNC and CT regimen combined with targeted therapy for r/m HNC.

Swallowing disorders after treatment for head and neck cancer.

BackgroundDysphagia is a common consequence of treatment for head and neck cancer (HNC). The purpose of the study was to evaluate the prevalence of dysphagia in a group of patients treated for HNC in Slovenia, and to identify factors contributing to the development of dysphagia.Patients and methodsOne-hundred-nine consecutive patients treated for HNC at two tertiary centers were recruited during their follow-up visits. They fulfilled EORTC QLQ-H&N35 and “Swallowing Disorders after Head and Neck Cancer Treatment questionnaire” questionnaires. Patients with dysphagia were compared to those without it.ResultsProblems with swallowing were identified in 41.3% of the patients. Dysphagia affected their social life (in 75.6%), especially eating in public (in 80%). Dysphagia was found the most often in the patients with oral cavity and/or oropharyngeal cancer (in 57.6%) and in those treated less than 2 years ago (p = 0.014). In univariate analysis, a significant relationship was observed between dysphagia prevalence and some of the consequences of anti-cancer treatment (impaired mouth opening, sticky saliva, loss of smell, impaired taste, oral and throat pain, persistent cough, and hoarseness), radiotherapy (p = 0.003), and symptoms of gastroesophageal reflux (p = 0.027). After multiple regression modelling only persistent cough remained.ConclusionsIn order to improve swallowing abilities and, consequently, quality of life of the patients with HNC a systematic rehabilitation of swallowing should be organized. A special emphasis should be given to gastroesophageal reflux treatment before, during and after therapy for HNC

Patient Safety Considerations Using Dose-response Models in External Radiation Therapy of Head-&amp;-neck and Breast Cancers: Clinical-dosimetric Predictors of Radiation-induced Hypothyroidism

Background: The effectiveness of the six mathematical models was evaluated for prediction of radiation-induced hypothyroidism (RHT) in patients with head-and-neck cancer (HNC) and breast cancer (BC). Methods: Clinical and dose-volume data of 62 patients treated with three-dimensional conformal radiation therapy (3DCRT) for HNC and BC were prospectively analyzed. Thyroid function assessment was evaluated by the level of thyroid hormones from patient serum sample. Cox semi-parametric regression models were used to predict the hazard of RHT. Model performance and model ranking was evaluated through the area under the receiver operating characteristic curve (AUC) and Akaike's information criterion (AIC), respectively. Results: 17 of 62 patients (median 53 years) developed RHT at a median follow-up of 11.4 months after radiotherapy. Kaplan-Meier curves showed a decrease in RHT hazard with thyroid mean dose less than 31 Gy when applied on the whole dataset. Simple and multiple analysis on the whole dataset revealed that RHT hazard was higher for smaller thyroid volumes. For patients with HNC, Vthyroid (thyroid gland volume) and Dmean (thyroid gland mean dose) were found to be influencing factors in prediction of RHT. Based on the AUC, Boomsma’s model and generalized equivalent-uniform-dose (EUD) model outperformed on the whole dataset. The ROC comparison showed no significant difference in the prediction capability of the six models on the whole dataset. Boomsma and gEUD models were ranked as the best models based on the AIC value. Conclusion: In this study, Vthyroid and Dmean were predominant variables for prediction of RHT. Boomsma and gEUD models provided a good prediction power for RHT hazard on the whole and HNC datasets. In conclusion, using these models in the clinic will fulfil the safety of patients against the complication probability following radiation therapy as high as possible.