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Background: Adding pembrolizumab, an anti-PD-1 antibody approved for treatment of head and neck squamous cell carcinoma (HNSCC) to neoadjuvant (induction-) chemotherapy utilizing docetaxel and cisplatin (TP) followed by radiotherapy may improve outcome in larynx organ-preservation (LOP) that is investigated in the European Larynx-Organ preservation Study (ELOS). As biomarkers for response to TP and pembrolizumab +TP are missing but may include cytokines, this work aims on determining cytokines potentially linked to outcome as prognostic markers sufficient to predict and/or monitor response to successful LOP. Methods: Collagenase IV digests were generated from 47 histopathological confirmed HNSCC tumor samples and seeded in 96-well plates containing pembrolizumab, docetaxel, cisplatin either solely or in binary or ternary combination. According to the FLAVINO protocol, supernatants were collected after 3 days, adherent cells fixed using ethanol, air-dried and pan-cytokeratin positive epithelial cells counted using fluorescence microscopy. The cytokines IL-6, IL-8, IFN-γ, IP-10, MCP-1, TNF-α, and VEGF in the supernatant were quantified by sandwich ELISA. Results: The mode of interaction between pembrolizumab and TP was assessed and correlated to outcome (overall, disease-specific and progression-free survival of patients). Suppression of MCP-1, IFN-γ and IL-6 production by pembrolizumab + TP exceeding the suppressive effect of TP was detected in the majority of samples and linked to improved survival. Multivariate Cox proportional hazard regression modeling revealed MCP-1, IFN-γ and IL-6 as independent outcome predictors. Conclusions: Comparing response to TP vs. pembrolizumab vs. TP + pembrolizumab may allow for identification of patients with superior outcome independent from treatment applied. [ABSTRACT FROM AUTHOR]

Introduction: The larynx organ preservation (LOP) trial DeLOS-II enrolled n = 173 patients with advanced laryngeal/hypopharyngeal squamous cell carcinoma (LHSCC) amenable (only curatively resectable) through total laryngectomy (TL) to receive induction chemotherapy (IC) with TPF [docetaxel (T), cisplatin (P), and 5-fluorouracil (F)] (arm A, 85 patients) or additional cetuximab (E) weekly (arm B, 88 patients). Responders with endoscopic estimated tumor surface shrinkage (ETSS) ≥30% after 1 cycle IC (IC-1) received a further two cycles of IC followed by radiotherapy (RT), whereas TL was recommended for non-responders. Arm B failed to show superior 24-month laryngectomy-free survival (LFS) and overall survival (OS), the protocol-specified primary and secondary endpoints. Ten years after the last per-protocol visit, we are interested in the long-term outcome of our clinic's DeLOS-II patients. Methods: Our cohort of 52 DeLOS-II patients accrued between 2007 and 2012 included 27 and 25 patients randomized to arms A and B, respectively. F was omitted because of severe toxicity with amendment 2 of the DeLOS-II protocol, leading to 21 and 31 patients receiving TPF and TP IC backbone, respectively. Follow-up data were collected using electronic health records and information from the German Centre for Cancer Registry Data to evaluate long-term LFS and OS in treatment groups. Results: According to ETSS ≥ 30%, 42 patients (80.8%; 21 and 21 corresponding to 77.8% and 84.0% in arms A and B, respectively) were responders to IC-1 and underwent the LOP attempt. Recommending early TL to non-responders (ETSS < 30%), eight patients (five and three in A and B, respectively) underwent early TL. At 125 months, 22 (eight and 14) patients were alive: 17 (six and 11) with a functioning larynx and five (two and three) without a larynx. Arm B had superior OS (p = 0.023). Disease-specific survival (DSS) and tumor-specific survival were not different, whereas non-cancer-related survival (NCRS) was impaired in arm A (p = 0.018). Receiving TP or TPF IC did not significantly influence survival. Pairwise comparing OS of patients receiving TP, TPF, TPE, and TPFE revealed a benefit from cetuximab in TPE vs. TP (p = 0.020). Conclusion: While the per-protocol DeLOS-II results earlier reported comparable 24-month LFS and OS in arms A and B, our subcohort's long-term follow-up data demonstrate a superior 125-month outcome in arm B. [ABSTRACT FROM AUTHOR]

The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS = 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) =30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70-72 Gy (EQD2/a/b = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic's multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL. [ABSTRACT FROM AUTHOR]

Background/Objectives: Laryngeal squamous cell carcinoma (LSCC) is among most frequent malignancies of the head and neck. Recent oncologic research focusses on advanced rather than on early stages. Thus, we aimed to improve the knowledge concerning prognostic factors and survival in early glottic (GC) and supraglottic cancer (SGC). Methods: We retrospectively investigated patients diagnosed in 2007 to 2020 with stage I or II GC (ICD-10-C32.0) or SGC (ICD-10-C32.1, C32.8 or C32.9). For precise discrimination of GC and SGC, pathology reports about biopsy and definitive excision were closely examined and information on clinical characteristics and risk factors were collected before analyzing patterns of risk factors for overall survival (OS) in multivariate Cox regression analyses (mvCox). Results: The cohort included 220 patients with early GC (n = 183) and SGC (n = 37). The GC patients showed significantly improved 5-year OS compared to SGC patients (83.6% vs. 64.9%; p = 0.004), whereas survival according to UICC stage (I vs. II) was not different (p = 0.177). Surgical resection was superior to definitive radiotherapy (RT) for 5-year OS (p < 0.001). Cumulative tobacco consumption of greater than 10 pack years drastically impaired OS (p = 0.024), especially in patients receiving RT (p < 0.001). Supraglottic localization, smoking, and re-resection after initial R1 status consistently were independent prognostic factors in mvCox. Conclusions: Our cohort of early LSCC patients demonstrates significant negative impact of supraglottic localization, older age, tobacco consumption, poor tumor differentiation, and re-resection on OS. Further research is required as there is still lack of evidence on optimal decision-making and therapeutic strategies. [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]

Frailty is an important risk factor for adverse events (AEs), especially in elderly patients. Therefore, assessing frailty before therapy is recommended. In head and neck squamous cell carcinoma (HNSCC) patients, frailty is prognostic for severe postoperative complications and declining quality of life (QoL) after HNSCC treatment. Thus, assessment of frailty may help to identify individuals at risk for AE caused by oncologic therapy. We investigated the relationship between frailty and symptom burden to better understand their interaction and impact on HNSCC patients. In this prospectively designed cross-sectional study, the presence of frailty and symptom burden was assessed by using the Geriatric 8 (G8) and Minimal Documentation System (MIDOS2) questionnaires. A total of 59 consecutively accrued patients with a first diagnosis of HNSCC before therapy were evaluated. Patients were considered frail at a total G8 score ≤ 14. The MIDOS2 symptom burden score was considered pathological with a total score ≥ 4 or any severe symptom (=3). Statistical correlations were analyzed using Spearman and Pearson correlation. Receiver operator characteristic (ROC) curves were used to analyze the potential of predicting frailty and MIDOS2. p-values < 0.05 were considered significant. A total of 41 patients (69.5%) were considered frail, and 27 patients (45.8%) had increased symptom burden. "Tiredness" was the most common (overall rate 57.8%) and "Pain" was the most often stated "severe" symptom (5 patients, 8.5%). G8 and MIDOS2 correlated significantly (ρ = −0.487, p < 0.001; r = −0.423, p < 0.001). Frailty can be predicted by MIDOS2 symptom score (AUC = 0.808, 95% CI 0.698–0.917, p < 0.001). Vice versa, the G8 score can predict pathological symptom burden according to MIDOS2 (AUC = 0.750, 95% CI 0.622–0.878, p < 0.001). Conclusions: The strong link between frailty and increased symptom burden assessed by G8 or MIDOS2 indicates a coherence of both risk factors in HNSCC patients. Considering at least one of both scores might improve the identification of individuals at risk and achieve higher QoL and reduced complication rates by decision making for appropriate therapy regimens. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)