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Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, intralesionally administered in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. Ten patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events (AEs), and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35-97) years with a median follow-up of 11.6months. Of these 10 patients, 5 had a complete response (CR), 3 had a partial response, 1 had stable disease and 1 showed progressive disease (PD) as their best response. Best overall response rate (ORR) was 80%. Median progression-free survival was 10.8 months (95% confidence interval, 2.2-19.4). Grade 1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 50% achieving a CR. This realworld data demonstrates promising results and suggests T-VEC can be an alternative to systemic therapy in this select, mostly elderly patient population.

Exciting advances in melanoma systemic therapies have presented the opportunity for surgical oncologists and their multidisciplinary colleagues to test the neoadjuvant systemic treatment approach in high-risk, resectable metastatic melanomas. Here we describe the state of the science of neoadjuvant systemic therapy (NAST) for melanoma, focusing on the surgical aspects and the key role of the surgical oncologist in this treatment paradigm. This paper summarizes the past decade of developments in melanoma treatment and the current evidence for NAST in stage III melanoma specifically. Issues of surgical relevance are discussed, including the risk of progression on NAST prior to surgery. Technical aspects, such as the definition of resectability for melanoma and the extent and scope of routine surgery are presented. Other important issues, such as the utility of radiographic response evaluation and method of pathologic response evaluation, are addressed. Surgical complications and perioperative management of NAST related adverse events are considered. The International Neoadjuvant Melanoma Consortium has the goal of harmonizing NAST trials in melanoma to facilitate rapid advances with new approaches, and facilitating the comparison of results across trials evaluating different treatment regimens. Our ultimate goals are to provide definitive proof of the safety and efficacy of NAST in melanoma, sufficient for NAST to become an acceptable standard of care, and to leverage this platform to allow more personalized, biomarker-driven, tailored approaches to subsequent treatment and surveillance.

Background: Neoadjuvant systemic therapy has shown promising results in the treatment of high-risk stage III melanoma; however, the effects on surgery are currently unknown. This study aims to compare the surgical outcomes, in terms of postoperative complications, postoperative morbidity, duration of surgery and textbook outcomes, of patients with high-risk stage III melanoma who received neoadjuvant systemic therapy followed by lymph node dissection with patients who received an upfront lymph node dissection. Methods: In this retrospective cohort study, patients with high-risk stage III melanoma treated with neoadjuvant anti-PD1 and anti-CTLA4 in the OpACIN (NCT02437279) and OpACIN-neo (NCT02977052) trial between October 2014 and August 2018 were included and compared to patients who received upfront surgery in the same time period. Results: A total of 120 patients were included in this study, of whom 44 received neoadjuvant systemic therapy and 76 underwent upfront surgery. There was no significant difference in the overall rate of postoperative complications between the neoadjuvant group and the upfront surgery group (31.8% versus 36.8%, p = 0.578) and neither in rate of postoperative morbidity (seroma 56.8% versus 57.9%, p = 0.908) (lymphedema 22.7% versus 13.2%, p = 0.175). There was a non-significant difference towards a slightly longer duration of surgery after neoadjuvant immunotherapy (105 versus 90 min, p = 0.077). There were no differences in textbook outcomes (50% versus 49%, p = 0.889). Conclusion: This study shows that the surgical outcomes for patients who underwent a lymph node dissection after neoadjuvant systemic immunotherapy or underwent upfront lymph node dissection for high-risk stage III melanoma are comparable.

Wound healing is a complex biological process subject to complications that might jeopardize the patient's postoperative care. Appropriately approaching surgical wounds after head and neck surgery positively influences the quality and speed of wound healing and increases patient comfort. A large variety of dressing materials currently exist that allow the care of different types of wounds. Nevertheless, there is limited literature on the most suitable types of dressings after head and neck surgery. The objective of the present article is to review the most commonly used wound dressings, their benefits, indications, and disadvantages, and to provide a systematic approach for wound care within the head and neck. The Woundcare Consultant Society distinguishes wounds into three groups: black, yellow, and red. Each type of wound represents distinctive underlying pathophysiological processes with unique needs. Utilizing this classification along with the TIME model allows a proper characterization of wounds and the identification of potential healing barriers. This evidence-based and systematic approach can facilitate and guide the head and neck surgeon in selecting a wound dressing upon acknowledging their properties, which are herein reviewed and exemplified with representative cases.

Simple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the introduction of immune and targeted therapy. In contrast, little is known about the effect of their introduction on the survival of MM. This study presents the incidence, clinical characteristics, treatment characteristics, and survival of MM over 30 years (1990-2019) in the Netherlands. We conclude that the incidence of MM remained stable, and survival has slightly improved when comparing the timeframe 2014-2019 with previous years. However, the prognosis of MM remains poor as compared to CM. Future studies addressing the effect of immune and targeted therapy in MM are needed to improve outcomes for patients with MM. Background: Mucosal melanoma (MM) is a rare tumour with a poor prognosis. Over the years, immune and targeted therapy have become available and have improved overall survival (OS) for patients with advanced cutaneous melanoma (CM). This study aimed to assess trends in the incidence and survival of MM in the Netherlands against the background of new effective treatments that became available for advanced melanoma. Methods: We obtained information on patients diagnosed with MM during 1990-2019 from the Netherlands Cancer Registry. The age-standardized incidence rate and estimated annual percentage change (EAPC) were calculated over the total study period. OS was calculated using the Kaplan-Meier method. Independent predictors for OS were assessed by applying multivariable Cox proportional hazards regression models. Results: In total, 1496 patients were diagnosed with MM during 1990-2019, mostly in the female genital tract (43%) and the head and neck region (34%). The majority presented with local or locally advanced disease (66%). The incidence remained stable over time (EAPC 3.0%, p = 0.4). The 5-year OS was 24% (95%CI: 21.6-26.0%) with a median OS of 1.7 years (95%CI: 1.6-1.8). Age >= 70 years at diagnosis, higher stage at diagnosis, and respiratory tract location were independent predictors for worse OS. Diagnosis in the period 2014-2019, MM located in the female genital tract, and treatment with immune or targeted therapy were independent predictors for better OS. Conclusion: Since the introduction of immune and targeted therapies, OS has improved for patients with MM. However, the prognosis of MM patients is still lower compared to CM, and the median OS of patients treated with immune and targeted therapies remains fairly short. Further studies are needed to improve outcomes for patients with MM.

Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates (pRRs) in clinical stage III nodal melanoma, and pathologic response is strongly associated with prolonged relapse-free survival (RFS). The PRADO extension cohort of the OpACIN-neo trial ( NCT02977052 ) addressed the feasibility and effect on clinical outcome of using pathologic response after neoadjuvant ipilimumab and nivolumab as a criterion for further treatment personalization. In total, 99 patients with clinical stage IIIb-d nodal melanoma were included and treated with 6 weeks of neoadjuvant ipilimumab 1 mg kg-1 and nivolumab 3 mg kg-1. In patients achieving major pathologic response (MPR, ≤10% viable tumor) in their index lymph node (ILN, the largest lymph node metastasis at baseline), therapeutic lymph node dissection (TLND) and adjuvant therapy were omitted. Patients with pathologic partial response (pPR; >10 to ≤50% viable tumor) underwent TLND only, whereas patients with pathologic non-response (pNR; >50% viable tumor) underwent TLND and adjuvant systemic therapy ± synchronous radiotherapy. Primary objectives were confirmation of pRR (ILN, at week 6) of the winner neoadjuvant combination scheme identified in OpACIN-neo; to investigate whether TLND can be safely omitted in patients achieving MPR; and to investigate whether RFS at 24 months can be improved for patients achieving pNR. ILN resection and ILN-response-tailored treatment were feasible. The pRR was 72%, including 61% MPR. Grade 3-4 toxicity within the first 12 weeks was observed in 22 (22%) patients. TLND was omitted in 59 of 60 patients with MPR, resulting in significantly lower surgical morbidity and better quality of life. The 24-month relapse-free survival and distant metastasis-free survival rates were 93% and 98% in patients with MPR, 64% and 64% in patients with pPR, and 71% and 76% in patients with pNR, respectively. These findings provide a strong rationale for randomized clinical trials testing response-directed treatment personalization after neoadjuvant ipilimumab and nivolumab.

Background: Merkel cell carcinoma (MCC) is a cutaneous tumor with a high tendency to metastasize, and a significant proportion of patients have metastases at first presentation. This study aims to determine the value of baseline ultrasound (US) and (18)fluorodeoxyglucose-positron emission tomography/computed tomography ((18)FDG-PET/CT) imaging in both patients with clinically localized MCC (Stage I/II) and patients who present with palpable lymph nodes (Stage III). Methods: This retrospective cohort included 135 MCC patients who underwent baseline US (with fine needle aspiration cytology (FNAC)) and/or FDG-PET/CT imaging between 2015 and 2021. Results: Of the 104 patients with clinically localized disease, 48% were upstaged to Stage III and 3% to Stage IV by imaging or sentinel lymph node biopsy (SLNB). FDG-PET/CT imaging identified regional metastases in 23%, while US with FNAC identified regional metastases in 19%. SLNB was performed in 56 patients, of whom 57% were upstaged to Stage III. Of the 31 patients who presented with palpable lymph nodes, 16% were upstaged to Stage IV by FDG-PET/CT imaging. Conclusion: Baseline imaging frequently upstages Stage I/II MCC patients to Stage III, both by US and FDG-PET/CT, Stage IV disease is rarely identified. Patients who present with palpable nodes are frequently upstaged to Stage IV by FDG-PET/CT imaging.

Simple Summary Immunotherapy may induce early treatment response in head and neck squamous cell carcinoma (HNSCC) for some patients. Routine imaging parameters fail to diagnose these responses; however, magnetic resonance (MR) diffusion-weighted imaging (DWI) may be able to do so. This study sought to correlate DWI parameters with treatment response early after immunotherapy treatment in HNSCC. We analyzed 24 patients with advanced HNSCC with imaging before and after the immunotherapy. We found that rounder tumors that were smaller in diameter before treatment were more likely to respond. A decrease in skewness of the tumor after treatment compared to before treatment, as well as an overall low skewness post-treatment, were linked to better treatment response. Though this study was explorative in nature, these results are promising for the predictive use of MR-DWI in HNSCC treated with immunotherapy. Background: Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. METHODS: 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. Results: MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Conclusion: Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation.

BACKGROUND: The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach.METHODS: Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I-V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3-4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS).RESULTS: Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92).CONCLUSION: This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND.

Background and purpose: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. Materials and methods: Between April 2015 and April 2019, 155 consecutive patients were treated with GTV to high-risk CTV margin of 10 mm and subsequently another 155 patients with 6 mm margin. The CTV-PTV margin was 3 mm for both groups. All patients were treated with volumetric-modulated arc therapy with daily image-guidance using cone-beam CT. End points of the study were acute and late toxicity and oncologic outcomes. Results: Overall acute grade 3 toxicity was significantly lower in 6 mm, compared to 10 mm group (48% vs. 67%, respectively, p < 0.01). The same was true for acute grade 3 mucositis (18% vs. 34%, p < 0.01) and grade > 2 dysphagia (67% vs. 85%, p < 0.01). Also feeding tube-dependency at the end of treatment (25% vs. 37%, p = 0.02), at 3 months (12% and 25%, p < 0.01), and at 6 months (6% and 15%, p = 0.01) was significantly less in 6 mm group. The incidence of late grade 2 xerostomia was also significantly lower in the 6 mm group (32% vs. 50%, p < 0.01). The 2-year rates of loco-regional control, disease-free and overall survival were 78.7% vs. 73.1%, 70.6% vs. 61.4%, and 83.2% vs. 74.4% (p > 0.05, all). Conclusion: The first study reporting on reduction of GTV to high-risk CTV margin from 10 to 6 mm showed significant reduction of the incidence and severity of radiation-related toxicity without reducing local-regional control and survival. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 162 (2021) 170-177

Objectives: To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL). DESIGN Randomized controlled trial. SETTING Tertiary cancer hospital. PATIENTS Adults to be treated with high-dose cisplatin (>= 75 mg/m(2)). INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated. Main Outcome Measure: Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a >= 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA(8-12.5)). Response to STS was defined as a threshold shift at PTA(8-12.5) in the STS-treated ear of >= 10 dB smaller than the untreated ear. Results: Twelve patients were treated. Average CIHL at PTA(8-12.5) was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA(8-12.5) in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients. Conclusion: Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale.

Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete- and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41–100% of all patients and 0–11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities.

Immune checkpoint blockade has shown clinical activity in a range of cancer types. To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on intratumoral T cells in head and neck squamous cell carcinoma, we analyzed immune infiltrates in tumor biopsies from responding and non-responding patients. At baseline, a higher ratio between active (4-1BB+) and inactive regulatory CD4+ T cells was associated with response to therapy. Furthermore, upon therapy, this active Treg population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional CD8+ T cells transitioned to a state of reduced activity and dysfunction in responding patients, while in non-responding patients, NK cells showed an increased cytotoxic transcriptional profile upon treatment. These data reveal the immunological changes in response to dual PD-1 and CTLA4 blockade, including a parallel remodeling of presumed tumor-reactive T cell compartments in responding patients, and indicate that the presence of an activated Treg compartment at baseline may predict response. Citation Format: Anne M. van der Leun, Joleen J. Traets, Joris L. Vos, Joris B. Elbers, Sanne Patiwael, Xiaohang Qiao, Mercedes Machuca-Ostos, Daniela S. Thommen, John B. Haanen, Ton N. Schumacher, Charlotte L. Zuur. Dual immune checkpoint blockade induces analogous alterations in the dysfunctional CD8+ T cell and activated Treg compartment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2281.

Background: Immune checkpoint inhibitors (ICI) can achieve remarkable clinical responses in urothelial cancer (UC). However, it remains unclear which aspects of the tumor microenvironment (TME) determine a patient’s response. The TME is usually characterized by immune cell density, which ignores cells’ spatial relationships relative to each other. Methods: Using multiplex immunofluorescence data (PanCK, CD20, CD68, CD3, CD8, and FoxP3 antibody panel) of 24 pre-ICI UC transurethral resections retrieved from the NABUCCO trial (NCT03387761), we spatially profiled cancer cells, macrophages, B-cells, and distinct T-cell populations. We first quantified the TME immune cell densities at the tumor and stroma tissue compartments. We then quantified the TME spatial relationships with a novel approach based on fitting a Weibull function to the first nearest neighbor (1-NN) distance distribution, allowing us to uniquely summarize spatial relationships with two parameters (Weibull approach). We compared this approach to conventional techniques (G-functions) that rely upon a predefined distance threshold. We performed a simulation study to identify sources of variation in the spatial relationship parameters. Lastly, we associated the TME parameters with ICI (ipilimumab + nivolumab) response. Results: Unlike the Weibull approach, the G-function quantifications manifested a variable effect size and statistical power in association studies because of its distance threshold dependence. We found that variation in density affected the spatial relationship metrics of rare cell types (i.e., B-cells) but not of abundant cell types (i.e., cancer cells). The spatial relationship metrics from the Weibull approach outperformed immune cell density in ICI response prediction. Specifically, immune cell density did not discriminate between ICI response groups (FDR>10%). In contrast, the spatial relationship between either CD8+ T-cells or macrophages to their closest cancer cell did associate with response to ICI (FDR=1%). Furthermore, non-responding tumors were characterized by CD8+ T-cells close to B-cells (FDR=9%). Importantly, we validated the association between proximity and response from CD8+ T-cells to cancer cells (FDR=1%) and from macrophages to cancer cells (FDR=1%) using data from 25 pre-ICI head and neck squamous cell carcinoma tumors from the IMCISION trial (NCT03003637, arm B, ipilimumab + nivolumab). Conclusion: We created a framework to quantify, study, interpret and analyze spatial relationships in the TME and illustrated its superior clinical relevance compared to density metrics for predicting ICI treatment response. Our findings emphasize the importance of spatial relationships in the TME for response and suggest that proximity between either macrophages or CD8+ T-cells to cancer cells are candidate biomarkers for ICI response. Citation Format: Alberto Gil-Jimenez, Nick van Dijk, Yoni Lubeck, Maurits L. van Montfoort, Dennis Peters, Erik Hooijberg, Annegien Broeks, Joris L. Vos, Charlotte L. Zuur, Bas van Rhijn, Daniel J. Vis, Michiel S. van der Heijden, Lodewyk F. Wessels. Spatial relationships in the tumor microenvironment predict response to immune checkpoint inhibitors in urothelial and head and neck cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5786.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P

Item does not contain fulltext BACKGROUND AND PURPOSE: Radiotherapy (RT) with cetuximab is an alternative for advanced-stage head and neck squamous cell carcinoma (HNSCC) patients who are unfit for cisplatin treatment. As 5-year overall survival is below 50%, it is of interest to test PD-L1 immune checkpoint blockade (avelumab) with cetuximab-RT in the curative setting. MATERIALS AND METHODS: Phase-I feasibility trial (planned n=10, NCT02938273) of conventional cetuximab-RT with avelumab (concurrent 10mg/kg Q2W+4months maintenance) for advanced-stage HNSCC patients unfit for cisplatin treatment. RESULTS: One of ten included patients experienced grade 2 cetuximab-related infusion reaction and withdrew from the study before avelumab was administered. One patient discontinued treatment after 2 courses of avelumab and 12x2Gy RT for personal reasons. In 2/8 remaining patients, avelumab was stopped after 4 and 8 courses because of toxicity and tumor progression, respectively. There was no grade 4-5 toxicity. Grade 3 immune-related toxicity was manageable and occurred in 4 patients. One patient was treated with topical steroids for grade 3 maculopapular rash and 3 patients received high-dose prednisone for grade 3 elevated liver enzymes (n=1) and pneumonitis (n=2). Seven patients experienced grade 3 RT-related toxicity with no severe specific cetuximab-related toxicity. Tumor recurrence occurred in 4/8 patients (50%) after a median of 12 (8-26) months follow-up. CONCLUSION: Cetuximab-RT plus avelumab is feasible in patients with advanced-stage HNSCC who are unfit for cisplatin treatment. Immune-related toxicity was transient and manageable and radiotherapy-related toxicity was in accordance with standard of care. This pilot study provides grounds for larger efficacy trials.

Importance: Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. Objective: To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. Design, Setting, and Participants: Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. Main Outcomes and Measures: Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. Results: A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. Conclusions and Relevance: The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.

Purpose To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. Methods In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11–50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. Results Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P P max (median − 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. Conclusions Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Trial registration https://www.clinicaltrials.gov/, NCT03003637, December 28, 2016.

Simple Summary Hearing loss (HL) can be a side effect of paediatric cancer treatment and can be caused by chemotherapy but also local therapies such as radiotherapy and/or surgery of the head and neck region. In this study, the frequency and patterns of HL were assessed in survivors of head and neck rhabdomyosarcoma (HNRMS). Our secondary aim was to look into the dose-effect relationship between radiotherapy dose on the cochlea and the presence of HL. Forty-nine survivors of HNRMS were included in this study, forty-two of them underwent audiological evaluation. HL was found in up to 19% of the survivors. Four survivors had low frequencies HL with normal hearing or milder HL in the higher frequencies. In our series, HL (>= Muenster 2b) was significantly associated with the maximum cochlear irradiation dose (p = 0.047). More research is needed on HL patterns in HNRMS survivors and on the radiotherapy dose-effect relationship. Purpose: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. Methods: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster >= 2b, CTCAE >= 2, and SIOP >= 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. Results: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (>= Muenster 2b) (p = 0.047). In our series, HL (>= Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. Conclusion: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P = 70% viable melanoma and incorporating additional criteria of

PURPOSE: Recurrent head and neck squamous cell carcinoma (HNSCC) after chemoradiation is a challenging clinical problem. Salvage surgery (SS) is often extensive and mutilating. Oncological outcomes of SS are relatively well known, but little is published about the course of disease after the first recurrence, especially in patients without salvage possibilities. The aim of this study was to analyze the course of disease in patients with recurrent HNSCC after chemoradiation.METHODS: We retrospectively analyzed and descriptively reported the disease course in 198 patients with recurrent HNSCC after chemoradiation in the time period after the first recurrence. We scored any type of event, salvage treatment, systemic treatment and overall survival (OS).RESULTS: Of the 198 patients with recurrent HNSCC, salvage surgery was attempted in 104 (53%). SS was more frequently given in patients with recurrent laryngeal cancer, isolated regional failure (p CONCLUSIONS: Main factors influencing the course of disease in recurrent HNSCC are the possibilities for SS and HPV-status. Therefore, SS should always be considered and discussed. In patients without possibilities for SS, overall survival is 3-6 months.

Objective: The aim of the current study was to determine the incidence of organ function preservation failure (OFPF) in patients with head and neck squamous cell carcinoma (HNSCC) treated by (chemo)radiotherapy and to identify its risk factors. Study Design: Retrospective cohort analysis. Setting: Tertiary cancer care center. Subjects and Methods: A single-center retrospective cohort analysis was done (n = 703) in which OFPF after (chemo)radiotherapy was assessed. OFPF was defined as local failure or pure functional failure in the absence of local failure because of major surgical intervention (total laryngectomy, commando resection, permanent tracheostomy) or feeding tube dependence >2 years. Results: OFPF occurred in 153 patients (21.8%). Reasons for OFPF were local failure in 103 patients (14.6%) and functional failure in 50 patients (7.2%). Evidence of functional failure included need for total laryngectomy (n = 9, 1.3%), commando resection (n = 2, 0.3%), permanent tracheostomy (n = 16, 2.3%), and/or long-term feeding tube for functional reasons (n = 23, 3.3%). In a Cox proportional hazards model, OFPF was worse for patients with T4 tumors (hazard ratio [HR]

Contains fulltext : 203208.pdf (Publisher’s version ) (Closed access) BACKGROUND AND PURPOSE: In recent decades, outcomes of patients with head and neck cancer (HNC) have improved as a result of implementing several strategies, such as chemoradiation. However, these improvements were achieved at the cost of increased toxicity. One way to reduce radiation-related toxicity is by reducing the margins. MATERIALS AND METHODS: Between 2013 and 2016, 206 consecutive patients were treated with CTV-PTV margin of 5mm and subsequently 208 patients with 3mm margin. This study evaluates the impact of reducing clinical target volume (CTV) to planning target volume (PTV) margin on outcome and toxicity. RESULTS: All patients were treated with volumetric modulated arc therapy (VMAT) with daily-image guidance using cone-beam CT (CBCT). Overall acute grade 3 toxicity was significantly lower in 3mm-group, compared to 5mm-group (53.8% vs. 65%, respectively, p=0.032). The same was true for acute grade 3 mucositis (30.8% vs. 42.2%, p=0.008) and for acute grade 3 dysphagia (feeding tube-dependence) (22.1% vs. 33.5%, p=0.026). The incidence of ongoing feeding tube-dependence after 3months of radiotherapy was 11.1% and 20.4%, respectively (p=0.012). The 2-year incidence of late grade >/=2 xerostomia was 15.8% and 19.4% (p=0.8). The 2-year loco-regional control rates of patients treated in 3mm and 5mm-groups were 79.9% and 79.2% (p=1.0). The figures for disease-free survival were 71.5% and 72.7 (p=0.6) and for overall survival were 75.2% and 75.1% (p=0.9). CONCLUSION: Reducing the CTV-PTV margin from 5 to 3mm combined with daily CBCT-guided VMAT reduced the severity, frequency, and duration of radiation-related toxicity without jeopardizing outcome. 7 p.

TPS9605 Background: Adjuvant treatment with anti-PD1 therapy improves the recurrence free survival (RFS) in resectable stage III melanoma. The Checkmate-238 and KEYNOTE-054 trials respectively reported a 4-year RFS of 52.5% for adjuvant nivolumab and a 3-year RFS of 63.7% for adjuvant pembrolizumab. Despite these improved outcomes, a considerable proportion of patients have a relapse in the years after therapeutic lymph node dissection (TLND). The OpACIN trial showed that neoadjuvant treatment with nivolumab (NIVO) plus ipilimumab (IPI) is feasible and induces a stronger and broader T-cell response. The subsequent OpACIN-neo trial identified 2 cycles of NIVO 3mg/kg + IPI 1mg/kg as a neoadjuvant dosing scheme with decreased toxicity and preserved high pathologic response rates (77%), which was confirmed in the PRADO trial. A favorable 2-year RFS (83,6%) was achieved in the overall OpACIN-neo population, although patients with a pathological partial or non-response have a worse prognosis and may therefore benefit from additional adjuvant therapy. The efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase III trial, before neoadjuvant therapy can be considered as a standard option for this patient population. Methods: This international, randomized phase 3 trial aims to compare the efficacy of neoadjuvant IPI + NIVO with adjuvant NIVO in macroscopic stage III melanoma. In total 420 patients diagnosed with recurrent or de novo melanoma, with at least one pathologically proven, clinically detectable lymph node (up to 3 in-transit metastases (ITMs) allowed), will be randomized to neoadjuvant or adjuvant treatment. The population will be stratified by BRAF mutation, continent and the presence of ITMs. Patients in arm A will receive 2 cycles of IPI 80mg + NIVO 240mg and will undergo TLND at week 6. In the case of pathological partial response or non-response, surgery will be followed by adjuvant NIVO (11 cycles) or adjuvant dabrafenib + trametinib (46 weeks) if BRAFV600-mutation is present. Patients in arm B will undergo upfront TLND followed by 12 cycles of NIVO 480mg. The primary endpoint will be the event free survival (EFS) defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. Final analysis will be performed after 132 events have been observed, or at latest 2 years after the last patient is included. Baseline biopsies and blood samples (screening, week 0, 3, 6, 9 and 12) will be collected for translational research. Quality of Life questionnaires and electronic Patient Reported Outcomes will be collected using the Kaiku application. The first patient was enrolled on the 23rd of July 2021. Clinical trial information: NCT04949113.

Approximately 15% of advanced head and neck squamous cell carcinomas (HNSCC) respond to anti-PD-(L)1 monotherapies. Tumor PD-L1 expression and human papillomavirus (HPV) status have been proposed as biomarkers to identify patients likely to benefit from these treatments. We aimed to understand the potential immune effects of HPV in HNSCC and to characterize additional potentially targetable immune-regulatory pathways in primary, treatment-naïve tumors. CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, PD-L2, LAG-3, IDO-1, and GITR cell densities were determined in 27 HNSCC specimens. IHC for PD-L1 assessed percentage of positive tumor cells and immune cells separately or as a combined positive score (CPS), and whether PD-L1 was expressed in an adaptive or constitutive pattern (i.e., PD-L1+ tumor cells juxtaposed to TILs or in the absence of TILs, respectively). HPV testing with p16 IHC was confirmed by HPV genotyping. When compared to HPV(−) tumors (n = 14), HPV+ tumors (n = 13) contained significantly higher densities of CD3+, CD4+, CD8+, CD20+, and PD-1+ cells (P < 0.02), and there was a trend towards increased density of FoxP3 + cells. PD-L1 expression patterns did not vary by tumor viral status, suggesting possible heterogeneous mechanisms driving constitutive vs adaptive PD-L1 expression patterns in HNSCC. IDO-1 expression was abundant (> 500 IDO-1+ cells/mm2 in 17/27 specimens) and was found on tumor cells as well as immune cells in 12/27 (44%) cases (range 5–80% tumor cells+). Notably, the studied markers varied on a per-patient basis and were not always related to the degree of T cell infiltration. These findings may inform therapeutic co-targeting strategies and raise consideration for a personalized treatment approach.

Background Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy. Methods Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR. Results A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions. Conclusions This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Significance Anthracyclines like doxorubicin are anticancer drugs, used by over 1 million cancer patients annually. However, they cause severe side effects, most notably, cardiotoxicity and therapy-related malignancies. It is unclear whether these side effects are directly linked to their anticancer activity. Doxorubicin exerts two activities: DNA damage and chromatin damage. Here, we show that both activities conspire in the cardiotoxicity, while doxorubicin variants with only chromatin-damaging activity remain active anticancer drugs devoid of side effects. This challenges the concept that doxorubicin works primarily by inducing DNA double-strand breaks and reveals another major anticancer activity, chromatin damage. Translating these observations will yield anticancer drugs for patients that are currently excluded from doxorubicin treatment and improve the quality of life of cancer survivors., The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

Objective: To compare outcome after definitive (chemo)radiotherapy (CRT group) with standard of care (surgery group) for advanced stage oral cavity carcinoma (OCC). Although definitive (chemo)radiotherapy is assumed to be inferior to surgery with regard to disease control, data on outcome of this approach are scarce. Methods: Retrospective analysis by chart review (2000–2013). Endpoints were locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS). Results: Between the CRT-group (n = 100) and Surgery-group (n = 109), baseline characteristics were equally distributed except stage and local tumor diameter (all p ≤ .001). In the CRT group, at 5 years the LRC rate was 49%, DFS 22%, DSS 39% and OS 22%. In the surgery group, at 5 years the LRC rate was 77%, DFS 45%, DSS 64% and OS 45%. The survival curves of the two groups significantly differed for LRC (p

Recurrent head and neck squamous cell carcinoma (HNSCC) after chemoradiation is a challenging clinical problem. Salvage surgery (SS) is often extensive and mutilating. Oncological outcomes of SS are relatively well known, but little is published about the course of disease after the first recurrence, especially in patients without salvage possibilities. The aim of this study was to analyze the course of disease in patients with recurrent HNSCC after chemoradiation.We retrospectively analyzed and descriptively reported the disease course in 198 patients with recurrent HNSCC after chemoradiation in the time period after the first recurrence. We scored any type of event, salvage treatment, systemic treatment and overall survival (OS).Of the 198 patients with recurrent HNSCC, salvage surgery was attempted in 104 (53%). SS was more frequently given in patients with recurrent laryngeal cancer, isolated regional failure (p 0.001) and HPV-positive disease (p = 0.09). The 2-year OS of the whole group was 31% and was significantly different by tumor site, type of failure and SS. HPV-positive disease and salvaged recurrences were significantly predictive for better survival. One third of that salvaged patients was still alive without second recurrence. Median survival in patients that received any palliative systemic treatment without surgery, compared to those were no treatment was given, was 6 and 3 months, respectively (p = 0.006).Main factors influencing the course of disease in recurrent HNSCC are the possibilities for SS and HPV-status. Therefore, SS should always be considered and discussed. In patients without possibilities for SS, overall survival is 3-6 months.

Objective: To illustrate a case of sensorineural hearing loss (SNHL) after immunotherapy based on T cell receptor (TCR) gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma.Patient: We present a 59-year-old woman with profound subacute bilateral SNHL including unilateral deafness after immunotherapy based on TCR gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma. Ten days after treatment, the patient developed hearing loss of 57 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 kHz in the right ear, and >100 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 in the left ear. The right ear recovered partially, while the left ear remained deaf, despite oral prednisolone (1.0 mg/kg) and salvage treatment with three transtympanic injections of 0.5 ml dexamethasone (4.0 mg/ml).Conclusion: Based on our presented case and a vast amount of literature there is circumstantial evidence that TCR gene therapy for melanoma targets the perivascular macrophage-like melanocytes in the stria vascularis, resulting in SNHL. We suggest that SNHL after TCR gene therapy may be caused by a disruption of the blood-labyrinth-barrier and the endolymphatic potential and/or a sterile inflammation of the stria vascularis. In severe cases like our subject, we posit that endolymphatic hydrops or hair cell loss may cause irreversible and asymmetrical deafness. Steroid prophylaxis via transtympanic application is debatable.

Item does not contain fulltext PURPOSE: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma (HNSCC) is known to result in poor prognosis. As there are only small and heterogeneous studies available with wide variety in outcome measures, our purpose was to select and pool literature according to specific criteria. METHODS: Systematic review and meta-analysis of clinical outcome after salvage surgery for recurrent advanced stage HNSCC following primary radiotherapy or chemoradiation. RESULTS: 16 of 3956 screened studies were included for analysis (729 patients). Pooled 5-year OS was 37% (95% CI 30-45%, 12 studies, 17 outcome measurements, 540 patients). Outcome was presented for larynx (6 studies, 397 patients), hypopharynx (2 studies, 47 patients), larynx and hypopharynx combined (3 studies, 69 patients) or separately (1 study, 134 patients), oral cavity (1 study, 11 patients), oropharynx (1 study, 34 patients) and multiple subsites combined (2 studies, 37 patients). There was no significant difference in survival outcome between subsites (pheterogeneity = 0.8116). The pooled tumor-positive resection margin rate was 32% and pooled re-operation rate 17%. Complication rates from the pooled data were: fistulas 33%, wound infections 24% and flap failure 3%. Treatment-related mortality rate was 1% and mean hospital stay was 23 days. CONCLUSIONS: Salvage surgery for recurrent advanced stage head and neck squamous cell carcinoma after primary (chemo)radiotherapy is a good last resort curative treatment option, resulting in 37% overall survival at 5 years. As data from advanced stage non-laryngeal tumors were sparse, no solid conclusions can be drawn with regard to outcome differences between tumor subsites.

Item does not contain fulltext OBJECTIVE: Most studies that report on salvage surgery after primary radiotherapy for head and neck squamous cell carcinoma (HNSCC) are small and heterogeneous. Subsequently, some relevant questions remain unanswered. We specifically focused on (1) difference in prognosis per tumor subsite, corrected for disease stage, and (2) differences in prognosis after salvage surgery for local, regional, and locoregional recurrences. STUDY DESIGN: Retrospective analysis. SETTING: Single-center study (2000-2016). SUBJECTS AND METHODS: Patients treated with salvage surgery for HNSCC recurrence after (chemo)radiotherapy. RESULTS: In total, 189 patients were included. Five-year overall survival (OS) was 33%, and median OS was 18 (95% confidence interval [CI], 11-26) months. Treatment-related mortality was 2%. Larynx carcinoma was associated with more favorable local (adjusted hazard ratio [HR] = 4.02; 95% CI, 1.46-11.10; P = .007) and locoregional control (adjusted HR = 5.34; 95% CI, 1.83-15.61; P = .002) than pharyngeal carcinoma. American Society of Anesthesiologists (ASA) score (>/=3 vs 1-2: adjusted HR = 3.04; 95% CI, 1.17-7.91; P = .023), pT stage (3-4 vs 1-2: adjusted HR = 4.41; 95% CI, 1.65-11.82; P = .003), and salvage surgery for locoregional recurrences (locoregional vs local: adjusted HR = 3.81; 95% CI, 1.13-11.82; P = .021) were independent predictors for disease-free survival (DFS). CONCLUSION: Salvage surgery for larynx carcinoma, regardless of disease stage and other prognostic factors, results in more favorable loco(regional) control but not favorable DFS than pharyngeal carcinoma. The observed difference in DFS between salvage surgery for local and regional recurrences was not significant after correction for confounders. However, survival following salvage surgery for locoregional disease is significantly worse. For this subgroup, we propose to consider T status and comorbidity for clinical decision making, as high pT stage and ASA score are independent predictors for worse DFS.

Background Human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is a highly immunogenic tumor and differences in tumor microenvironment might contribute to the improved survival of HPV‐positive OPSCC patient. Methods A comprehensive multivariate analysis with clinical and immune variables (human leukocyte antigen [HLA] I/II, programmed death ligand 1 (PD‐L1), programmed death receptor 1 (PD1), T cells, and macrophages) was performed in 142 OPSCC patients. Results We found an inverse correlation between the expression of HLA class II molecules on tumor cells and CD68+ CD163+ tumor‐associated macrophages (TAMs). High HLA‐DP/DQ/DR expression and low number of TAMs were associated with longer disease‐specific survival and disease‐free survival (DFS). Furthermore, a new population of CD8+ FoxP3+ T cells was correlated with shorter DFS in multivariate analysis. Conclusions \We identified new prognostic markers for patients with oropharyngeal cancer, which can be used for selecting patients that can benefit from immunotherapy.

e22089 Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus, which is used as an oncolytic immunotherapy in stage IIIB-IVM1a melanoma patients. It is known to be an effective therapy for injectable cutaneous, subcutaneous and nodal melanoma lesions, as approved by the European Medicines Agency (EMA). Combination therapy is not yet approved by EMA pending the results of the phase 3 Masterkey-265 trial. The objective of the current study was to identify prognostic factors for achieving a complete response (CR) that can be used to select patients for treatment with T-VEC monotherapy. Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2019-05 with a follow-up time > 6 months, were included. Data was collected on baseline characteristics, responses and adverse events (AEs). Durable response rate (DRR) was defined as the percent of patients with a CR or partial response (PR) maintained continuously > 6 months. Univariable analyses were conducted and a prediction model was developed to identify prognostic factors associated with complete response. Results: For this study, a total of 71 patients were included with a median follow-up of 16.1 months. The median age was 70 years (range: 35-90). As best response, 47 patients (66%) had a CR and 10 patients (14%) had a PR, resulting in an overall response rate of 80%. Twenty-one patients (30%) stopped treatment because of progressive disease and sixteen patients (23%) developed a recurrence during follow-up after achieving a PR or CR. Median duration of CR was 11 months. The durable response rate was 42%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, previous treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving a CR and for progression-free survival. Achieving a CR was associated with a reduced risk of death. The prediction model includes tumor size, type of metastases (only cutaneous vs. subcutaneous (+/- cutaneous) vs. nodal (+/- cutaneous/subcutaneous)) and number of lesions as predictors. Conclusions: This study shows that intralesional T-VEC monotherapy for stage IIIB-IVM1a melanoma is able to achieve high complete and durable response rates. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting T-VEC should perhaps be used earlier in the course of the disease.

Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well.

ImportancePatients with head and neck cancer may experience chemoradiotherapy-induced hearing loss, but the weighing of involved variables has been subjective. Identification of patient and treatment characteristics to predict the absolute posttreatment hearing level is important for effective counseling of patients undergoing chemoradiotherapy.ObjectiveTo predict treatment-induced hearing loss among patients with head and neck cancer.Design, Setting, and ParticipantsA retrospective cohort study was performed at The Netherlands Cancer Institute. One hundred and fifty-six patients with head and neck cancer treated with concomitant chemoradiotherapy as the primary treatment modality from January 1, 1997, through December 31, 2011, were enrolled. Follow-up was complete on March 1, 2012, and data were analyzed from April 1, 2011, through November 5, 2013.InterventionsHigh-dose intravenously administered cisplatin-based concomitant chemoradiotherapy. Cisplatin, 100 mg/m2, was administered in 3 courses on days 1, 22, and 43 during 7 weeks of radiotherapy (total radiation dose, 70 Gy in 35 fractions).Main Outcomes and MeasuresPosttreatment bone conduction hearing threshold at pure-tone average frequencies of 1, 2, and 4 kHz, based on pure-tone audiometry after completion of treatment. Predictors included baseline hearing levels, radiation dose to the cochlea, and cisplatin dose. A multilevel mixed-effects linear regression model for predicting whether or not posttreatment hearing was at least 35 dB was established, and cross-validated sensitivity and specificity were obtained.ResultsOf 156 patients who received high-dose concomitant chemoradiotherapy, 15 were missing the exact radiation dose to the cochlea and 41 had no data on posttreatment pure-tone audiometry. Nineteen patients had a hearing level of at least 35 dB for at least 1 ear before the treatment. The remaining 81 patients (162 ears) had a total cumulative cisplatin dose ranging from 315 to 600 (median, 546) mg. The radiation dose to the cochlea ranged from 1.1 to 70.9 (median, 13.6) Gy. Based on data from the 81 patients (162 ears), the area under the receiver operating characteristic curve was 0.68, with a sensitivity of 29% (95% CI, 13%-51%) and a specificity of 97% (95% CI, 88%-100%), resulting in a positive predictive value of 78%.Conclusions and RelevancePatient and treatment characteristics can be used to predict hearing level after concomitant chemoradiotherapy for head and neck cancer. This step may constitute the first in evidence-based individual counseling for treatment-induced hearing loss.

Objectives/Hypothesis The purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not. Study Design Long-term (LT) follow-up study. Methods Between 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging. Results Long-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045). Conclusion CCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment.

Background Both radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT. Methods Comprehensive search of Medline and Embase with the terms “radiotherapy” combined with “ototoxicity,” “head and neck squamous cell carcinoma,” and synonyms. Results Of the 2507 studies found, 21 were included in this study. Pooled analysis could not be committed because of heterogeneity. Incidence rates of SNHL after RT and CRT varied considerably, with percentages ranging from 0% to 43% and 17% to 88%, respectively. Factors that influenced the risk of SNHL were radiation dose to the cochlea, follow-up time, age, baseline hearing level, and cisplatin dose. Conclusion The wide range of SNHL incidence rates makes it impossible to draw any conclusions on the severity of RT- and CRT-induced ototoxicity. To allow for future comparison of study outcomes, development of uniform criteria is of utmost importance. © 2014 Wiley Periodicals, Inc. Head Neck 37: 281-292, 2015

Objectives: To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. Design: Cross-sectional long-term follow-up study. Setting: Tertiary comprehensive cancer centre. Participants: Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). Main outcome measures: We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. Methods: We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). Results: Seventy-three survivors were included (median follow-up 11years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. Conclusions: One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors.

e18020Background: To assess safety, toxicity and efficacy of neo-adjuvant nivolumab ± ipilimumab administration to (salvage) surgery for squamous cell carcinoma of the head and neck (HNSCC). Method...

e18019Background: Radiotherapy (RT) with concurrent EGFR inhibition (cetuximab) is standard of care in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) unfit for ...