Stereotactic ablative radiotherapy for treating primary head and neck cancer and locoregional recurrence: A comprehensive review of the literature.

Introduction: Although stereotactic ablative radiotherapy (SABR) has advance to standard-of-care for many different indications like lung and liver malignancies, it still remains in its infancy for treating head and neck cancer. Nevertheless there is a growing body of experience and evidence, which is summarized in this review Methods A thorough search of the literature was performed and critically reviewed both for SABR as a primary treatment as well as for treating locoregionally recurrent disease in a pre-irradiated field. Results: There exist only few prospective data published so far for treating head and neck cancer with SABR. In the primary situation especially implementing SABR as a boost after definitive radiotherapy or a single-modality for locally limited, small glottic cancer appear promising. On the other hand, SABR can be a useful modality for treating local recurrence in a pre-irradiated field. However, caution is needed in the case of proximity to a pre-irradiated carotid artery or other serial organs at risk. Usually only limited gross volumes are treated with 3-6 fractions every other day and a cumulative dose of 24-44 Gy in dedicated radiosurgery platforms or modern linacs with the possibility of online image-guidance and adequate immobilsation. Conclusions: SABR is an innovative, effective and promising treatment modality for small targets, especially in near proximity to organs at risk or in a pre-irradiated region. Prospective trials are further needed for this technique to become standard-of care.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

Patterns of metastatic spread and tumor burden in unselected cancer patients using PET imaging: Implications for the oligometastatic spectrum theory.

Introduction and background: Metastatic disease has been proposed as a continuum, with no clear cut-off between oligometastatic and polymetastatic disease. This study aims to quantify tumor burden and patterns of spread in unselected metastatic cancer patients referred for PET-based staging, response assessment of restaging. Materials and methods: All oncological fluorodeoxyglucose (FDG-) and prostate-specific membrane antigen (PSMA-) positron emission tomography (PET) scans conducted at a single academic center in 2020 were analyzed. Imaging reports of all patients with metastatic disease were reviewed and assessed. Results: For this study, 7,000 PET scans were screened. One third of PET scans (n = 1,754; 33 %) from 1,155 unique patients showed presence of metastatic disease from solid malignancies, of which 601 (52 %) and 554 (48 %) were classified as oligometastatic (maximum 5 metastases) and polymetastatic (>5 metastases), respectively. Lung and pleural cancer, skin cancer, and breast cancer were the most common primary tumor histologies with 132 (23.8 %), 88 (15.9 %), and 72 (13.0 %) cases, respectively. Analysis of the number of distant metastases showed a strong bimodal distribution of the metastatic burden with 26 % of patients having one solitary metastasis and 43 % of patients harboring >10 metastases. Yet, despite 43 % of polymetastatic patients having >10 distant metastases, their pattern of distribution was restricted to one or two organs in about two thirds of patients, and there was no association between the number of distant metastases and the number of involved organs. Conclusion: The majority of metastatic cancer patients are characterized by either a solitary metastasis or a high tumor burden with >10 metastases, the latter was often associated with affecting a limited number of organs. These findings support both the spectrum theory of metastasis and the seed and soil hypothesis and can support in designing the next generation of clinical trials in the field of oligometastatic disease.

A multi-centric dataset on patient-individual pathological lymph node involvement in head and neck squamous cell carcinoma.

Dataset: We provide a dataset on lymph node metastases in 968 patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC). All patients received neck dissection and we report the number of metastatic versus investigated lymph nodes per lymph node level (LNL) for every individual patient. Additionally, clinicopathological factors including T-category, primary tumor subsite (ICD-O-3 code), age, and sex are reported for all patients. The data is provided as three datasets: Dataset 1 contains 373 HNSCC patients treated at Centre Léon Bérard (CLB), France, with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. Dataset 2 contains 332 HNSCC patients treated at the Inselspital, Bern University Hospital (ISB), Switzerland with primary tumor location in the oral cavity, oropharynx, hypopharynx, and larynx. For these patients, additional information is provided including lateralization of the primary tumor, size and location of the largest metastases, and clinical involvement based on computed tomography (CT), magnetic resonance imaging (MRI), and/or 18FDG-positron emission tomography (PET/CT) imaging. Dataset 3 consists of 263 oropharyngeal SCC patients underlying a previous publication by Bauwens et al. [1], which were treated at CLB. For these patients, additional information including HPV status, lateralization of the primary tumor and clinically diagnosed lymph node involvement is provided. Reuse Potential: The data may be used to quantify the probability of occult lymph node metastases in each LNL, depending on an individual patient's characteristics of the primary tumor and the location of clinically diagnosed lymph node metastases. As such, the data may contribute to further personalize the elective treatment of the neck for HNSCC patients, i.e. definition of the elective clinical target volume (CTV-N) in radiotherapy (RT) and the extent of neck dissection (ND) in surgery. There exists only one similar publicly available dataset that reports clinical involvement per LNL in 287 oropharyngeal SCC patients [2]. The data presented in this article substantially extends the available data, it additionally includes pathologically assessed involvement per LNL, and it provides data for multiple subsites in the head and neck region.

Dosimetric Analysis of Proximal Bronchial Tree Subsegments to Assess The Risk of Severe Toxicity After Stereotactic Body Radiation Therapy of Ultra-central Lung Tumors.

•Stereotactic body radiation therapy (SBRT) for ultra-central lung tumors is associated with high toxicity rates.•To evaluate differences in radiosensitivity within the proximal bronchial tree (PBT), the PBT was sub-segmented into seven anatomical sections.•A risk-adapted SBRT regimen of EQD2_10 = 54.4 Gy in 8 or 10 fractions results in excellent local control and low rates of severe toxicity.•Data from a recent meta-analysis, the NORDIC Hilus trial and dosimetric data from this study were combined to create a NTCP model.•A dose threshold of EQD2_3 = 100 Gy to the PBT or any of its subsegments is expected to result in low rates of severe bronchial toxicity.

The Use of MR-Guided Radiation Therapy for Head and Neck Cancer and Recommended Reporting Guidance.

Although magnetic resonance imaging (MRI) has become standard diagnostic workup for head and neck malignancies and is currently recommended by most radiological societies for pharyngeal and oral carcinomas, its utilization in radiotherapy has been heterogeneous during the last decades. However, few would argue that implementing MRI for annotation of target volumes and organs at risk provides several advantages, so that implementation of the modality for this purpose is widely accepted. Today, the term MR-guidance has received a much broader meaning, including MRI for adaptive treatments, MR-gating and tracking during radiotherapy application, MR-features as biomarkers and finally MR-only workflows. First studies on treatment of head and neck cancer on commercially available dedicated hybrid-platforms (MR-linacs), with distinct common features but also differences amongst them, have also been recently reported, as well as "biological adaptation" based on evaluation of early treatment response via functional MRI-sequences such as diffusion weighted ones. Yet, all of these approaches towards head and neck treatment remain at their infancy, especially when compared to other radiotherapy indications. Moreover, the lack of standardization for reporting MR-guided radiotherapy is a major obstacle both to further progress in the field and to conduct and compare clinical trials. Goals of this article is to present and explain all different aspects of MR-guidance for radiotherapy of head and neck cancer, summarize evidence, as well as possible advantages and challenges of the method and finally provide a comprehensive reporting guidance for use in clinical routine and trials.

The value of subcutaneous xenografts for individualised radiotherapy in HNSCC: Robust gene signature correlates with radiotherapy outcome in patients and xenografts.

PURPOSE: To assess the robustness of prognostic biomarkers and molecular tumour subtypes developed for patients with head and neck squamous cell carcinoma (HNSCC) on cell-line derived HNSCC xenograft models, and to develop a novel biomarker signature by combining xenograft and patient datasets. MATERIALS AND METHODS: Mice bearing xenografts (n = 59) of ten HNSCC cell lines and a retrospective, multicentre patient cohort (n = 242) of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) were included. All patients received postoperative radiochemotherapy (PORT-C). Gene expression analysis was conducted using GeneChip Human Transcriptome Arrays. Xenografts were stratified based on their molecular subtypes and previously established gene classifiers. The dose to control 50 % of tumours (TCD50) was compared between these groups. Using differential gene expression analyses combining xenograft and patient data, a gene signature was developed to define risk groups for the primary endpoint loco-regional control (LRC). RESULTS: Tumours of mesenchymal subtype were characterized by a higher TCD50 (xenografts, p < 0.001) and lower LRC (patients, p < 0.001) compared to the other subtypes. Similar to previously published patient data, hypoxia- and radioresistance-related gene signatures were associated with high TCD50 values. A 2-gene signature (FN1, SERPINE1) was developed that was prognostic for TCD50 (xenografts, p < 0.001) and for patient outcome in independent validation (LRC: p = 0.007). CONCLUSION: Genetic prognosticators of outcome for patients after PORT-C and subcutaneous xenografts after primary clinically relevant irradiation show similarity. The identified robust 2-gene signature may help to guide patient stratification, after prospective validation. Thus, xenografts remain a valuable resource for translational research towards the development of individualized radiotherapy.

A Multicenter Evaluation of Different Chemotherapy Regimens in Older Adults With Head and Neck Squamous Cell Carcinoma Undergoing Definitive Chemoradiation.

PURPOSE: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. METHODS AND MATERIALS: The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine-Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. RESULTS: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P < .05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P = .05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P = .46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P > .05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P = .02), increased PFS (HR, 0.66 [0.51-0.87]; P = .003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P = .004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P = .009). CONCLUSIONS: Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC.

Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

A multi-centric evaluation of self-learning GAN based pseudo-CT generation software for low field pelvic magnetic resonance imaging.

Purpose/objectives: An artificial intelligence-based pseudo-CT from low-field MR images is proposed and clinically evaluated to unlock the full potential of MRI-guided adaptive radiotherapy for pelvic cancer care. Materials and method: In collaboration with TheraPanacea (TheraPanacea, Paris, France) a pseudo-CT AI-model was generated using end-to-end ensembled self-supervised GANs endowed with cycle consistency using data from 350 pairs of weakly aligned data of pelvis planning CTs and TrueFisp-(0.35T)MRIs. The image accuracy of the generated pCT were evaluated using a retrospective cohort involving 20 test cases coming from eight different institutions (US: 2, EU: 5, AS: 1) and different CT vendors. Reconstruction performance was assessed using the organs at risk used for treatment. Concerning the dosimetric evaluation, twenty-nine prostate cancer patients treated on the low field MR-Linac (ViewRay) at Montpellier Cancer Institute were selected. Planning CTs were non-rigidly registered to the MRIs for each patient. Treatment plans were optimized on the planning CT with a clinical TPS fulfilling all clinical criteria and recalculated on the warped CT (wCT) and the pCT. Three different algorithms were used: AAA, AcurosXB and MonteCarlo. Dose distributions were compared using the global gamma passing rates and dose metrics. Results: The observed average scaled (between maximum and minimum HU values of the CT) difference between the pCT and the planning CT was 33.20 with significant discrepancies across organs. Femoral heads were the most reliably reconstructed (4.51 and 4.77) while anal canal and rectum were the less precise ones (63.08 and 53.13). Mean gamma passing rates for 1%1mm, 2%/2mm, and 3%/3mm tolerance criteria and 10% threshold were greater than 96%, 99% and 99%, respectively, regardless the algorithm used. Dose metrics analysis showed a good agreement between the pCT and the wCT. The mean relative difference were within 1% for the target volumes (CTV and PTV) and 2% for the OARs. Conclusion: This study demonstrated the feasibility of generating clinically acceptable an artificial intelligence-based pseudo CT for low field MR in pelvis with consistent image accuracy and dosimetric results.

Efficacy and safety analysis in metastatic cancer patients treated with multiple courses of repeat radiation therapy.

Background and purpose: Due to advances in oncology, a growing proportion of patients is treated with repetitive courses of radiotherapy. The aim of this study is to analyze whether radiotherapy maintains its safety and efficacy profile in patients treated with multiple repeat courses of irradiation. Material and methods: All patients treated between 2011 and 2019 at our institution were screened for a minimum of five repeat irradiation courses, to analyze treatment characteristics, survival, safety and efficacy. The type of re-irradiation was classified according to ESTRO-EORTC consensus guidelines. Results: A total of n = 112 patients receiving n = 660 radiotherapy courses were included in this retrospective cohort study. The most frequent primary tumors were lung cancer in 41.9 % (n = 47) and malignant melanoma in 8.9 % (n = 10). The most frequent re-irradiation types were repeat irradiation and Type 2 re-irradiation in 309 (46.8 %) and 113 (17.1 %) cases, respectively. Median survival after the first course of radiotherapy was 3.6 (0.3-13.4) years. Response to radiotherapy was observed in 548 (83.0 %) cases and CTCAE toxicity grade ≥ 3 was observed in 21 (3.2 %) cases. An increasing number of RT courses (HR: 1.30, p=<0.0001), Type 1 re-irradiation (HR 3.50, p = 0.008) and KPS ≤ 80 % (HR: 2.02, p = 0.002) were associated with significantly worse treatment responses. Toxicity rates remained stable with increasing numbers of RT courses. Conclusion: Multiple courses of repeat radiotherapy maintain a favorable therapeutic ratio of high response combined with reasonable safety profile.

Re-irradiation in clinical practice: Results of an international patterns of care survey within the framework of the ESTRO-EORTC E2-RADIatE platform.

BACKGROUND: Re-irradiation is an increasingly utilized treatment for recurrent, metastatic or new malignancies after previous radiotherapy. It is unclear how re-irradiation is applied in clinical practice. We aimed to investigate the patterns of care of re-irradiation internationally. MATERIAL/METHODS: A cross-sectional survey conducted between March and September 2022. The survey was structured into six sections, each corresponding to a specific anatomical region. Participants were instructed to complete the sections of their clinical expertise. A total of 15 multiple-choice questions were included in each section, addressing various aspects of the re-irradiation process. The online survey targeted radiation and clinical oncologists and was endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC). RESULTS: 371 physicians from 55 countries across six continents participated. Participants had a median professional experience of 16 years, and the majority (60%) were affiliated with an academic hospital. The brain region was the most common site for re-irradiation (77%), followed by the pelvis (65%) and head and neck (63%). Prolonging local control was the most common goal (90-96% across anatomical regions). The most common minimum interval between previous radiotherapy and re-irradiation was 6-12 months (45-55%). Persistent grade 3 or greater radiation-induced toxicity (77-80%) was the leading contraindication. Variability in organs at risk dose constraints for re-irradiation was observed. Advanced imaging modalities and conformal radiotherapy techniques were predominantly used. A scarcity of institutional guidelines for re-irradiation was reported (16-19%). Participants from European centers more frequently applied thoracic and abdominal re-irradiation. Indications did not differ between academic and non-academic hospitals. CONCLUSION: This study highlights the heterogeneity in re-irradiation practices across anatomical regions and emphasizes the need for high-quality evidence from prospective studies to guide treatment decisions and derive safe cumulative dose constraints.

Multitask Learning with Convolutional Neural Networks and Vision Transformers Can Improve Outcome Prediction for Head and Neck Cancer Patients.

Neural-network-based outcome predictions may enable further treatment personalization of patients with head and neck cancer. The development of neural networks can prove challenging when a limited number of cases is available. Therefore, we investigated whether multitask learning strategies, implemented through the simultaneous optimization of two distinct outcome objectives (multi-outcome) and combined with a tumor segmentation task, can lead to improved performance of convolutional neural networks (CNNs) and vision transformers (ViTs). Model training was conducted on two distinct multicenter datasets for the endpoints loco-regional control (LRC) and progression-free survival (PFS), respectively. The first dataset consisted of pre-treatment computed tomography (CT) imaging for 290 patients and the second dataset contained combined positron emission tomography (PET)/CT data of 224 patients. Discriminative performance was assessed by the concordance index (C-index). Risk stratification was evaluated using log-rank tests. Across both datasets, CNN and ViT model ensembles achieved similar results. Multitask approaches showed favorable performance in most investigations. Multi-outcome CNN models trained with segmentation loss were identified as the optimal strategy across cohorts. On the PET/CT dataset, an ensemble of multi-outcome CNNs trained with segmentation loss achieved the best discrimination (C-index: 0.29, 95% confidence interval (CI): 0.22-0.36) and successfully stratified patients into groups with low and high risk of disease progression (p=0.003). On the CT dataset, ensembles of multi-outcome CNNs and of single-outcome ViTs trained with segmentation loss performed best (C-index: 0.26 and 0.26, CI: 0.18-0.34 and 0.18-0.35, respectively), both with significant risk stratification for LRC in independent validation (p=0.002 and p=0.011). Further validation of the developed multitask-learning models is planned based on a prospective validation study, which has recently completed recruitment.

Dosimetric analysis of 17 cardiac Sub-structures, Toxicity, and survival in ultra central lung tumor patients treated with SBRT.

•Data on cardiac toxicity after SBRT for ultra-central lung tumors remains limited.•We analyzed the dose to 18 cardiac sub-structures and cardiovascular toxicity.•A SBRT regimen of 45 Gy in 8-10 fractions yields good local control and low toxicity.•The highest cardiac doses were observed in the pulmonary artery and left atrium.•Higher doses to the base of the heart seem to be associated with non-cancer deaths.

Synthetic computed tomography for low-field magnetic resonance-only radiotherapy in head-and-neck cancer using residual vision transformers.

Background and purpose: Synthetic computed tomography (sCT) scans are necessary for dose calculation in magnetic resonance (MR)-only radiotherapy. While deep learning (DL) has shown remarkable performance in generating sCT scans from MR images, research has predominantly focused on high-field MR images. This study presents the first implementation of a DL model for sCT generation in head-and-neck (HN) cancer using low-field MR images. Specifically, the use of vision transformers (ViTs) was explored. Materials and methods: The dataset consisted of 31 patients, resulting in 196 pairs of deformably-registered computed tomography (dCT) and MR scans. The latter were obtained using a balanced steady-state precession sequence on a 0.35T scanner. Residual ViTs were trained on 2D axial, sagittal, and coronal slices, respectively, and the final sCTs were generated by averaging the models' outputs. Different image similarity metrics, dose volume histogram (DVH) deviations, and gamma analyses were computed on the test set (n = 6). The overlap between auto-contours on sCT scans and manual contours on MR images was evaluated for different organs-at-risk using the Dice score. Results: The median [range] value of the test mean absolute error was 57 [37-74] HU. DVH deviations were below 1% for all structures. The median gamma passing rates exceeded 94% in the 2%/2mm analysis (threshold = 90%). The median Dice scores were above 0.7 for all organs-at-risk. Conclusions: The clinical applicability of DL-based sCT generation from low-field MR images in HN cancer was proved. High sCT-dCT similarity and dose metric accuracy were achieved, and sCT suitability for organs-at-risk auto-delineation was shown.

Mortality during or shortly after curative-intent radio-(chemo-) therapy over the last decade at a large comprehensive cancer center.

Background and Introduction: Definitive surgical, oncological and radio-oncological treatment may result in significant morbidity and acute mortality. Mortality during or shortly after treatment in patients undergoing curative radio-(chemo)-therapy has not been studied systematically. We reviewed all curative radio-(chemo-)therapies at a large comprehensive cancer center over the last decade. Materials and Methods: The institutional record was screened for patients who received curative-intent radio-(chemo-)therapy and deceased during or within 30 days after radiotherapy. Curative therapy was defined as prescribed dosage of EQD2 ≥ 50 Gy for radiotherapy alone and EQD2 ≥ 40 Gy for radiochemotherapies. Data on demographics, disease and treatment were assembled and assessed. Results: Of 15,255 radiotherapy courses delivered at our center, 8,515 (56%) were performed with curative-intent. During or within 30 days after radio-(chemo-)therapy, 78 patients died (0.9% of all curative-intent courses). Median age of the deceased patients was 70 (IQR, 62-78) years, and 36% (28/78) were female. Median pre-therapeutic ECOG-PS was 1 (IQR, 0-2) and Charlson-Comorbidity-Index was 3+ (IQR, 2-3+). The most common primary malignancies were head and neck cancer (33/78; 42%) and central nervous system tumors (13/78; 17%). Peritherapeutic mortality varied by primary tumor, with the highest prevalence observed in head and neck and gastrointestinal cancer patients with 2.9% (33/1,144) and 2.4% (8/332), respectively. Among patients with known cause of death (34/78; 44%), tumor progression (12/34; 35%) and pulmonary complications/causes (11/34; 35%) were most common. On multivariable regression analysis, a worse ECOG-PS was associated with a relatively earlier peri-radiotherapeutic death (p = 0.014). Conclusion: Mortality during or within 30 days of curative-intent radio-(chemo-)therapy was low, yet highest for head and neck (2.9%) and gastrointestinal tumor (2.4%) patients. Reasons for these findings include rapid tumor progression in some cancers, good patient selection, with ECOG-PS being most useful and predictive for avoiding early mortality. Future research should help refine predictors for peri-RT mortality.

Histopathological Analysis of Nodal Disease After Chemoradiation Reveals Viable Tumor Cells as the most Important Prognostic Factor in Head and Neck Squamous Cell Carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), salvage neck dissection (ND) is required after primary chemoradiation in case of residual nodal disease. Upon histopathological examination, viability of tumor cells is assessed but little is known about other prognostic histopathological features. In particular, the presence of swirled keratin debris and its prognostic value is controversial. The aim of this study is to examine histopathological parameters in ND specimens and correlate them with patient outcome to determine the relevant parameters for histopathological reporting. MATERIALS AND METHODS: Salvage ND specimen from a cohort of n = 75 HNSCC (oropharynx, larynx, hypopharynx) patients with prior (chemo) radiation were evaluated on H&E stains for the following parameters: viable tumor cells, necrosis, swirled keratin debris, foamy histiocytes, bleeding residues, fibrosis, elastosis, pyknotic cells, calcification, cholesterol crystals, multinucleated giant cells, perineural, and vascular invasion. Histological features were correlated with survival outcomes. RESULTS: Only the presence / amount (area) of viable tumor cells correlated with a worse clinical outcome (local and regional recurrence-free survival, (LRRFS), distant metastasis-free survival, disease-specific survival, and overall survival, p < 0.05) in both the univariable and multivariable analyses. CONCLUSION: We could confirm the presence of viable tumor cells as a relevant negative prognostic factor after (chemo) radiation. The amount (area) of viable tumor cells further substratified patients with worse LRRFS. None of the other parameters correlated with a distinctive worse outcome. Importantly, the presence of (swirled) keratin debris alone should not be considered viable tumor cells (ypN0).

Overview of the HECKTOR Challenge at MICCAI 2022: Automatic Head and Neck Tumor Segmentation and Outcome Prediction in PET/CT.

This paper presents an overview of the third edition of the HEad and neCK TumOR segmentation and outcome prediction (HECKTOR) challenge, organized as a satellite event of the 25th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) 2022. The challenge comprises two tasks related to the automatic analysis of FDG-PET/CT images for patients with Head and Neck cancer (H&N), focusing on the oropharynx region. Task 1 is the fully automatic segmentation of H&N primary Gross Tumor Volume (GTVp) and metastatic lymph nodes (GTVn) from FDG-PET/CT images. Task 2 is the fully automatic prediction of Recurrence-Free Survival (RFS) from the same FDG-PET/CT and clinical data. The data were collected from nine centers for a total of 883 cases consisting of FDG-PET/CT images and clinical information, split into 524 training and 359 test cases. The best methods obtained an aggregated Dice Similarity Coefficient (DSCagg) of 0.788 in Task 1, and a Concordance index (C-index) of 0.682 in Task 2.

Effect of 0.35 T and 1.5 T magnetic fields on superficial dose in MR-guided radiotherapy of laryngeal cancer.

Background: Treatment of head and neck cancer on linear accelerators with on-board magnetic resonance imaging (MR-linac) might be beneficial to reduce side effects and increase accuracy. For many head and neck cancer patients, dose coverage of the often superficially located planning target volumes (PTVs) is required. This study examines the impact of the electron return effect (ERE) on the surface dose in MR-guided radiotherapy (MRgRT) compared to conventional radiotherapy. Materials and methods: For this bicentric dosimetric study, 14 cases of laryngeal carcinomas with PTVs reaching up to the skin surface were included. For each patient, five different plans were compared, two VMAT plans (with and without a 5 mm bolus) and three IMRT MRgRT plans (0.35 T, 1.5 T and 0 T, each without bolus). Dose distributions were also validated with film measurements. Results: A similar coverage on the most superficial 3-5 mm of the PTV was achieved in the VMAT plans with bolus and the MRgRT plans for both 0.35 T and 1.5 T. However, coverage on this region was usually not achieved for VMAT without bolus and the 0 T plans. The film measurements on phantoms confirmed the results with the relative error never exceeding the calculated differences between the plans. Conclusion: The present study could demonstrate that the ERE for both commercially available MR-linac variants provides sufficient coverage of the superficial tissue layers in MRgRT-plans for laryngeal carcinoma.

DNA-Methylome-Based Tumor Hypoxia Classifier Identifies HPV-Negative Head and Neck Cancer Patients at Risk for Locoregional Recurrence after Primary Radiochemotherapy.

PURPOSE: Tumor hypoxia is a paradigmatic negative prognosticator of treatment resistance in head and neck squamous cell carcinoma (HNSCC). The lack of robust and reliable hypoxia classifiers limits the adaptation of stratified therapies. We hypothesized that the tumor DNA methylation landscape might indicate epigenetic reprogramming induced by chronic intratumoral hypoxia. EXPERIMENTAL DESIGN: A DNA-methylome-based tumor hypoxia classifier (Hypoxia-M) was trained in the TCGA (The Cancer Genome Atlas)-HNSCC cohort based on matched assignments using gene expression-based signatures of hypoxia (Hypoxia-GES). Hypoxia-M was validated in a multicenter DKTK-ROG trial consisting of human papillomavirus (HPV)-negative patients with HNSCC treated with primary radiochemotherapy (RCHT). RESULTS: Although hypoxia-GES failed to stratify patients in the DKTK-ROG, Hypoxia-M was independently prognostic for local recurrence (HR, 4.3; P = 0.001) and overall survival (HR, 2.34; P = 0.03) but not distant metastasis after RCHT in both cohorts. Hypoxia-M status was inversely associated with CD8 T-cell infiltration in both cohorts. Hypoxia-M was further prognostic in the TCGA-PanCancer cohort (HR, 1.83; P = 0.04), underscoring the breadth of this classifier for predicting tumor hypoxia status. CONCLUSIONS: Our findings highlight an unexplored avenue for DNA methylation-based classifiers as biomarkers of tumoral hypoxia for identifying high-risk features in patients with HNSCC tumors. See related commentary by Heft Neal and Brenner, p. 2954.