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Introduction: Larynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing. Materials and Methods: We utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)- matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2. Results: The 52 DeLOS-II patients (whole intent-to-treat cohort) and three PSmatched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all p > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, p = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92-2.43), 1.49 (1.15-3.18), and 1.81 (1.11-2.96) for OS; and 2.07 (0.944-4.58), 3.02 (1.32-6.89), and 3.40 (1.58-7.31) for TSS. Conclusion: In addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Effective immune surveillance requires a functioning immune system and natural killer (NK) and T cells for adequate innate and antigenspecific immune responses critically depending on human leukocyte antigens (HLAs) and haplotypes representing advantageous combinations of HLA antigens. Recently, we reported a link between altered frequencies of HLA alleles and haplotypes and developing head and neck squamous cell carcinoma (HNSCC). Whereas the majority of HNSCCs seem to be related to classical risk factors alcohol and tobacco, a subset of HNSCC and especially oropharyngeal squamous cell carcinoma (OPSCC) were etiologically linked to human papillomavirus (HPV) recently. Here, we demonstrate in HPVdriven (p16-positive high risk-HPV DNA-positive) HNSCC a deviating distribution of HLA antigens and haplotypes and their relevance to outcome. Methods: Leukocyte DNA of n = 94 HPV-driven HNSCC patients (n = 57 OPSCC, n = 37 outside oropharynx) underwent HLA SSO typing, allowing allele, antigen (allele group), and haplo-typing. Besides comparing these frequencies with those of German blood donors, we analyzed their impact on outcome using Kaplan-Meier plots and Cox proportional hazard regression. Results: Antigen and haplotype frequencies demonstrate enrichment of rare antigens and haplotypes. The HLA score for unselected HNSCC patients was not predictive for outcome here. However, together with alcohol consumption, tobacco smoking, T category, and extranodal extension of locoregional metastases and treatment applied, eight HLA traits allow for predicting progression-free and tumor-specific survival. Conclusion: Patients can be categorized into low, intermediate-low, intermediate-high, and high risk groups. Using a new PFS risk score for HPV-driven HNSCC may allow to improve prognostication. [ABSTRACT FROM AUTHOR]

Background: Immune-checkpoint blockade (ICB) of programmed-death-1 (PD-1) with pembrolizumab or nivolumab is approved for treating recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). NadiHN and ADRISK are phase IIB trials investigating in locally advanced (LA) HNSCC having low or high risk of recurrence the potential benefits from adding nivolumab to post-operative radiotherapy or pembrolizumab to cisplatin based radio-chemotherapy. Methods: Along five randomized controlled ICB trials including NadiHN and ADRISK, blood samples were taken before and after starting ICB in n=25 patients. Concentrations of vascular endothelial growth factor A (VEGF), CCL2 (MCP-1), interleukin-6 (IL-6), IL-8, interferon-gamma (IFN-γ), and CXCL10 (IP-10) pre- and post-ICB in EDTA-anticoagulated plasma and serum were compared. We used receiver operating characteristic (ROC) curves to identify optimal cutoff for defining subgroups before analyzing overall survival (OS) applying Kaplan–Meier plots and multivariate Cox regression. Results: We detected huge heterogeneity between cytokine patterns in pre-and post-ICB plasma and serum. We observed high correlation between concentrations of some cytokines. Despite absent systematic OS differences after ICB with pembrolizumab or nivolumab or between LA-HNSCC versus R/M HNSCC patients, we noticed improved outcome of patients having lower IFN-γ concentrations pre- and post-ICB and following ICB reduced concentrations of VEGF, IL-6, and IL-8 but not MCP-1. Contrarily, increases in IL-6, IL-8, and VEGF levels correlated with impaired outcome. Multivariate Cox regression revealed five independent OS predictors among cytokines; using natural logarithms of their hazard ratios to estimate an individual’s risk of dying, three cytokine-expression pattern (CEP)-risk groups with no death within mean (95% confidence interval) follow-up of 29.2 (22.1–36.2) months and median OS of 11.3 (8.8–13.8) and 2.9 (0.4-5.4) months were found. Conclusion: Whereas individual pre- or post-ICB cytokine concentrations in serum or plasma alone failed to predict the survivor group, CEP-risk groups may support the identification of individual patients with long-lasting benefit from ICB. [ABSTRACT FROM AUTHOR]

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo) therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after upfront surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N=2) after surgery will be eligible. Two hun-dred forty patients will be randomly assigned (1:1) to either standard aRCT with cisplatin (standard arm) or aRCT with cisplatin + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months) (interventional arm). Endpoints are event-free and overall survival. Recruitment started in August 2018 and is ongoing. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to determine whether postoperative additive systemic steroid administration in chronic rhinosinusitis with nasal polyps (CRSwNP) impacted selected endoscopic, subjective and objective outcome measures. Methods: This was a prospective, randomized, double-blind, placebo-controlled, noninferiority multicenter trial of n=106 patients with CRSwNP. All patients underwent primary functional endoscopic sinus surgery (FESS) followed by topical nasal steroids. Patients were randomized to a systemic steroid or placebo for 1 month. Patients were followed up for 2 years over 9 time points. The primary outcome measures were the differences between groups with respect to the nasal polyp score (NPS) and sinonasal quality of life (SNQoL). Secondary outcome measures included interactions with respect to the Lund-Kennedy score (LKS), sinonasal symptoms, general quality of life (GQoL), 16-item odor identification test scores, recurrence rates, need for revision surgery and mucus biomarker levels. Results: 106 patients were randomized to either the placebo or the systemic steroid group (n=53 per group). Postoperative systemic steroids were not superior to placebo with respect to all primary (p= 0.077) and secondary outcome measures (p>0.05 for all). Reported adverse events were similar between the two groups. Conclusion: In conclusion, the addition of postoperative systemic steroids after primary FESS did not confer a benefit over topical steroid nasal spray alone with respect to NPS, SNQOL, LKS, GQOL, sinonasal symptoms, smell scores, recurrence rates, the need for revision surgery or biomarkers over a short-term follow-up of up to 9 months and a long-term follow-up of up to 24 months in CRSwNP patients. Functional endoscopic surgery did, however, show a strong effect on all outcome measures, which remained relatively stable up to the endpoint at 2 years. [ABSTRACT FROM AUTHOR]

This study compared oral health in oropharyngeal squamous cell carcinoma (OPSCC) patients with positive or negative human papillomavirus (HPV) status and analysed whether oral health was associated with survival. Patients referred for dental assessment prior to radio(chemo)therapy between 2009 and 2019 were included. Patient-related risk factors for OPSCC (alcohol, tobacco, HPV status), age, sex, treatment (primary treatment, intent), performance status, tumor/node/metastasis (TNM) staging, and oral health parameters (DMFT, periodontal status, teeth with/without root canal treatment and with/without periodontitis apicalis) were compared between HPV-negative and HPV-positive patients. Survival was assessed using Kaplan-Meier statistics. The effect of patient-related risk factors and oral health parameters was analysed by cox regression analyses (α=5%). A total of 119 patients (n=50 HPV-negative, n=69 HPV-positive) was included. HPV-positive patients showed more present teeth, a higher number of filled teeth, were less often edentulous and presented a lower DMFT compared to HPV-negative patients (padj.≤0.003). Among dentulous patients, HPV-positive patients showed more present teeth and fewer teeth with periodontitis apicalis lacking a root canal treatment (padj.≤0.036). Survival probability differed between groups (p=0.006) and trended towards being associated with HPV status, tobacco exposure, performance status, T stage, N stage, and the number of missing or filled teeth as well as the number of root canal treated teeth with periodontitis apicalis and the number of teeth with periodontitis apicalis lacking a root canal treatment (p≤0.077). However, only tobacco exposure, performance status, and the number of teeth with periodontitis apicalis lacking a root canal treatment in dentulous patients remained significant in the multivariate analyses (p≤0.047). HPV-negative patients with OPSCC showed a poorer oral health compared to HPV-positive patients, but survival was not associated with oral health. [ABSTRACT FROM AUTHOR]

Background: Pembrolizumab and cetuximab are antibodies under investigation in head and neck squamous cell carcinoma (HNSCC) either as single agents or combined with cisplatin and other chemotherapeutic drugs, e.g., 5-fluorouracil and/or docetaxel. However, also the combination of both antibodies may have potential in recurrent/metastatic (R/M) HNSCC, in particular in cisplatin-resistant or -refractory cases or patients with comorbid disease, e.g. patients with impaired renal function. Methods: To clarify potential benefit that may result from such combination, we used the FLAVINO assay, a short-time ex vivo assay to compare responsiveness of HNSCC to pembrolizumab, cetuximab and both combined regarding colony formation of epithelial cells of biopsy-derived tumor samples and their cytokine production within three days either without or with stimulation with 10 ng/mL interferon gamma (IFN-γ). Vascular endothelial growth factor A (VEGF), monocyte chemoattractant protein 1 (MCP-1 or CCL2), interleukin 6 (IL-6), IL-8, IFN-γ, and interferon gamma-induced protein 10 (IP-10 or CXCL10) in supernatants were measured by ELISA. Results: We detected huge heterogeneity in response to cetuximab, pembrolizumab and both combined with and without IFN-γ stimulation. Moreover, we detected a link between IFN-γ induced IP-10 release and improved outcome in those HNSCC patients who were capable to respond to IFN-γ and pembrolizumab, cetuximab and both combined with a further increase in IP-10 production. We derived an "IP-10 score" that independent from clinical characteristics of HNSCC patients and therapy regimens applied was able to predict their outcome. Conclusions: The heterogeneity in the ex vivo response of cetuximab, pembrolizumab and both combined with and without IFN-γ stimulation identifies subgroups of HNSCC patients with deviating OS. [ABSTRACT FROM AUTHOR]

Background: Standardized staging procedures and presentation of oral squamous cell carcinoma (OSCC) patients in multidisciplinary tumor boards (MDTB) before treatment and utilization of elective neck dissection (ND) are expected to improve the outcome, especially in local advanced LAOSCC (UICC stages III–IVB). As standardized diagnostics but also increased heterogeneity in treatment applied so far have not been demonstrated to improve outcome in LAOSCC, a retrospective study was initiated. Methods: As MDTB was introduced into clinical routine in 2007, 316 LAOSCC patients treated during 1991-2017 in our hospital were stratified into cohort 1 treated before (n =104) and cohort 2 since 2007 (n =212). Clinical characteristics, diagnostic procedures and treatment modality of patients were compared using Chi-square tests and outcome analyzed applying Kaplan-Meier plots and log-rank tests as well as Cox proportional hazard regression. Propensity scores (PS) were used to elucidate predictors for impaired distant metastasis-free survival (DMFS) in PS-matched patients. Results: Most patient characteristics and treatment modalities applied showed insignificant alteration. Surgical treatment included significantly more often resection of the primary tumor plus neck dissection, tracheostomy and percutaneous endoscopic gastrostomy tube use. Cisplatin-based chemo-radiotherapy was the most frequent. Only insignificant improved disease- (DFS), progression- (PFS) and event-free (EFS) as well as tumor-specific (TSS) and overall survival (OS) were found after 2006 as local (LC) and loco-regional control (LRC) were significantly improved but DMFS significantly impaired. Cox regression applied to PS-matched patients elucidated N3, belonging to cohort 2 and cisplatin-based chemo-radiotherapy as independent predictors for shortened DMFS. The along chemo-radiotherapy increased dexamethasone use in cohort 2 correlates with increased DM. Conclusions: Despite standardized diagnostic procedures, decision-making considering clear indications and improved therapy algorithms leading to improved LC and LRC, shortened DMFS hypothetically linked to increased dexamethasone use had a detrimental effect on TSS and OS. [ABSTRACT FROM AUTHOR]

Background: About five to 10% of cancers in the head and neck region are neck squamous cell carcinoma of unknown primary (NSCCUP). Their diagnosis and treatment are challenging given the risk of missing occult tumors and potential relapse. Recently, we described human papillomavirus (HPV)-related NSCCUP-patients (NSCCUP-P) as a subgroup with superior survival. However, standardized diagnostic workup, novel diagnostic procedures, decision-making in the multidisciplinary tumor board (MDTB) and multimodal therapy including surgery and post-operative radio-chemotherapy (PORCT) may also improve survival. Methods: For assessing the impact of standardized diagnostic processes simultaneously established with the MDTB on outcome, we split our sample of 115 NSCCUP-P into two cohorts treated with curative intent from 1988 to 2006 (cohort 1; n = 53) and 2007 to 2018 (cohort 2; n = 62). We compared diagnostic processes and utilized treatment modalities applying Chi-square tests, and outcome by Kaplan–Meier plots and Cox regression. Results: In cohort 2, the standardized processes (regular use of [18F]-FDG-PET-CT imaging followed by examination under anesthesia, EUA, bilateral tonsillectomy and neck dissection, ND, at least of the affected site) improved detection of primaries (P = 0.026) mostly located in the oropharynx (P = 0.001). From 66.0 to 87.1% increased ND frequency (P = 0.007) increased the detection of extracapsular extension of neck nodes (ECE+) forcing risk factor-adapted treatment by increased utilization of cisplatin-based PORCT that improved 5-years progression-free and overall survival from 60.4 and 45.3 to 67.7% (P = 0.411) and 66.1% (P = 0.025). Conclusions: Standardized diagnostic workup followed by ND and risk-factor adapted therapy improves survival of NSCCUP-P. [ABSTRACT FROM AUTHOR]

The disease and treatment of patients with head and neck cancer can lead to multiple late and long-term sequelae. Especially pain, psychosocial problems, and voice issues can have a high impact on patients' health-related quality of life. The aim was to show the feasibility of implementing an electronic Patient-Reported Outcome Measure (PROM) in patients with head and neck cancer (HNC). Driven by our department's intention to assess Patient-Reported Outcomes (PRO) based on the International Classification of Functioning during tumor aftercare, the program "OncoFunction" has been implemented and continuously refined in everyday practice. The new version of "OncoFunction" was evaluated by 20 head and neck surgeons and radiation oncologists in an interview. From 7/2013 until 7/2017, 846 patients completed the PROM during 2,833 of 3,610 total visits (78.5%). The latest software version implemented newly developed add-ins and increased the already high approval ratings in the evaluation as the number of errors and the time required decreased (6 vs. 0 errors, 1.35 vs. 0.95 min; p <0.01). Notably, patients had different requests using PRO in homecare use. An additional examination shows that only 59% of HNC patients use the world wide web. Using OncoFunction for online-recording and interpretation of PROM improved data acquisition in daily HNC patients' follow-up. An accessory timeline grants access to former consultations and their visualization supported and simplified structured examinations. This provides an easy-to-use representation of the patient's functional outcome supporting comprehensive aftercare, considering all aspects of the patient's life. [ABSTRACT FROM AUTHOR]

Patients treated for head and neck cancer (HNC) often suffer from severe and visible loss of function as the cancer itself and the side effects of aggressive treatments have the potential to severely affect quality of life. Therefore, the aim of follow-up is not only the early detection of potentially curable recurrences and second primary tumors but also the diagnosis and rehabilitation of functional impairments. Clear guidelines determining the frequency of follow-up visits are missing, and the impact of follow-up visits on patient's prognosis is unclear. An intensive post-treatment follow-up is needed to detect functional impairments and to initiate their treatment. The aim is an optimal rehabilitation of the patients. This article focusses on goals of aftercare treatment and describes the spectrum of long-term sequelae, and the impact of Patient Reported Outcome (PRO) instruments of which three will be introduced. [ABSTRACT FROM AUTHOR]

In the locoregional advanced group of larynx and hypopharyngeal squamous cell carcinomas (LHSCC), there are two kinds of patients: those who are candidates for functional larynx organ preservation (LP) by avoiding ablative surgery and those who are not. Currently, the distinction between them is depending on the patient's needs and desires, the experience and recommendation of the surgeon, the philosophy of the institution and others. The milestone VA trial established non-surgical LP in advanced LHSCC utilizing induction-chemotherapy (IC) with PF (cisplatin, P plus 5-fluorouracil, F) followed by irradiation (IC+RT) as appropriate alternative treatment to total laryngectomy (TL) already in the 1990s. Even thou the VA trial's findings were verified by the EORTC 24891 trial we have an ongoing debate about the best protocol balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options preserving the larynx, only IC+RT and primary concurrent chemo-radiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is still recommended as best protocol to achieve cure of the disease and LP. But current views on long term survival with functional organ preservation and still high failure rates are addressing the need of better selection of patients which will be discussed as follows taking the current debate in literature and in particular the recently published data of the DeLOS-II trial in consideration. [ABSTRACT FROM AUTHOR]

Induction chemotherapy (ICT) is an attractive option for advanced head and neck squamous cell carcinoma (HNSCC) patients which has been prospectively evaluated in the context of a multimodality treatment approach. The theoretical benefit is the ability to suppress distant metastases and shrink the tumor while chemotherapy is better tolerated when given sequentially than concurrently. However, clinical trials have failed to show consistent benefit of ICT over concurrent radio-chemotherapy and due to so far lacking level 1 evidence ICT outside larynx organ preservation remains rather investigational. Immune modulation by inhibition of immune checkpoints is an exciting recent development in HNSCC which has mainly been investigated as second line treatment after progression on platinum-based chemotherapy in patients with recurrent/metastatic HNSCC. Due to the promising results in these trials and even more in the first-line trial KEYNOTE-048 and encouraging first preliminary results of preoperative Anti-PD1-application, the role of neoadjuvant immunotherapy is currently under investigation in HNSCC. [ABSTRACT FROM AUTHOR]

Background: In personalized medicine and treatment stratification of head and neck squamous cell carcinoma (HNSCC), the heterogeneous genetic background of patients is not considered. Human leukocyte antigen (HLA) alleles and HLA haplotypes (HLA traits) are linked to development of HNSCC and affect progression-free survival (PFS) of HNSCC patients but most head and neck oncologists are not familiar with HLA typing. Hence, we developed an HLA-score abstracting from complexity of HLA-typing results tofacilitate potential use of HLA-associated hazard ratios (HR) for prognostic stratification. Methods: The HR for PFS of 8 HLA traits shown to be independent predictors (Pi) of PFS in a test cohort (TC) of 90 HNSCC patients were used to build the HLA-score based on the natural logarithm (ln) of the Pi-associated HR. Crude ln-transformed HR of the eight Pi, alleles B*13 (2), B*35 (1), B*51 (2), DQB1*06 (1), homozygous Cw (1), homozygous DRB4 (2), and haplotypes A*01/B*08 (-6) and B*08/C*07 (4), were summed up to yield the individual patient's HLA-score. Receiver operating characteristic (ROC) and Kaplan-Meier curves were used to proof the suitability of the HLA-score as prognostic marker for PFS. An independent validation cohort (iVC) of 32 patients treated in the larynx-organ preservation trial DeLOS-II was utilized for validation. Results: The individual HLA-scores (range -2 to 6) in TC classified HNSCC patients regarding PFS. ROC analysis (area under the curve = 0.750, 95% CI 0.665-0.836; P = 0.0000034) demonstrated an optimum cutoff for the HLA-score at 0.5 (97.9% sensitivity, 34.7% specificity), and 70/90 patients in TC with HLA-score > 0 had significant reduced PFS (P = 0.001). Applying the same classifier (HLA-score > 0) confirmed these findings in the iVC revealing reduced PFS of 25/32 patients (P = 0.040). Conclusion: HLA traits constitute critical Pi. Considering the HLA-score may potentially facilitate the use of genetic information from HLA typing for prognostic stratification, e.g., within clinical trials. [ABSTRACT FROM AUTHOR]