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Opinion Statement The main purpose of the TNM system is to provide an anatomic-based classification to adequately depict cancer prognosis. Accurate cancer staging is important for treatment selection and outcome prediction, research design, and cancer control activities. To maintain clinical relevance, periodical updates to TNM are necessary. The recently published 8th edition TNM classification institutes the following changes to the staging of head and neck (excluding thyroid cancer): new stage classifications [HPV-related oropharyngeal cancer (HPV+ OPC) and soft tissue sarcoma of the head and neck (HN-STS)] and modification of T and N categories [T and N categories for nasopharyngeal cancer (NPC), T categories for oral cavity squamous cell carcinomas (OSCC), N categories for non-viral related head and neck cancer and unknown primary (CUP), and T categories for head and neck cutaneous carcinoma]. These changes reflect better understanding tumor biology and clinical behavior (e.g., HPV+ OPC and HN-STS), improved outcomes associated with technical advances in diagnosis and treatment (e.g., NPC), evolving knowledge about additional prognostic factors and risk stratification from research and observation (e.g., inclusion of depth of invasion variable for OSCC, inclusion of extranodal extension variable for all non-viral head and neck cancer, and reintroduction of size criteria for non-Merkel cell cutaneous carcinoma of the head and neck). This review summarizes the changes and potential advantages and limitations/caveats associated with them. Further evidence is needed to evaluate whether these changes would result in improvement in TNM stage performance to better serve the needs for clinical care, research, and cancer control.

Opinion statementTaste sensation is vital for a healthy body as it influences our food intake, acts as a defense mechanism and elicits pleasure. Majority of the head and neck cancer (HNC) patients undergoing radiotherapy suffer from altered taste function and often complain of inability to taste their food, reduced food intake, and weakness. However, there are not many studies conducted to assess this commonly reported side effect. Furthermore, clinical research on radiotherapy-induced taste alterations has proven to be difficult, considering a lack of reliable and validated study tools for assessing objective and subjective outcomes. Developing standardized tools for assessment of taste function and conducting prospective studies in larger population of HNC is the need of the hour. Taste sensation being critically important for sustenance, we need to focus on ways to preserve it. The physical properties of proton particle enable localization of the radiation dose precisely to the tumor and minimizing the exposure of the adjacent healthy tissues. By using Intensity-Modulated Proton Therapy in HNC patients, we anticipate preserving the taste sensation by reducing the dose of radiation to the taste buds.

SummaryPurpose Vorinostat is a potent HDAC inhibitor that sensitizes head and neck squamous cell carcinoma (HNSCC) to cytotoxic therapy while sparing normal epithelium. The primary objective of this Phase I study was to determine the maximally tolerated dose (MTD) and safety of Vorinostat in combination with standard chemoradiation therapy treatment in HNSCC. Patients and Methods Eligible patients had pathologically confirmed Stage III, IVa, IVb HNSCC, that was unresectable or borderline resectable involving the larynx, hypopharynx, nasopharynx, and oropharynx. Vorinostat was administered at the assigned dosage level (100-400 mg, three times weekly) in a standard 3 + 3 dose escalation design. Vorinostat therapy began 1 week prior to initiation of standard, concurrent chemoradiation therapy and continued during the entire course of therapy. Results Twenty six patients met eligibility criteria and completed the entire protocol. The primary tumor sites included tonsil (12), base of tongue (9), posterior pharyngeal wall (1), larynx (4) and hypopharynx (3). Of the 26 patients, 17 were HPV-positive and 9 were HPV-negative. The MTD of Vorinostat was 300 mg administered every other day. Anemia (n = 23/26) and leukopenia (n = 20/26) were the most commonly identified toxicities. The most common Grade3/4 events included leukopenia (n = 11) and lymphopenia (n = 17). No patient had Grade IV mucositis, dermatitis or xerostomia. The median follow time was 33.8 months (range 1.6–82.9 months). Twenty four of 26 (96.2%) patients had a complete response to therapy. Conclusion Vorinostat in combination with concurrent chemoradiation therapy is a safe and highly effective treatment regimen in HNSCC. There was a high rate of complete response to therapy with toxicity rates comparable, if not favorable to existing therapies. Further investigation in Phase II and III trials is strongly recommended.

Opinion statement Human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.

Opinion statement Significant advancements have been made in the treatment of locally advanced head and neck cancer, predominantly driven by the integration of concurrent chemotherapy with radiation therapy as a standard of care for many patients. The most heavily investigated chemotherapeutic is cisplatin, yet many patients are ineligible for cisplatin due to the presence of pre-existing medical comorbidities. Moreover, given the toxicity profile of cisplatin, identifying which patients stand to benefit from cisplatin is challenging, which is particularly evident in older patients. Efforts to better risk-stratify patients based on age, performance status, and the degree of pre-existing comorbidities are ongoing and have been increasingly utilized in national clinical trials. In parallel, exploration into alternative systemic agents, including novel targeted therapies and immunotherapies, in cisplatin-ineligible patients are rapidly expanding. Cumulatively, identifying appropriate treatment paradigms in patients who harbor contraindications to cisplatin can not only improve clinical outcomes but also critically mitigate detrimental adverse effects.

Oral mucositis (OM) causes significant detriment to patient quality of life. Despite advances in RT, chemotherapy, and surgery for HNC which have led to improved local control and survival, management of certain toxicities such as OM have not kept pace. Numerous strategies have emerged with demonstrable benefit in preventing severe OM. However, ones which are not only effective, but practical and affordable to implement are rare. For example, infusion of growth factors or free radical scavengers, and daily treatment of intra-oral sites with lasers are supported by high-quality evidence but have not become widely adopted. It falls to familiarity of the physician with the available preventative measures and ultimately, patient preference in accepting which strategies for OM amelioration are used. In this review, we present a pathophysiological-based review of prevention techniques available for reducing the incidence and duration of severe OM.

Purpose Deep learning–based knowledge‐based planning (KBP) methods have been introduced for radiotherapy dose distribution prediction to reduce the planning time and maintain consistent high‐quality plans. This paper presents a novel KBP model using an attention‐gating mechanism and a three‐dimensional (3D) U‐Net for intensity‐modulated radiation therapy (IMRT) 3D dose distribution prediction in head‐and‐neck cancer. Methods A total of 340 head‐and‐neck cancer plans, representing the OpenKBP—2020 AAPM Grand Challenge data set, were used in this study. All patients were treated with the IMRT technique and a dose prescription of 70 Gy. The data set was randomly divided into 64%/16%/20% as training/validation/testing cohorts. An attention‐gated 3D U‐Net architecture model was developed to predict full 3D dose distribution. The developed model was trained using the mean‐squared error loss function, Adam optimization algorithm, a learning rate of 0.001, 120 epochs, and batch size of 4. In addition, a baseline U‐Net model was also similarly trained for comparison. The model performance was evaluated on the testing data set by comparing the generated dose distributions against the ground‐truth dose distributions using dose statistics and clinical dosimetric indices. Its performance was also compared to the baseline model and the reported results of other deep learning‐based dose prediction models. Results The proposed attention‐gated 3D U‐Net model showed high capability in accurately predicting 3D dose distributions that closely replicated the ground‐truth dose distributions of 68 plans in the test set. The average value of the mean absolute dose error was 2.972 ± 1.220 Gy (vs. 2.920 ± 1.476 Gy for a baseline U‐Net) in the brainstem, 4.243 ± 1.791 Gy (vs. 4.530 ± 2.295 Gy for a baseline U‐Net) in the left parotid, 4.622 ± 1.975 Gy (vs. 4.223 ± 1.816 Gy for a baseline U‐Net) in the right parotid, 3.346 ± 1.198 Gy (vs. 2.958 ± 0.888 Gy for a baseline U‐Net) in the spinal cord, 6.582 ± 3.748 Gy (vs. 5.114 ± 2.098 Gy for a baseline U‐Net) in the esophagus, 4.756 ± 1.560 Gy (vs. 4.992 ± 2.030 Gy for a baseline U‐Net) in the mandible, 4.501 ± 1.784 Gy (vs. 4.925 ± 2.347 Gy for a baseline U‐Net) in the larynx, 2.494 ± 0.953 Gy (vs. 2.648 ± 1.247 Gy for a baseline U‐Net) in the PTV_70, and 2.432 ± 2.272 Gy (vs. 2.811 ± 2.896 Gy for a baseline U‐Net) in the body contour. The average difference in predicting the D99 value for the targets (PTV_70, PTV_63, and PTV_56) was 2.50 ± 1.77 Gy. For the organs at risk, the average difference in predicting the Dmax ${D_{max}}$(brainstem, spinal cord, and mandible) and Dmean ${D_{mean}}$(left parotid, right parotid, esophagus, and larynx) values was 1.43 ± 1.01 and 2.44 ± 1.73 Gy, respectively. The average value of the homogeneity index was 7.99 ± 1.45 for the predicted plans versus 5.74 ± 2.95 for the ground‐truth plans, whereas the average value of the conformity index was 0.63 ± 0.17 for the predicted plans versus 0.89 ± 0.19 for the ground‐truth plans. The proposed model needs less than 5 s to predict a full 3D dose distribution of 64 × 64 × 64 voxels for a new patient that is sufficient for real‐time applications. Conclusions The attention‐gated 3D U‐Net model demonstrated a capability in predicting accurate 3D dose distributions for head‐and‐neck IMRT plans with consistent quality. The prediction performance of the proposed model was overall superior to a baseline standard U‐Net model, and it was also competitive to the performance of the best state‐of‐the‐art dose prediction method reported in the literature. The proposed model could be used to obtain dose distributions for decision‐making before planning, quality assurance of planning, and guiding‐automated planning for improved plan consistency, quality, and planning efficiency.

PurposeCancer stem cells (CSCs) are held accountable for the progress of head and neck squamous cell carcinoma (HNSCC). In the presented study, the authors evaluated the prognostic value of CSC markers in two particular HNSCC cohorts.MethodsThis two cohort study consisted of 85 patients with advanced stage HNSCC, treated with primary radio(chemo)therapy (pRCT), and 95 patients with HNSCC, treated with surgery and partially adjuvant radio(chemo)therapy. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were assessed. Samples were assessed for the expression of different molecular stem cell markers (ALDH1, BCL11B, BMI‑1, and CD44).ResultsIn the pRCT cohort, none of the baseline patient and tumor features exhibited a statistically significant relation with survival in either the cohort or the human papillomavirus (HPV)-stratified subcohorts. High expression of BMI‑1 significantly decreased OS and DFS, while high expression of CD44 decreased all modes of survival. Multivariate analysis showed significant prognostic influence for all tested CSC markers, with high BMI‑1 and CD44 decreasing survival (BMI-1: OS, DFS, DSS; CD44: OS, DFS) and high ALDH1 and BCL11B showing a beneficial effect on survival (ALDH1: OS, DFS; BCL11B: OS, DSS). In the surgical cohort, classical prognosticators such as HPV status, R1 resection, and nodal status in HPV-negative HNSCC played a significant role, but the tested CSC markers showed no significant effect on prognosis.ConclusionAlthough validation in independent cohorts is still needed, testing for CSC markers in patients with advanced or late stage HNSCC might be beneficial, especially if many comorbidities exist or disease is irresectable. The findings might guide the development and earlier use of targeted therapies in the future.

Sarcopenia is associated with reduced survival and increased toxicity in malignant diseases. The prevalence of sarcopenia increases with age and is an important cause of functional decline. We analyzed sarcopenia and sarcopenia dynamics in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiation. Skeletal muscle mass of 280 elderly HNSCC-patients (>65 yrs) receiving curative (chemo)radiation was manually outlined and quantified on CT scans at the level of the C3 (C3MA). Cross-sectional muscle area at L3 (L3MA) was calculated and normalized to height (L3MI). Frequency distributions of clinical parameters as well as overall survival (OS), progression-free survival (PFS) and locoregional control (LRC) were calculated regarding sarcopenia. Calculated L3MA correlated with pretherapeutic hemoglobin-levels (ρ = 0.280) bodyweight (ρ = 0.702) and inversely with patient-age (ρ = −0.290). Sarcopenic patients featured larger tumors (T3/4 69.0% vs. 52.8%, p < 0.001), a higher burden of comorbidity (age-adjusted Charlson Comorbidity Index 4.8 vs. 4.2, p = 0.015) and more severe chronic toxicities (CTCAE grade 3/4 24.0% vs. 11.8%, p = 0.022). OS was significantly deteriorated in sarcopenic patients with a median of 23 vs. 91 months (logrank p = 0.002) (HR 1.79, CI 1.22–2.60, p = 0.003) and sarcopenia remained an independent prognostic factor for reduced OS in the multivariate analysis (HR 1.64, CI 1.07–2.52, p = 0.023). After therapy, 33% of previously non-sarcopenic patients developed sarcopenia, while 97% of pre-treatment sarcopenic remained sarcopenic. Median bodyweight decreased by 6.8%, whereas median calculated L3MA decreased by 2.4%. In contrast to pretherapeutic, post-therapeutic sarcopenia is no prognosticator for reduced OS. Pretherapeutic sarcopenia is a significant prognostic factor in elderly HNSCC patients undergoing (chemo-)radiation and should be considered in pretherapeutic decision-making. Its role as a predictive marker for tailored supportive interventions merits further prospective evaluation.

The demographics of head and neck cancer (HNC) survivors are changing, contributing to a growing number of survivors and a greater length of survivorship. Curative treatment involves intense multimodal therapy, which contributes to both short-term toxicities and long-term treatment-related effects. Delivering high-quality, relevant cancer survivorship care is a growing national priority. Various survivorship models and tools, such as survivorship care plans, have been utilized in an attempt to enhance care and optimize outcomes. However, an essential, yet understudied, component of high-quality survivorship care is the identification and management of late and long-term treatment-related effects. In this article, we will describe the current advancements in survivorship care as well as the research related to late and long-term treatment effects. While there is a growing body of literature that describes the prevalence of treatment-related effects and their impact on quality of life, more work is needed. Research that investigates the interplay of these complex treatment effects, the biological mechanisms that contribute to their variability, and interventions designed to mitigate them are desperately needed. While de-intensification offers the potential to alleviate these effects for future survivors, we need clinically meaningful assessment tools and therapies to provide the survivors we evaluate and treat daily. Targeted patient-reported outcomes and objective measures validated through clinical research are needed to help us systematically identify and treat late and long-term effects. In order to tailor and optimize the care we provide to our HNC survivors, we will need to leverage these tools as well as the expertise of all members of our multidisciplinary survivorship teams.