Efficacy of chemoradiotherapy in elderly patients with stage IV inoperable head and neck cancer.

OBJECTIVES: This study aimed to compare the efficacy of chemoradiotherapy (CRT) with radiotherapy (RT) alone for elderly patients (≥ 65 years) with stage IV inoperable head and neck cancer (IV-HNC). METHODS: Elderly patients diagnosed with inoperable IV-HNC from 2010 to 2015 were identified using the SEER database. Then, we performed a 1:1 propensity-score matched (PSM) analysis to reduce treatment selection bias, and the prognostic role of CRT was investigated using Kaplan-Meier analysis, log-rank test, and Cox proportional hazard models. The main outcome was overall survival (OS), and the secondary outcome was cancer-specific survival (CSS). RESULTS: A total of 3318 patients were enrolled, of whom 601 received RT alone and 2717 received CRT. Through PSM, 526 patients were successfully matched, and balances between the two treatment groups were reached. In the matched dataset, multivariable Cox analysis revealed that CRT was associated with better OS (HR = 0.580, P < 0.001) and CSS (HR = 0.586, P < 0.001). Meanwhile, subgroups of patients with IV-HNC (younger age, male sex, being married, black race, grade I-II, oral cavity site, T3-T4 stage, N0-N1 stage, M1 stage) were inclined to benefit more from CRT treatment. Furthermore, the survival benefit of CRT was more pronounced in patients aged 65 to 80 years, but was absent in patients aged 80 years or older. CONCLUSIONS: This study indicated that CRT resulted in better survival than RT alone in elderly patients with inoperable IV-HNC, especially for those subpopulations that benefit more from CRT treatment.

Speech and Swallowing Rehabilitation Potentially Decreases Body Weight Loss and Improves Survival in Head and Neck Cancer Survivors.

This retrospective observational cohort study aims to assess the outcomes and associated factors in head and neck cancer (HNC) survivors with dysphagia, and to investigate the relationship between outcomes and speech and swallowing rehabilitation (SSR). We enrolled patients who were diagnosed with HNC between October 2016 and July 2018; we included 393 patients who developed dysphagia after definite treatment and were referred to speech-language pathologists (SLPs). We then classified patients into groups according to whether they received SSR. We used the clinical variables-including age, sex, site of malignancy, cancer stage, treatment modality, SSR, initial ECOG score, initial KPS, initial body weight (BW), and initial BMI-to evaluate the association between the percentage of BW change and overall survival (OS). There were 152 (39%) and 241 (61%) patients who received and did not receive SSR, respectively. In multivariate linear regression, SSR was significantly associated with percentage change in BW at 3 months post-treatment. Having SSR was positively associated with the percentage change in BW and decreased the BW loss [ß coefficient (95% CIs) = 2.53 (0.92 to 4.14)] compared to having no SSR. In the multivariate Cox regression, SSR was an independent factor for OS. Compared to no SSR, the hazard ratio (95% CIs) for patients who received SSR was 0.48 (0.31 to 0.74). SSR helps to avoid BW loss and increases overall survival. HNC patients who develop dysphagia after treatment should be encouraged to participate in SSR.

Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy.

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.

DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival.

Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting.

Dose difference between anisotropic analytical algorithm (AAA) and Acuros XB (AXB) caused by target's air content for volumetric modulated arc therapy of head and neck cancer.

Background: We clarified the dose difference between the anisotropic analytical algorithm (AAA) and Acuros XB (AXB) with increasing target's air content using a virtual phantom and clinical cases. Materials and methods: Whole neck volumetric modulated arc therapy (VMAT) plan was transferred into a virtual phantom with a cylindrical air structure at the center. The diameter of the air structure was changed from 0 to 6 cm, and the target's air content defined as the air/planning target volume (PTV) in percent (air/PTV) was varied. VMAT plans were recalculated by AAA and AXB with the same monitor unit (MU) and multi-leaf collimator (MLC) motions. The dose at each air/PTV (5%-30%) was compared between each algorithm with D98%, D95%, D50% and D2% for the PTV. In addition, MUs were also compared with the same MLC motions between the D95% prescription with AAA (AAA_D95%), AXB_D95%, and the prescription to 100% minus air/PTV (AXB_D100%-air/PTV) in clinical cases of head and neck (HNC). Results: When air/PTV increased (5-30%), the dose differences between AAA and AXB for D98%, D95%, D50% and D2% were 3.08-15.72%, 2.35-13.92%, 0.63-4.59%, and 0.14-6.44%, respectively. At clinical cases with air/PTV of 5.61% and 28.19%, compared to AAA_D95%, the MUs differences were, respectively, 2.03% and 6.74% for AXB_D95% and 1.80% and 0.50% for AXB_D100%-air/PTV. Conclusion: The dose difference between AAA and AXB increased as the target's air content increased, and AXB_D95% resulted in a dose escalation over AAA_D95% when the target's air content was ≥ 5%. The D100%-air/PTV of PTV using AXB was comparable to the D95% of PTV using AAA.

Impact of HPV status on metastatic patterns and survival in non-oropharyngeal head and neck cancer with distant metastasis.

PURPOSE: Because of the lack of data and studies on metastatic non-oropharyngeal head and neck cancer (non-OP HNC), the role of human papillomavirus (HPV) status in non-OP HNC with distant metastasis is still unclear. Therefore, we conducted a study to explore the differences in metastatic patterns, survival and treatment responses in metastatic non-OP HNC based on HPV status. METHODS: A total of 333 metastatic non-OP HNC patients were diagnosed from 2010 to 2016 in the Surveillance, Epidemiology and End Results (SEER) database. The chi-square test and Fisher's exact test were used to make comparisons for categorical variables. The Kaplan-Meier method and Cox regression analyses were used to analyse survival. RESULTS: HPV status was a significant prognostic variable for patients with non-OP HNC with distant metastasis. HPV- patients were more likely to have distant metastasis and worse prognosis and treatment response than HPV+ patients. Only chemotherapy was an independent prognostic factor for HPV+ patients with distant metastasis, while chemotherapy and radiotherapy were both independent prognostic factors for HPV- patients with distant metastasis. The treatment response was associated with the metastatic pattern in both HPV+ and HPV- populations and showed significant differences based on HPV status and metastatic pattern. CONCLUSIONS: For non-OP HNC with distant metastasis, HPV+ and HPV- patients formed two different cohorts in terms of metastatic pattern, survival and treatment. Therefore, it is helpful to classify metastatic non-OP HNC into different groups to choose appropriate treatment strategies according to HPV status and metastatic pattern.

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies.

Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly heterogeneous group of tumors characterized by an incidence of 650,000 new cases and 350,000 deaths per year worldwide and a male to female ratio of 3:1. The main risk factors are alcohol and tobacco consumption and Human Papillomavirus (HPV) infections. HNSCC cases are divided into two subgroups, the HPV-negative (HPV-) and the HPV-positive (HPV+) which have different clinicopathological and molecular profiles. However, patients are still treated with the same therapeutic regimens. It is thus of utmost importance to characterize the molecular mechanisms underlying these differences to find new biomarkers and novel therapeutic targets towards personalized therapies. Epigenetic alterations are a hallmark of cancer and can be exploited as both promising biomarkers and potential new targets. E6 and E7 HPV oncoviral proteins besides targeting p53 and pRb, impair the expression and the activity of several epigenetic regulators. While alterations in DNA methylation patterns have been well described in HPV+ and HPV- HNSCC, accurate histone post-translational modifications (hPTMs) characterization is still missing. Herein, we aim to provide an updated overview on the impact of HPV on the hPTMs landscape in HNSCC. Moreover, we will also discuss the sex and gender bias in HNSCC and how the epigenetic machinery could be involved in this process, and the importance of taking into account sex and/or gender also in this field.

Rising incidence of late-stage head and neck cancer in the United States.

BACKGROUND: The current study was conducted to determine whether the incidence of late-stage head and neck cancer (HNC) is decreasing and to estimate the risk of late-stage HNC diagnosis based on race and sex. METHODS: Age-adjusted incidence rates for patients aged ≥18 years with stage IV HNC were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2015). Rates were stratified by race, sex, and age. Joinpoint regression estimated annual percent changes (APCs) in rates over time, and logistic regression estimated adjusted odds ratios (aORs). RESULTS: There were 57,118 patients with stage IV HNC in the current study cohort, with an average age of 61.9 years. From 2004 to 2015, the age-adjusted incidence rates for stage IV HNC significantly increased by 26.1% (6.11 per 100,000 person-years in 2004 to 7.70 per 100,000 person-years in 2015). White and Asian/Pacific Islander/American Indian/Alaska Native patients had significant increases in incidence (APC for white patients, 3.03 [P < .01] and APC for other races, 1.95 [P < .01]), whereas rates among black patients remained stable but were highest across racial groups. Incidence was higher among males compared with females. When restricted only to patients with stage IVC (metastatic) HNC, there remained a significant increase in incidence, especially for oropharyngeal cancer, which showed a 22.9% increase (0.21 per 100,000 person-years in 2004 vs 0.25 per 100,000 person-years in 2015). Despite a decreasing overall incidence of stage IV HNC in black patients (aOR, 1.28; 95% CI, 1.22-1.34) they, along with males (aOR, 3.95; 95% CI, 3.80-4.11), had significantly increased risks of being diagnosed with late-stage HNC. CONCLUSIONS: There is an increasing incidence of late-stage HNC in the United States, with male patients and black individuals faring the worst.

A systematic review of psychological interventions for patients with head and neck cancer.

AIM: The purpose of this systematic review is to identify psychological interventions that have been effective at improving quality of life and reducing psychological distress (depression and anxiety) in patients with head and neck cancer. METHODS: All relevant peer-reviewed articles published between March 1980 and March 2017 were identified through an electronic search of five databases: Medline, Embase, PsycINFO, Scopus, and Academic Search Complete. Risk of bias was independently assessed by two reviewers using the Crowe Critical Appraisal Tool (CCAT). Following this, a narrative synthesis of the findings was completed. RESULTS: Twenty-one unique intervention studies were identified. Interventions tested included cognitive behavioural therapy (CBT), psychoeducation, meditation/mindfulness, group therapy, and telehealth initiatives. Ten studies utilised a randomised controlled design. Five of these investigated CBT and three examined psychoeducation, with the greatest empirical support found for these intervention types. However, the majority of studies were underpowered to detect significant effects and did not examine whether improvements in quality of life and psychological well-being were sustained over time. CONCLUSIONS: Further research is needed to investigate the effects of psychological interventions among patients with head and neck cancer, using randomised controlled designs, adequately powered samples, and long-term follow-up. This would allow evidence-based recommendations to be made regarding the most appropriate interventions to implement in clinical practice. TRIAL REGISTRATION: CRD42017069851.

Long Non-coding RNAs as Important Biomarkers in Laryngeal Cancer and Other Head and Neck Tumours.

Head and neck carcinoma (HNC) is a heterogeneous disease encompassing a variety of tumors according to the origin. Laryngeal cancer (LC) represents one of the most frequent tumors in the head and neck region. Despite clinical studies and advance in treatment, satisfactory curative strategy has not yet been reached. Therefore, there is an urgent need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as suitable therapeutic targets. Long non-coding RNAs (lncRNA) are reported as important regulators of gene expression and represent an innovative pharmacological application as molecular biomarkers in cancer. The purpose of this review is to discuss the most relevant epigenetic and histological prognostic biomarkers in HNC, with particular focus on LC. We summarize the emerging roles of long non-coding RNAs in HNC and LC development and their possible use in early diagnosis.

Prevalence and sociodemographic factors associated with depression among hospitalized patients with head and neck cancer-Results from a national study.

OBJECTIVE: Depression is a significant problem for patients with head and neck cancer (HNC). This study explored the prevalence of and sociodemographic and clinical factors associated with depression, among patients with HNC. METHODS: We performed a retrospective analysis of 71 541 cases of HNC using a national dataset, the Nationwide Inpatient Sample, from 2008 to 2013. Weighted, multivariate logistic regression analysis estimated association between sociodemographic/clinical factors and tumor anatomical site with diagnosis of a major depressive disorder. RESULTS: Overall prevalence of major depressive disorder in HNC was 9.3%; highest prevalence was found in patients with laryngeal cancer (28.5%). Compared with laryngeal cancer, there were lower odds of depression among patients with oral cavity cancer (adjusted odds ratio [aOR] = 0.90; 95% CI, 0.84-0.97) and other anatomic sites (aOR = 0.87; 95% CI, 0.81-0.94), except oropharyngeal cancer (aOR = 1.00; 95% CI, 0.93-1.08). For every unit increase in comorbidities, odds of depression increased by 20% (aOR = 1.20; 95% CI, 1.19-1.23). Sociodemographic factors associated with increased odds of depression included being female (aOR = 1.77; 95% CI, 1.68-1.87), white (aOR = 1.75; 95% CI, 1.59-1.92), and having Medicaid (aOR = 1.09; 95% CI, 1.01-1.19) or Medicare insurance (aOR = 1.19; 95% CI, 1.10-1.27). CONCLUSIONS: Depression odds vary depending on HNC anatomic site, and one in four patients with laryngeal cancer may be depressed. Since depression is prevalent in this survivor cohort, it is important that psychosocial assessment and intervention are integrated into mainstream clinical care for patients with HNC.

A Self-Regulatory Intervention for Patients with Head and Neck Cancer: Pilot Randomized Trial.

BACKGROUND: Research is yet to investigate whether psychological interventions delivered early after diagnosis can benefit patients with head and neck cancer (HNC). PURPOSE: The aim of this study was to investigate the effectiveness of a brief self-regulatory intervention (targeting illness perceptions and coping) at improving HNC patient health-related quality of life (HRQL). METHODS: A pilot randomized controlled trial was conducted, in which 64 patients were assigned to receive three sessions with a health psychologist in addition to standard care or standard care alone. Participants completed questionnaires assessing HRQL, general distress, and illness perceptions at baseline and again 3 and 6 months later. RESULTS: Compared to the control group, patients who received the intervention had increased treatment control perceptions at 3 months (p = .01), and increased social quality of life at 6 months (p = .01). The intervention was particularly helpful for patients exhibiting distress at baseline. CONCLUSION: A brief psychological intervention following HNC diagnosis can improve patient perceptions of treatment and social quality of life over time. Such interventions could be targeted to patients who are distressed in order to confer the greatest benefit. TRIAL REGISTRATION NUMBER: 12614000813684.

A systematic literature review of health state utility values in head and neck cancer.

BACKGROUND: Health state utility values (HSUVs) are essential parameters in model-based economic evaluations. This study systematically identifies HSUVs in head and neck cancer and provides guidance for selecting them from a growing body of health-related quality of life studies. METHODS: We systematically reviewed the published literature by searching PubMed, EMBASE and The Cochrane Library using a pre-defined combination of keywords. The Tufts Cost-Effectiveness Analysis Registry and the School of Health and Related Research Health Utilities Database (ScHARRHUD) specifically containing health utilities were also queried, in addition to the Health Economics Research Centre database of mapping studies. Studies were considered for inclusion if reporting original HSUVs assessed using established techniques. The characteristics of each study including country, design, sample size, cancer subsite addressed and demographics of responders were summarized narratively using a data extraction form. Quality scoring and critical appraisal of the included studies were performed based on published recommendations. RESULTS: Of a total 1048 records identified by the search, 28 studies qualified for data extraction and 346 unique HSUVs were retrieved from them. HSUVs were estimated using direct methods (e.g. standard gamble; n = 10 studies), multi-attribute utility instruments (MAUIs; n = 13) and mapping techniques (n = 3); two studies adopted both direct and indirect approaches. Within the MAUIs, the EuroQol 5-dimension questionnaire (EQ-5D) was the most frequently used (n = 11), followed by the Health Utility Index Mark 3 (HUI3; n = 2), the 15D (n = 2) and the Short Form-Six Dimension (SF-6D; n = 1). Different methods and types of responders (i.e. patients, healthy subjects, clinical experts) influenced the magnitude of HSUVs for comparable health states. Only one mapping study developed an original algorithm using head and neck cancer data. The identified studies were considered of intermediate quality. DISCUSSION: This review provides a dataset of HSUVs systematically retrieved from published studies in head and neck cancer. There is currently a lack of research for some disease phases including recurrent and metastatic cancer, and treatment-related complications. In selecting HSUVs for cost-effectiveness modeling purposes, preference should be given to EQ-5D utility values; however, mapping to EQ-5D is a potentially valuable technique that should be further developed in this cancer population.

Abrasion and blunt tissue trauma study of a novel flexible robotic system in the porcine model.

OBJECTIVES: The objective of this study was to determine if a flexible robotic system caused increased tissue reaction when accessing the oropharynx and hypopharynx compared to intubation controls in only 2 scenarios: high speed tissue impact and multiple unit insertions and retractions. The data obtained were submitted as part of the entirety of information submitted for FDA approval. METHODS: This study consisted of 5 groups of Yorkshire pigs (2 animals per group). On Day 0, all animals were intubated. For group 1 (control), a second endotracheal tube was advanced to just above the vocal cords. In abrasion groups 2 and 3, the flexible robotic system was advanced against the oropharyngeal and hypopharyngeal tissues, respectively. In blunt trauma groups 4 and 5, the flexible robotic system was advanced at maximum speed (22mm/s) to collide with oropharyngeal and hypopharyngeal tissues, respectively. Pre- and post-procedure endoscopic assessments of tissue reaction were performed daily for 4 days. An independent reviewer graded tissue reaction using a 0-3 point scale. RESULTS: Tissue reaction scores at each observation time point for all test groups were less than or equal to control scores except for one instance of moderate scoring (2 out of 3) on Day 2 for an animal in the blunt trauma group where reaction was likely intubation-related rather than device impact related. Otherwise, all flexible robotic system-treated animal scores were less than 1 by Day 4. CONCLUSIONS: In this limited study, the flexrobotic system afforded surgical access to the oropharynx and hypopharynx without an increased level of abrasion or tissue trauma when compared to intubation alone.

Illness perceptions and coping predict post-traumatic stress in caregivers of patients with head and neck cancer.

PURPOSE: There is evidence to suggest that caregivers of patients with head and neck cancer (HNC) are susceptible to post-traumatic stress disorder (PTSD) symptoms. The aim of this study was to investigate whether illness perceptions and coping strategies contribute to the development of these symptoms. METHODS: Seventy-eight caregivers completed questionnaires to assess distress, illness perceptions, and coping at diagnosis. Six months later, PTSD symptoms were assessed. Correlation and regression analyses were performed to examine relationships between illness perceptions and coping at diagnosis and PTSD symptoms at 6 months in 48 caregivers. RESULTS: Nineteen percent of caregivers met criteria for estimated PTSD caseness at 6-month follow-up. A regression analysis demonstrated that caregiver perceptions of low treatment benefit and many cancer symptoms, as well as use of avoidant coping techniques, predicted subsequent PTSD. CONCLUSIONS: This preliminary study suggests that caregivers who have perceptions of low benefits from treatment and many patient symptoms, and those using avoidant coping strategies, are at increased risk of experiencing symptoms of PTSD. Psychological interventions that target illness perceptions and coping may help to reduce the prevalence of PTSD in caregivers of patients with HNC.

Phase IV study on the use of benzydamine mouthwash in radiation-induced oral mucositis in patients with head and neck cancer.

Introduction: Oral mucositis (OM) is a main side effect of treatment for head and neck cancer (HNC) and causes severe pain, reduces quality of life, and may interrupt HNC treatment. This study assessed the activity and feasibility of benzydamine mouthwash in the prevention and treatment of radiation-induced OM in patients with HNC during radiation therapy (RT). Methods: This phase IV, international, open-label, single-group study conducted from December 2021 to September 2022. In total, 89 patients were enrolled across seven centers in Hungary and Poland. Patients used benzydamine mouthwash at home two to three times daily. Data were collected during clinical visits at baseline (V0, start of RT) and then weekly for seven visits (V1-V7). The safety population and the modified intention-to-treat (m-ITT) analysis sets contained 89 patients; the per protocol (PP) analysis set contained 67 patients. Results: The m-ITT set was 80.9% male; mean age was 61.4 years. At baseline, 73.0% of patients had stage T3-T4, 23.6% had stage T1-T2, 61.8% had stage N2-N3, and 34.9% had stage N0-N1. Within the m-ITT population, 33.7% (n=30) responded to treatment (NRS < 5) during the study. The PP set responded similarly (29.9%). Most patients were treatment compliant (n=77; 86.5%). OM severity was assessed using the WHO OM grading scale. No patients had severe mucositis at baseline or V1. At V7, 34.1% had mild mucositis, 45.1% had moderate mucositis, 15.9% had severe mucositis, and 1.2% had life-threatening mucositis. In total, 26 patients (29.2%) developed severe mucositis during the study period (V2-V7). From V1 to V4, one patient reported hospitalization due to mucositis or associated complications, two patients at V5, three patients at V6, and four patients at 7. Discussion: This was the first study to assess feasibility of a treatment for radiation-induced OM with benzydamine mouthwash in patients with HNC. Treatment compliance suggested that benzydamine was well tolerated in patients with moderate to severe mucositis. Benzydamine's anesthetic and anti-inflammatory properties might have reduced pain, which potentially influenced patients' compliance with RT. Few patients in the study required hospitalization for OM or an associated complication, suggesting that benzydamine might improve healthcare resource utilization.

A narrative review of oncologic emergencies in patients with head and neck cancers: initial management and the role of radiation therapy.

BACKGROUND AND OBJECTIVE: Head and neck cancers (HNCs) encompass a complex group of malignancies with high morbidity, often leading to critical emergencies such as pain crises, airway obstruction and hemorrhage. This review aims to outline an evidence-based approach to the multidisciplinary management of HNC oncologic emergencies with a focus on the role of emergent radiotherapy (RT). METHODS: A literature search was performed using Medline, Embase and the Cochrane Central Register of Controlled Trials databases with a focus on three common oncological emergencies using the following keywords: "head and neck cancer", "radiation OR radiotherapy", "pain", "bleeding OR haemorrhage", and "airway obstruction". All English language articles published up to April 2022 were screened to identify studies pertaining to the management of oncologic emergencies in HNC. KEY CONTENT AND FINDINGS: The management of oncologic emergencies in HNC present a unique set of challenges that require early recognition and aggressive treatment. In this narrative review, we summarize the evidence supporting the role of RT in the management of HNC patients presenting with pain crisis, malignant airway obstruction and acute haemorrhage. We demonstrate that while RT can be used as a primary or adjunct therapy, optimal management depends on the involvement of a multi-disciplinary team that includes head and neck surgeons, interventional radiology and palliative care. CONCLUSIONS: RT plays a critical role in the multidisciplinary management of HNC oncological emergencies. Further prospective and comparative studies are needed to assess optimal management strategies.

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

BACKGROUND: Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy. METHODS: Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy. RESULTS: PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period. CONCLUSION: Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Type I interferon signaling promotes radioresistance in head and neck cancer.

Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.

Phase I trials of single-agent new drugs in head and neck cancer: a scoping review.

BACKGROUND: The conventional method of drug development in oncology typically progresses through phase I, phase II and randomized phase III trials. Nevertheless, some recent drug approvals for head and neck cancer (HNC) relied on findings from single-arm phase II trials. This underscores the significance of disease-specific phase I trials as a crucial step in exploring new drugs for HNC patients. The purpose of this review is to present the currently available data of phase I clinical trials conducted in HNC and to provide an overview of ongoing therapeutic trends in HNC. METHODS: We performed a scoping review of phase I trials evaluating single-agent treatments specifically designed for HNC patients. The PubMed database was searched using "(phase I) AND (head and neck)". To ensure exhaustiveness, we also performed a search from the American Society of Clinical Oncology, European Society for Medical Oncology and American Association for Cancer Research websites. RESULTS: We screened 1,134 articles and selected 29 trials that met eligibility criteria, published between 1994 and 2023, for a total of 741 patients. Twenty-one trials comprised patients with different sites of HNSCC and only 8 trials (27%) focused on a specified subsite of head and neck. Most of trials investigated treatments in recurrent/metastatic (R/M) settings (86%). Immunotherapeutic agents were the most examined followed by targeted agents, cytotoxic drugs and "others" including a nanoparticle, a therapeutic gene, a fusion protein and a modulator of gene expression. Among trials reporting activity for R/M head and neck patients (n=23), the global median overall response rate (ORR) was 12% and four trials (17%) did not report any response. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was low (7%). However, in seven trials safety results are not clearly assessable from the published data. CONCLUSIONS: Phase I trials of single agents designed for head and neck patients were generally safe but with a low ORR. Future development of new drugs dedicated for HNC patients that can more accurately reflect the heterogeneity of HNC and provide more detailed subgroup analyses is warranted.