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Background: Management of patients with head and neck cancer of unknown primary (HNCUP) is challenging., Aims/objectives: To provide a long-term analysis focusing on protective survival factors for clinical decision-making. Furthermore, the prognostic value of the current N classification system was evaluated., Material and Methods: We retrospectively analyzed patients with HNCUP between 2003 and 2016. Univariate and multivariate analyses were used to investigate predictors of overall survival (OS)., Results: A primary tumor was found in 67 of 290 patients with suspected HNCUP, leaving after exclusion 141 HNCUP cases for analysis, who received multi-step therapy (MST) ( n  = 108) or single therapy ( n  = 28). Chemotherapy (CT) ( n  = 101), curative MST, ≤3 positive lymph nodes (LN) ( n  = 33), squamous cell carcinoma (SCC) ( n  = 123), HPV+ ( n  = 21), M0 ( n  = 70) increased OS by 21.8%, 24.4%, 12.7%, 6.8%, 18.7%, 29.6%, respectively. 5- and 10-year OS was 78.1%/66.6%. The number of metastatic LNs predicted OS is better than N classification., Conclusion and Significance: Aspects for clinical decision-making: Curative MST and SCC histology were the most significant predictors for improved OS. Categorizing LN into 1, 2-3, and >3 LNs was more significant than the traditional N classification. The addition of CT to curative MST has a stronger impact on survival than HPV and N classifications.

Aim: In the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy., Methods: Patients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3-14 days before (pre-ICIT) and 21-28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu)., Results: Thirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value., Conclusion: FDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value., Trial Registry: ClinicalTrials.gov identifier: NCT03426657., (© 2022. The Author(s).)

Purpose: The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed., Methods: Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%., Results: Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%)., Conclusions: The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS., Trial Registration Number: The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST)., Competing Interests: Competing interests: MH conflict of interest with Merck Serono (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); MSD (advisory role, speakers’ bureau, honoraria, travel expenses, research funding); AstraZeneca (research funding); Novartis (research funding); BMS (advisory role, honoraria, speakers’ bureau); Teva (travel expenses). ME conflict of interest with Diaceutics (employment, honoraria, advisory role, speakers’ bureau, travel expenses); Cepheid (research funding, advisory role); AstraZeneca (honoraria, advisory role, speakers’ bureau, travel expenses); Roche (honoraria, travel expenses); MSD (honoraria, speakers’ bureau); GenomicHealth (honoraria, advisory role, speakers bureau, travel expenses); Astellas (honoraria, speakers’ bureau); Janssen-Cilag (honoraria, advisory role, research funding, travel expenses); Stratifyer (research funding, patents). SR conflict of interest with AstraZeneca (research funding); MSD (research funding). GK conflict of interest with BMS (advisory role); Lilly (advisory role); Roche (advisory role). SL conflict of interest with AstraZeneca (honoraria, advisory role); BMS (honoraria, advisory role, speakers’ bureau); MSD (honoraria, advisory role); Merck Serono (honoraria, speakers’ bureau); ISA-Pharmaceuticals (research funding). MGH conflict of interest with Roche (stock); Varian (stock); Sanofi (stock); AstraZeneca (honoraria); BMS (honoraria, advisory role); MSD (honoraria, advisory role); Merck Serono (honoraria); Celgene (honoraria). AHi conflict of interest with Roche (honoraria). SS conflict of interest with Strycker (stock); Varian (stock); Abbot (stock); Crispr Techn. (stock); Pfitzer (stock); Merck Serono (stock); Symrise (stock); Ortho (honoraria, advisory role, speakers’ bureau, research funding, travel expenses); PharmaMar (speakers’ bureau, travel expenses); Haema (speakers’ bureau). AHa. conflict of interest with BMS (honoraria, advisory role); MSD (honoraria, advisory role); Roche (honoraria, advisory role, research funding); AstraZeneca (honoraria, advisory role, research funding); Boehringer Ingelheim (honoraria); Abbvie (honoraria); Cepheid (advisory role, research funding); Quiagen (advisory role); Janssen-Cilag (honoraria, advisory role, research funding); Ipsen (honoraria, advisory role); NanoString Technologies (advisory role, research funding, expert testimony); Illumina (advisory role); 3DHistech (advisory role); Diaceutics (advisory role); BioNTech (research funding). WB conflict of interest with BMS (advisory role); MSD (advisory role); Merck Serono (advisory role); Pfitzer (advisory role); AstraZeneca (advisory role). UG conflict of interest with AstraZeneca (advisory role, research funding); BMS (advisory role); MSD (research funding); Sennewald Medizintechnik (advisory role, travel expenses). RF conflict of interest with MSD (honoraria, advisory role, research funding, travel expenses); Fresenius (honoraria); BrainLab (honoraria); AstraZeneca (honoraria, advisory role, research funding, travel expenses); Merck Serono (advisory role, research funding, travel expenses); Novocure (advisory role, speakers’ bureau, research funding); Sennewald (speakers’ bureau, travel expenses). The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In contrast to head and neck squamous cell carcinoma (HNSCC), the effect of treatment duration in HNSCC-CUP has not been thoroughly investigated. Thus, this study aimed to assess the impact of the time interval between surgery and adjuvant therapy on the oncologic outcome, in particular the 5-year overall survival rate (OS), in advanced stage, HPV-negative CUPs at a tertiary referral hospital. 5-year disease specific survival rate (DSS) and progression free survival rate (PFS) are defined as secondary objectives., Material and Methods: Between January 1st, 2007, and March 31st, 2020 a total of 131 patients with CUP were treated. Out of these, 59 patients with a confirmed negative p16 analysis were referred to a so-called CUP-panendoscopy with simultaneous unilateral neck dissection followed by adjuvant therapy. The cut-off between tumor removal and delivery of adjuvant therapy was set at the median, i.e. patients receiving adjuvant therapy below or above the median time interval., Results: Depending on the median time interval of 55 days (d) (95% CI 51.42-84.52), 30 patients received adjuvant therapy within 55 d (mean 41.69 d, SD = 9.03) after surgery in contrast to 29 patients at least after 55 d (mean 73.21 d, SD = 19.16). All patients involved in the study were diagnosed in advanced tumor stages UICC III (n = 4; 6.8%), IVA (n = 27; 45.8%) and IVB (n = 28; 47.5%). Every patient was treated with curative neck dissection. Adjuvant chemo (immune) radiation was performed in 55 patients (93.2%), 4 patients (6.8%) underwent adjuvant radiation only. The mean follow-up time was 43.6 months (SD = 36.7 months). The 5-year OS rate for all patients involved was 71% (95% CI 0.55-0.86). For those patients receiving adjuvant therapy within 55 d (77, 95% CI 0.48-1.06) the OS rate was higher, yet not significantly different from those with delayed treatment (64, 95% CI 0.42-0.80; X 2 (1)  = 1.16, p = 0.281). Regarding all patients, the 5-year DSS rate was 86% (95% CI 0.75-0.96). Patients submitted to adjuvant treatment in less than 55 d the DSS rate was 95% (95% CI 0.89-1.01) compared to patients submitted to adjuvant treatment equal or later than 55 d (76% (95% CI 0.57-0.95; X 2 (1)  = 2.32, p = 0.128). The 5-year PFS rate of the entire cohort was 72% (95% CI 0.59-0.85). In the group < 55 d the PFS rate was 78% (95% CI 0.63-0.94) and thus not significantly different from 65% (95% CI 0.45-0.85) of the group ≥55 d; (X 2 (1)  = 0.29, p = 0.589)., Conclusions: The results presented suggest that the oncologic outcome of patients with advanced, HPV-negative CUP of the head and neck was not significantly affected by a prolonged period between surgery and adjuvant therapy. Nevertheless, oncologic outcome tends to be superior for early adjuvant therapy., (© 2021. The Author(s).)

Background: There is a large lack of evidence for optimal treatment in oligometastatic head and neck cancer and it is especially unclear which patients benefit from radical local treatment of all tumour sites., Methods: 40 patients with newly diagnosed oligometastatic head and neck cancer received radical local treatment of all tumour sites from 14.02.2008 to 24.08.2018. Primary endpoint was overall survival. Time to occurrence of new distant metastases and local control were evaluated as secondary endpoints as well as prognostic factors in univariate und multivariate Cox's regression analysis. To investigate the impact of total tumour volume on survival, all tumour sites were segmented on baseline imaging., Results: Radical local treatment included radiotherapy in 90% of patients, surgery in 25% and radiofrequency ablation in 3%. Median overall survival from first diagnosis of oligometastatic disease was 23.0 months, 2-year survival was 48%, 3-year survival was 37%, 4-year survival was 24% and 5-year survival was 16%. Median time to occurrence of new distant metastases was 11.6 months with freedom from new metastases showing a tail pattern after 3 years of follow-up (22% at 3, 4- and 5-years post-treatment). In multivariate analysis, better ECOG status, absence of bone and brain metastases and lower total tumour volume were significantly associated with improved survival, whereas the number of metastases and involved organ sites was not., Conclusions: Radical local treatment in oligometastatic head and neck cancer shows promising outcomes and needs to be further pursued. Patients with good performance status, absence of brain and bone metastases and low total tumour volume were identified as optimal candidates for radical local treatment in oligometastatic head and neck cancer and should be considered for selection in future prospective trials.

Objectives: There exist no uniform decision criteria for conservative organ preservation treatments in head and neck cancer patients. Even with 18 F-FDG-PET/CT after induction chemotherapy patient selection is challenging. This study correlated metabolic tumor response with treatment types and recurrence patterns., Materials and Methods: Decrease in SUVmax in 18 F-FDG-PET/CT was measured 21-28 days after IC-1 in 102 patients and correlated to cancer-specific endpoints., Results: Residual SUVmax (resSUVmax) values were uniformly distributed across five cut-off levels (0-0.2 vs. >0.2-0.4 vs. >0.4-0.6 vs. >0.6-0.8 vs. >0.8) containing 20%, 25% 25%, 15% and 15% of patients. Patients were stratified into three response categories according to residual SUVmax (Group A: 0-0.4 = high response Group B: >0.4-0.8 = moderate response, Group C > 0.8 = non-response), 5-year local control rates were 90.5% (Group A) vs. 78.9% (Group B; univariate p = 0.07, multivariate: HR: 3.6, p = 0.03) vs. 49.4% (Group C vs. B; univariate p = 0.04, multivariate: HR 5.5, p < 0.01). After IC-1, Group A received chemoradiotherapy (CRT) only. Group B received surgery plus either (chemo)radiotherapy (B&#95;S + RT/CRT) or chemoradiotherapy (B&#95;CRT), yielding local control rates of 100% and 74.2% (p = 0.11). Group C received surgery plus CRT or CRT alone; both achieved equally poor local control (p = 0.71). Group C had significantly worse distant metastasis-free survival and overall survival than Groups A and B (p < 0.05)., Conclusion: Metabolic response after IC-1 differentiates HNC patients into three subgroups predicting local tumor control. Non-response was associated with a poor outcome., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The response to induction chemotherapy (IC) predicts local control after conservative treatment of laryngeal, meso- and hypopharyngeal head and neck squamous cell carcinoma (HNSCC) and can thus help to avoid surgery. Single-cycle induction chemotherapy may help to maintain a low local recurrence rate while keeping the overall toxicity manageable. However, long-term data on single-cycle IC response by tumor location is lacking., Methods: N = 102 patients with functionally inoperable primary HNSCC of the larynx (n = 43), hypopharynx (n = 42) or mesopharynx/tongue (n = 17) received one cycle of docetaxel (75 mg/m 2 , d1) plus cisplatin (30 mg/m 2 , d1-3) or carboplatin (AUC 1.5, d1-3) and a response evaluation 3 weeks later. Responders (≥ 30% tumor size reduction and ≥ 20% SUVmax decrease in 18 F-FDG PET/CT) were recommended chemoradiotherapy (CRT), and non-responders surgery., Results: The overall response rate was 72.5%. All 74 responders and 10 non-responders received primary CRT, and 18 patients received primary surgery after single-cycle IC. Overall 10-year local recurrence-free survival (LRFS) was 73.7%. Three-year LRFS was 88.2% (mesopharynx/tongue), 88.2% (larynx), and 73.3% (hypopharynx); p = 0.17. 3-year distant metastasis-free survival (DMFS) was 94.1% (mesopharynx/tongue), 88.0% (larynx) and 76.4% (hypopharynx); p > 0.05. This influenced the 3-year cancer-specific survival (CSS) for larynx (91.2%) vs. hypopharynx tumors (60.8%); p = 0.003, but CSS was not different to tumors in the mesopharynx/tongue (81.4%); p > 0.05., Conclusions: A single-cycle induction chemotherapy for HNSCC enables surgery plus adjuvant therapy as well as chemoradiotherapy. The long-term local and distant disease control was good but varied between tumors in the larynx and mesopharynx/tongue vs. hypopharynx.

Objectives: To investigate local control and functional outcome following state-of-the-art fractionated stereotactic radiotherapy (FSRT) for paragangliomas of the head and neck., Methods: In total, 40 consecutive patients with paragangliomas of the head and neck received conventionally FSRT from 2003 to 2016 at the Department of Radiation Oncology of the University Hospital Erlangen. Local control, toxicities, and functional outcome were examined during follow-up. In total, 148 magnetic resonance imaging studies were subjected to longitudinal volumetric analysis using whole tumor segmentation in a subset of 22 patients., Results: A total of 80.0% (32/40) of patients received radiotherapy as part of their primary treatment. In 20.0% (8/40) of patients, radiation was used as salvage treatment after tumor recurrence in patients initially treated with surgery alone. The median dose applied was 54.0 Gy (interdecile range, 50.4 to 56.0 Gy) in single doses of 1.8 or 2 Gy. Local control was 100% after a median imaging follow-up of 52.2 months (range, 0.8 to 152.9 mo). The volumetric analysis confirmed sustained tumor control in a subset of 22 patients and showed transient enlargement (range, 129.6% to 151.2%) in 13.6% of cases (3/22). After a median volumetric follow-up of 24.6 months mean tumor volume had diminished to 86.1% compared with initial volume. In total, 52.5% (21/40) of patients reported improved symptoms after radiotherapy, 40% (16/40) observed no subjective change with only 7.5% (3/40) reporting significant worsening., Conclusions: State-of-the-art FSRT provides excellent control and favorable functional outcome in patients with paragangliomas of the head and neck. The volumetric analysis provides improved evidence for sustained tumor control.

Objective: To compare efficacy, in terms of disease control/survival in advanced hypopharyngeal and laryngeal lesions, according to treatment strategy (primary surgery, PS or primary chemoradiotherapy, CRT) and invasion pattern (cartilage, CAI or soft tissue involvement, STI)., Methods: Records from 463 patients with T3 and T4a carcinoma with CAI (n=221) or STI (n=242) treated at a university clinic over 18 years were retrospectively reviewed., Results: Disease-specific survival (DSS) for the CAI group was 70.1% (PS) and 38.4% (CRT), and 76.6% and 46% for the STI group, respectively. Overall survival (OS) for STI was 56.4% (PS) and 30.6% (CRT), and for CAI 51.1% (PS) and 28.5% (CRT) respectively. Positive resection margins and regional neck metastases reduced survival. T3 lesions treated non-operatively still had significantly improved survival versus T4a by >20%., Conclusion: Surgery remains an indispensable part of treatment in local advanced hypopharyngeal and laryngeal cancer with high survival results. It should be part of a concept that includes adjuvant (C)RT. For T3 lesions, primary CRT is also acceptable and CAI is not a contraindication for primary CRT. Regional disease is a strong prognostic factor. In spite of adjuvant treatment, DSS deteriorates by about 20% in cases with positive resection margins., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: There is controversy over the concept of function and organ preservation by chemotherapy/chemoradiation instead of surgery in locally advanced cancer of the larynx or pharynx. Tumor response to induction chemotherapy (ICT) can help in choosing between conservative and surgical treatment. This study compared 3 methods of assessing response to ICT: endoscopy, computed tomography, and (18) F-FDG-PET/CT., Methods: Primary response to 1 cycle of ICT with docetaxel plus platinum was assessed by the aforementioned methods in 62 laryngopharyngeal cancer patients. Endoscopic response was the deciding factor for selecting further treatment: surgery for endoscopic nonresponders (<30% tumor response) versus chemoradiotherapy for endoscopic responders., Results: ICT achieved endoscopic response in 48 of 62 patients (77%). Individual relative residual tumor activity of standardized uptake value (resSUV(max)) in (18)F-FDG-PET/CT was a median 0.38 of baseline (0.09-1.71), whereas residual tumor extent in CT (resCT) was 0.75 of baseline (0.32-1.20). Endoscopic responders and nonresponders differed significantly in SUV(max) after ICT (postSUVmax , 6.0 vs 14.5; P < .001), resSUV(max) (0.34 vs 0.81, P < .001), and resCT (0.71 vs 0.87, P = .004), but not in maximum tumor diameter after ICT (14 vs 20 mm, P = .11). resSUV(max) <0.8 and absolute postSUV(max) <10 provided the best discriminatory power for long-term success criteria (tumor-free survival, overall survival)., Conclusions: Metabolic tumor response showed very good correlation with clinical tumor response to ICT. The value of metabolic response detected by (18)F-FDG-PET/CT should be explored in a prospective clinical trial., (© 2014 American Cancer Society.)

Background and Purpose: Although poor-risk patients represent no minority in inoperable non-small cell lung cancer (NSCLC), there is little experience with concurrent radiochemotherapy (RCT) in this group. Here, the authors report on the feasibility and efficacy of RCT with vinorelbine plus carboplatin or cisplatin in NSCLC patients with comorbidities and poor general health or advanced age., Patients and Methods: A total of 66 patients (ten women, 56 men, median age 68 years) with inoperable NSCLC and an increased risk of treatment side effects (WHO performance score of 2-3; cardiac, pulmonary or renal failure or extensive weight loss before treatment, or an age of 71-78 years) were treated with vinorelbine 12.5 mg/m(2) on days 1, 8, 15, 29, 36, and 43 in combination with either carboplatin 70 mg/m(2) (n = 59) or cisplatin 20 mg/m(2) (n = 7) on days 1-5 and 29-33 in addition to receiving conventional fractionated radiotherapy with doses of up to 63 Gy (90% isodose)., Results: 62 of 66 patients (94%) reached the 90% level of the prescribed radiation dose, and 41/66 patient (62%) received at least two cycles of the platinum compound and four cycles of vinorelbine. The following hematologic side effects (CTC classification [Common Toxicity Criteria]) were observed: grade 3 (12%) and grade 4 (15%) thrombocytopenia, grade 3 (38%) and grade 4 (4%) leukocytopenia, and anemia requiring transfusion (26%). Other side effects (CTC) included grade 3 (3%) and grade 4 (2%) esophagitis and grade 3 pneumonitis (3%). The response rates were as follows: complete remission 18%, partial remission 56%, stable disease 21%, and progressive disease 5%. The cumulative survival rates were 53%, 24%, and 8% at 12 months, 24 months, and 5 years, respectively., Conclusion: After including a larger group of patients than in 2003 and following the patients for several years, the authors determine that concurrent RCT consisting of vinorelbine plus a platinum compound and conventional fractionated radiotherapy can be carried out with manageable toxicity, even in this negatively selected population of patients. Their survival rates were comparable to those achieved in other studies with simultaneous RCT.