[Update: Epidemiology and Prevention of Oropharyngeal Cancer]. / Update: Epidemiologie und Prävention des Oropharynxkarzinoms.

Due to the association with the causal HPV-16 infection, the oropharyngeal carcinoma spreads into two separate entities depending on HPV-16 positivity. More recent data show a diversified picture of the importance and prevalence of the surrogate parameter p16 (discordance) for a definitive HPV-16 association, which varies worldwide. In the context of prevention options, vaccination is of major and HPV screening of healthy people only of little importance.

Connecting chronic stress and anxiety: a multi-dimensional perspective.

Studies show a connection between anxiety and stress, but with little differentiation between different domains of stress. In this article, we utilize a multi-dimensional approach to better understand the relationship between different chronic stress domains and anxiety. This will allow researchers to identify and address those areas of stress that are most relevant with regard to anxiety. We used data from a sub sample of the LIFE-Adult-Study (n = 1085) to analyze the association between nine different areas of chronic stress (Trier Inventory for Chronic Stress, TICS) and anxiety (General Anxiety Disorder 7, GAD-7), controlling for sociodemographic variables, personality, and social support. There was a significant and positive association between Work Overload, Pressure to Perform, Social Tensions, Social Isolation, Chronic Worrying, and anxiety. After including the control variables, only Work Overload and Chronic Worrying remained significant. By focusing on Work Overload and Chronic Worrying researchers, practitioners, and policy makers can help to mitigate anxiety and related health problems in the population in an efficient way.

[Frailty in Head and Neck Oncology]. / Frailty und ihre Bedeutung in der Kopf-Hals-Onkologie.

Since treatment of elderly patients with head and neck cancer is often challenging due to preexisting comorbidities, continuous efforts are required to raise awareness for frailty, which is a multidimensional state of diminished physiologic reserve resulting in decreased resiliency and increased vulnerability to stressors. Frailty is a predictor of poor clinical outcomes in head and neck cancer patients, but until now there is no standardization of frailty assessment. Pretherapeutic frailty assessment among head and neck cancer patients should be incorporated into routine multidisciplinary management to predict adverse outcomes and tailor a personalized treatment. This article would like to explain the complex syndrome frailty and its importance for head and neck oncology.

[Current Therapy Standards for Soft Tissue Sarcomas in the Head and Neck Area - Part 1]. / Weichgewebesarkome im Kopf-Hals-Bereich: Aktuelle Therapie ­ Teil 1.

The present work discusses soft tissue sarcoma in the head and neck area, due to the new published German S3-Guideline "adult soft tissue sarcoma". The head and neck surgeon plays the central role in the diagnosis and treatment of the vast majority of cases. It is crucial to admit the patients immediately to specialized centers for diagnoses and specific treatment. Regarding correct diagnostic procedures, in contrast to squamous cell carcinoma, a larger accidental excisional biopsy within the tumor tissue is strongly prognostic negative. After confirmation of histology and tumor extension, it is mandatory to discuss the interdisciplinary treatment concept. If possible, introduction of the patient in ongoing clinical studies is key.

[Current Therapy Standards for Soft Tissue Sarcomas in the Head and Neck Area - Part 2]. / Weichgewebesarkome im Kopf-Hals-Bereich: Aktuelle Therapie ­ Teil 2.

In September 2021, the first version of the German S3 guideline on adult soft tissue sarcomas, version 1.0 (AWMF register number 032/044OL) was presented as part of the oncology guideline program of the DKG, German Cancer Aid and the AWMF. After the basic features of soft tissue sarcomas were presented in Part 1, Part 2 describes the specific options for surgical therapy depending on the location in the head and neck area.

Dysphagia, voice problems, and pain in head and neck cancer patients.

PURPOSE: Head and neck cancer (HNC) and its treatment can leave devastating side effects with a relevant impact on physical and emotional quality of life (QoL) of HNC patients. The objectives were to examine the amount of dysphagia, voice problems, and pain in HNC patients, the impact of sociodemographic, behavioral, and clinical factors on these symptoms, the psychometric properties of the EAT-10, and the relationship between these symptoms and QoL variables. METHODS: HNC patients attending for regular follow-up from 07/2013 to 09/2019 completed questionnaires (Eating Assessment Tool-10 (EAT-10); questions from the EORTC QLQ-C30 and EORTC H&N35) on dysphagia, voice problems, pain, fatigue, and QoL collected with the software OncoFunction. Associations between prognostic factors and symptoms were tested with analyses of variance (ANOVAs). Associations between the symptom scales and QoL variables were expressed with Pearson correlations. RESULTS: Of 689 patients, 54.9% suffered from dysphagia, the EAT-10 proved to be a reliable measure. The mean voice score was 37.6 (± 33.9) [range 0-100], the mean pain score 1.98 (± 2.24) [range 0-10]. Trimodality treatment was associated with the highest dysphagia scores. Dysphagia, voice problems, and pain significantly correlated with each other, the highest association was found for dysphagia and pain (r = 0.51). QoL was strongly correlated with dysphagia and pain (r = - 0.39 and r = - 0.40, respectively), while the association with voice problems was weaker (r = - 0.28). CONCLUSION: Dysphagia is an important symptom in HNC patients greatly affecting patients' QoL and significantly correlating with voice problems and pain.

[Update Treatment HPV-16-positive Oropharyngeal Carcinoma]. / Update zur Therapie des HPV-16-positiven Oropharynxkarzinoms.

BACKGROUND: Oropharynx carcinoma (OPSCC) is a genetically heterogeneous tumor group with high prognostic diversity due to its worldwide increase in incidence and the association with the human papillomavirus HPV 16, but also chronic tobacco/alcohol consumption. OBJECTIVE: The review attempts to present the current view on therapy and prevention of OPSCC with respect to association with HPV 16. MATERIAL & METHODS: The overview is based on the current relevant literature as well as current studies. RESULTS & DISCUSSION: The OPSCC presents itself as a very complex, genetically heterogeneous group of head and neck tumors, which should therefore be considered in detail. The currently contradictory trial situation of retrospective studies versus prospective trials, the current TNM classification (8th edition) and the scarce prospective data arguing for non-inferiority of therapy de-intensification attempts currently admonish to encourage a more conservative treatment.

[Trials in head and neck cancer - Highlights of the ASCO Annual Meeting 2021]. / Therapiestudien zu Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2021.

The therapeutic options in head and neck oncology are rapidly developing, especially through the use of checkpoint inhibitors. Currently, numerous therapeutic studies with new molecular targets or new drug combinations are underway in patients with head and neck cancer. The most important results of the studies presented at the ASCO Annual Meeting 2021 on head and neck cancer will be presented in this paper.

[Immuno oncology treatment in head and neck cancer]. / Immunonkologie bei Kopf-Hals-Tumoren.

In the near future, immunotherapy with checkpoint inhibitors will not only reach the relevant ENT clinics, but also the oncologically integrated ENT practice, since more and more patients under long-term therapy (currently up to 2 years) also have to be seen during clinical follow-up in the specialist practice. In this respect, we also consider as necessary that the basics of immuno-oncology in head and neck tumors are already taught as part of the ENT specialist training. In this review article, the background and the definitions of the therapy sections (first, second line treatment, marker, etc.) should be discussed in detail and the basic tools for understanding this new therapy option should be provided. Since 2017, we have been experiencing a high level of approval dynamics for checkpoint inhibitors in Germany, which is to be assessed as an expression of a new effective principle of action and, after surgery, radiation and chemotherapy, is establishing a fourth strong pillar in the multimodal spectrum against head and neck tumors. Right from the start, the checkpoint inhibitors in the first phase 1b, 2 and 2b studies achieved overall response rates of 16-22 % with overall survival rates of 6-8 months in seriously ill patients with HNSCC who already had a first- and/or even second-line therapy. Nivolumab and Pembrolizumab are currently approved in Germany for the first and second line therapy of relapsed/metastatic squamous cell carcinoma of the head and neck region (HNSCC), Cemiplimab for recurrent/metastatic cutaneous squamous cell carcinoma and Avelumab for metastatic recurrent Merkel-cell carcinoma. The synopsis article about immune checkpoint inhibitors is intended to convey the basic understanding of the principle of action, the indication, toxicity management and the further development within trials in head and neck oncology.

Extracapsular extension of neck nodes and absence of human papillomavirus 16-DNA are predictors of impaired survival in p16-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinomas (OPSCCs) demonstrate superior outcome compared with HPV-negative OPSCCs. The eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, lymph node, metastasis (TNM) classification (TNM 2017) modifies OPSCC staging based on p16 positivity as a surrogate for HPV-driven disease. In p16-negative OPSCCs, lymph node (N) categories include extracapsular/extranodal extension (ECE); and, in p16-positive OPSCCs, N categories are based on the number of positive neck lymph nodes omitting ECE status. The objective of the current study was to assess the prognostic impact of positive ECE status and the detection of HPV16 DNA in patients with p16-positive OPSCC. METHODS: In a cohort of 92 patients with p16-positive, lymph node (N)-positive (stage III-IVB) OPSCC who underwent surgery and neck dissection, allowing for a pathologic examination of positive lymph nodes, 66 of 92 patients (71.4%) were p16-positive/HPV16 DNA-positive, 62 of 92 (67%) were ECE-positive, and 45 of 62 (72.6%) were ECE-positive, p16-positive, and HPV16 DNA-positive. Differences in outcome were assessed using Kaplan-Meier plots and Cox proportional hazard regression (CoxR) for tumor-specific survival and overall survival (OS). RESULTS: The mean numbers of positive lymph nodes in ECE-positive patients (5.0 positive lymph nodes; 95% CI, 3.8-6.4 positive lymph nodes) and ECE-negative patients (2.4 positive lymph nodes; 95% CI, 1.8-2.9 positive lymph nodes) were different (P = .0007). ECE affected OS and tumor-specific survival in p16-positive patients (P = .007 and P = .047, respectively) and in p16-positive/HPV16 DNA-positive patients (P = .013 and P = .026, respectively). Related to the unequal distributions of ECE-positive/HPV16 DNA-negative tumors, the TNM 2017 failed to discriminate OS in patients with UICC stage I, II, and III disease (mean OS, 54.5, 73.4, and 45 months, respectively; median OS, 64.7 months, not reached, and 41.1 months, respectively). According to a univariate CoxR, the presence of ECE predicted impaired OS in patients with p16-positive OPSCC (hazard ratio, 3.40; 95% CI, 1.17-9.89; P = .025) and even greater impaired OS in those with p16-positive/HPV16 DNA-positive OPSCC (HR, 8.64; 95% CI, 1.12-66.40; P = .038). Multivariate CoxR confirmed ECE and HPV16 DNA detection as independent predictors. CONCLUSIONS: ECE and HPV16 DNA status should be included in the prognostic staging of patients with p16-positive OPSCC because several lines of evidence demonstrate their impact on survival.

[Automatic calculation and visualization of comorbidity scores for decision-making in tumor boards]. / Automatisierte Berechnung und Visualisierung von Komorbiditätsindizes für den Tumorboard-Entscheid.

OBJECTIVE: Comorbidity reduces treatment options for patients with head and neck cancer (HNC). Utilization of ICD-10 codes instead of manual research may facilitate estimation of comorbidity relevant for decision-making in the interdisciplinary tumor board (TB). Providing this information immediately in an intuitively ascertainable way whenever registering a patient for the TB would trigger awareness for comorbidities and shows potentially missing information. MATERIAL AND METHODS: Administrative data was extracted of four databases at our clinic (hospital information system (HIS*-MED), the clinic's tumor database, OncoFlow® and OncoFunction®). After data extraction and record linkage facilitated by python libraries Pandas and Record linkage, ICD-10 codes were rated applying the Charlson Score and prepared for visualization within OncoFlow®. Coding quality was tested assessing the imported and manually researched diabetes status of a 1:1 matched cohort of 240 patients. RESULTS: 29 073 ICD-10 codes of 2087 HNC patients were extracted. Matched data are immediately made available whenever registering a patient for the TB and are visualized in a pictogram within OncoFlow® providing information about comorbidities and missing diagnostics. The precision of diagnostic coding at our clinic was 95.0 %. CONCLUSIONS: The high prevalence of comorbidities in HNC patients with impact on their eligibility for particular treatment indicates the usefulness of our algorithm for providing automatic comorbidity assessment from administrative data for clinical routine and requires high quality of coding diagnoses.

Patterns of antibody responses to nonviral cancer antigens in head and neck squamous cell carcinoma patients differ by human papillomavirus status.

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

Antibodies against human papillomaviruses as diagnostic and prognostic biomarker in patients with neck squamous cell carcinoma from unknown primary tumor.

Treatment of patients with neck lymph node metastasis of squamous cell carcinoma (SCC) from unknown primary tumor (NSCCUP) is challenging due to the risk of missing occult tumors or inducing toxicity to unaffected sites. Human papillomavirus (HPV) is a promising biomarker given its causal link to oropharyngeal SCC and superior survival of patients with HPV-driven oropharyngeal SCC and NSCCUP. Identification of HPV-driven NSCCUP could focus diagnostic work-up and treatment on the oropharynx. For the first time, we assessed HPV antibodies and their prognostic value in NSCCUP patients. Antibodies against E6 and E7 (HPV16/18/31/33/35), E1 and E2 (HPV16/18) were assessed in 46 NSCCUP patients in sera collected at diagnosis, and in follow-up sera from five patients. In 28 patients, HPV tumor status was determined using molecular markers (HPV DNA, mRNA and cellular p16INK4a ). Thirteen (28%) NSCCUP patients were HPV-seropositive for HPV16, 18, 31, or 33. Of eleven patients with HPV-driven NSCCUP, ten were HPV-seropositive, while all 17 patients with non-HPV-driven NSCCUP were HPV-seronegative, resulting in 91% sensitivity (95% CI: 59-100%) and 100% specificity (95% CI: 80-100%). HPV antibody levels decreased after curative treatment. Recurrence was associated with increasing levels in an individual case. HPV-seropositive patients had a better overall and progression-free survival with hazard ratios of 0.09 (95% CI: 0.01-0.42) and 0.03 (95% CI: 0.002-0.18), respectively. For the first time, seropositivity to HPV proteins is described in NSCCUP patients, and high sensitivity and specificity for HPV-driven NSCCUP are demonstrated. HPV seropositivity appears to be a reliable diagnostic and prognostic biomarker for patients with HPV-driven NSCCUP.

Rückkehr in das Erwerbsleben nach kurativer Therapie von Kopf-Hals-Karzinomen.

OBJECTIVE: Reintegration of cancer patients into occupational life is an important social and economic factor. Data for the "return to work" in Head and Neck Cancer (HNC) patients are sparse, especially compared with other tumor entities. MATERIAL AND METHODS: In a selective literature research, original articles dealing with the theme complex "return to work in patients with HNC", between 1997 and 2018 were included and analyzed. RESULTS: 18 relevant articles were identified. After curative therapy, 10-52 % of previously employed patients retired from their work. The influence of the predictors tumor localization, therapy modality and gender were not consistent. However, age, socioeconomic status, therapy-related impairment (e. g. fatigue, depression) and co-morbidity were significant factors for return to work. Rehabilitation exerts a positive effect. CONCLUSIONS: HNC patients have a high risk to retire from work. The heterogenous methods, the non-standardized points in time used for the assessments and inhomogeneous distribution in tumor localization make it difficult to compare these studies. There is an unmet need of further research in HNC patients to develop evidence-based concepts to facilitate their return to work.

Sensitivity and specificity of antibodies against HPV16 E6 and other early proteins for the detection of HPV16-driven oropharyngeal squamous cell carcinoma.

To determine the sensitivity and specificity of HPV16 serology as diagnostic marker for HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), 214 HNSCC patients from Germany and Italy with fresh-frozen tumor tissues and sera collected before treatment were included in this study. Hundred and twenty cancer cases were from the oropharynx and 94 were from head and neck cancer regions outside the oropharynx (45 oral cavity, 12 hypopharynx and 35 larynx). Serum antibodies to early (E1, E2, E6 and E7) and late (L1) HPV16 proteins were analyzed by multiplex serology and were compared to tumor HPV RNA status as the gold standard. A tumor was defined as HPV-driven in the presence of HPV16 DNA and HPV16 transformation-specific RNA transcript patterns (E6*I, E1∧ E4 and E1C). Of 120 OPSCC, 66 (55%) were HPV16-driven. HPV16 E6 seropositivity was the best predictor of HPV16-driven OPSCC (diagnostic accuracy 97% [95%CI 92-99%], Cohen's kappa 0.93 [95%CI 0.8-1.0]). Of the 66 HPV-driven OPSCC, 63 were HPV16 E6 seropositive, compared to only one (1.8%) among the 54 non-HPV-driven OPSCC, resulting in a sensitivity of 96% (95%CI 88-98) and a specificity of 98% (95%CI 90-100). Of 94 HNSCC outside the oropharynx, six (6%) were HPV16-driven. In these patients, HPV16 E6 seropositivity had lower sensitivity (50%, 95%CI 19-81), but was highly specific (100%, 95%CI 96-100). In conclusion, HPV16 E6 seropositivity appears to be a highly reliable diagnostic marker for HPV16-driven OPSCC with very high sensitivity and specificity, but might be less sensitive for HPV16-driven HNSCC outside the oropharynx.

Variation of HPV Subtypes with Focus on HPV-Infection and Cancer in the Head and Neck Region.

The human papillomavirus (HPV) comprises a heterogeneous group of double-strand DNA viruses with variable potential to infect human epithelial cells and trigger neoplastic transformation. Its 8 kb genome encodes proteins required for virus replication and self-organized formation of infectious particles but also for early proteins E6 and E7 able to trigger neoplastic transformation. E6 and E7 of high-risk (HR) HPV subtypes can bind to p53 or release E2F and abrogate replication control. Due to variable amino acid sequence (AAS) in the binding sites of E6 and E7 particular HR-HPV variants within subtypes are essentially heterogeneous in efficacy triggering neoplastic transformation and cancer development. This could explain differences in the clinical course of HPV-driven head and neck cancer.

Should We De-escalate the Treatment for HPV-Positive Tumors?

De-escalation or de-intensification of therapy is discussed since many retrospective analyses of former trials demonstrated significantly better outcome for patients suffering from p16/HPV16-positive oropharyngeal squamous cell carcinoma of head and neck (OHNSCC). These observations are comprehensively addressed, but the reader has to keep in mind that none of the currently discussed data result from prospective controlled trials addressing the HPV-discrimination in the primary endpoint design. Identification of the true HPV16-related tumors is still challenging and in addition with different clinical reports and lack of data of prospective trials not mature for routine clinical decision making in 2016. Independent of the currently lacking evidence for HPV-dependent treatment de-escalation, there are some relevant arguments to address this question in ongoing and future trials.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Cancer-associated financial burden in German head and neck cancer patients.

Background: The financial toxicity of cancer causes higher morbidity and mortality. As the financial burden due to head and neck cancer (HNC) in European healthcare systems with legally established compulsory health insurance is still poorly understood, we set up an investigation to assess the financial impact of HNC. Methods: Between August 2022 and March 2023, HNC consecutive patients (n = 209) attending the cancer aftercare program of a university hospital in an outpatient setting were surveyed utilizing self-administered questionnaires about their socioeconomic situation, income loss, and out-of-pocket payments (OOPPs). Results: The majority of HNC patients (n = 119, 59.5%) reported significant financial burden as a consequence of OOPP (n = 100, 50.0%) and/or income loss (n = 51, 25.5%). HNC patients reporting financial burden due to OOPP had on average 1,716 € per year costs related to their disease, whereas patients reporting an income loss had a mean monthly income loss of 620.53 €. Advanced UICC (7th edition, 2017) stage, T3 or T4 category, and larynx/hypopharynx cancer are significant predictors of financial burden. Conclusion: HNC survivors suffer from significant financial burden after HNC treatment, even in Germany with a healthcare system with statutory health insurance. The findings from this study offer valuable insights for healthcare professionals and policymakers, helping them acknowledge the economic impact of HNC.