The contemporary management of cancers of the sinonasal tract in adults.

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials.

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

Lost in the plot: missing visual elements in Kaplan-Meier plots of phase III oncology trials.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research.

Inconsistent Partitioning and Unproductive Feature Associations Yield Idealized Radiomic Models.

Background Radiomics is the extraction of predefined mathematic features from medical images for the prediction of variables of clinical interest. While some studies report superlative accuracy of radiomic machine learning (ML) models, the published methodology is often incomplete, and the results are rarely validated in external testing data sets. Purpose To characterize the type, prevalence, and statistical impact of methodologic errors present in radiomic ML studies. Materials and Methods Radiomic ML publications were reviewed for the presence of performance-inflating methodologic flaws. Common flaws were subsequently reproduced with randomly generated features interpolated from publicly available radiomic data sets to demonstrate the precarious nature of reported findings. Results In an assessment of radiomic ML publications, the authors uncovered two general categories of data analysis errors: inconsistent partitioning and unproductive feature associations. In simulations, the authors demonstrated that inconsistent partitioning augments radiomic ML accuracy by 1.4 times from unbiased performance and that correcting for flawed methodologic results in areas under the receiver operating characteristic curve approaching a value of 0.5 (random chance). With use of randomly generated features, the authors illustrated that unproductive associations between radiomic features and gene sets can imply false causality for biologic phenomenon. Conclusion Radiomic machine learning studies may contain methodologic flaws that undermine their validity. This study provides a review template to avoid such flaws. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Jacobs in this issue.

Early detection of mandible osteoradionecrosis risk in a high comorbidity veteran population.

OBJECTIVE: Osteoradionecrosis (ORN) of the mandible is a devastating complication of external beam radiation therapy (EBRT) for head and neck squamous cell carcinoma (HNSCC). We sought to ascertain ORN risk in a Veteran HNSCC population treatment with definitive or adjuvant EBRT and followed prospectively. STUDY DESIGN: Retrospective analysis of prospective cohort. SETTING: Tertiary care Veterans Health Administration (VHA) medical center. METHODS: Patients with HNSCC who initiated treatment at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) are prospectively tracked for quality of care purposes through the end of the cancer surveillance period (5 years post treatment completion). We retrospectively analyzed this patient cohort and extracted clinical and pathologic data for 164 patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who received definitive or adjuvant EBRT (2016-2020). RESULTS: Most patients were dentate and 80 % underwent dental extractions prior to EBRT of which 16 (16 %) had complications. The rate of ORN was 3.7 % for oral cavity SCC patients and 8.1 % for oropharyngeal SCC patients. Median time to ORN development was 156 days and the earliest case was detected at 127 days post EBRT completion. All ORN patients were dentate and underwent extraction prior to EBRT start. CONCLUSION: ORN development can occur early following EBRT in a Veteran population with significant comorbid conditions but overall rates are in line with the general population. Prospective tracking of HNSCC patients throughout the post-treatment surveillance period is critical to early detection of this devastating EBRT complication.

Modeling symptom drivers of oral intake in long-term head and neck cancer survivors.

PURPOSE: This study examined the relationship between self-reported symptom severity and oral intake in long-term head and neck cancer (HNC) survivors. METHODS: An observational survey study with retrospective chart abstraction was conducted. HNC patients who had completed an MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) questionnaire and also had clinician graded oral intake ratings (Functional Oral Intake Scale [FOIS]) were included. Correlation coefficients were computed. FOIS scores were regressed on MDASI-HN symptom items using stepwise backwards elimination for multivariate models. RESULTS: One hundred and fifty-two survey pairings were included in the analysis (median 44 months follow-up, range 7-198). Per FOIS, 28% of survivors maintained a total oral diet with no restrictions, 67% reported a restricted oral diet (without tube), 3% were partially tube-dependent with some oral intake, and 2% were NPO. Of the 22 symptom items, the most severe items in decreasing order were dry mouth, difficulty swallowing\chewing, problems with mucus, tasting food, and choking/coughing. Significant bivariate correlations, after Bonferroni correction for multiple comparisons, were present for 8 of 22 symptoms with FOIS. On multivariate analysis, symptom severity for difficulty swallowing and problems with teeth/gums remained significantly associated with FOIS. CONCLUSIONS: Oral intake in HNC survivorship is a multidimensional issue and functional outcome that is impacted not only by dysphagia but also by dental status. Symptom drivers of oral intake likely differ in acute survivorship. Nonetheless, these findings highlight the lack of specificity in this end point and also the need for multidisciplinary supportive care to optimize oral intake in survivors.

Use of the g-index for assessment of citation-based scholarly activity of United States radiation oncology residents and subsequent choice of academic versus private practice career.

INTRODUCTION: The Hirsch index (h-index) evaluates citation-based scholarly activity, but has limited ability to acknowledge those publishing a smaller number of manuscripts with exceedingly high citations. The g-index addresses this limitation by assessing the largest number of manuscripts (g) by an author cited at least (g × g) times, but has yet to be applied to radiation oncology resident productivity. METHODS: A list of recent radiation oncology resident graduates (comprising 86% of the 2016 graduating class) and their post-residency career choice was compiled. The Scopus bibliometric citation database was searched to collect and calculate g-index data for each resident. RESULTS: The mean g-index score for all resident graduates was 7.16. Residents with a PhD had significantly higher g-index scores (11.97 versus 5.80; p < 0.01), while there was no statistically significant difference in g-index scores between male and female residents. Residents choosing academic careers had higher g-index scores than those choosing private practice (9.47 versus 4.99; p < 0.01). Programs graduating at least three residents produced significantly higher g-index scores/resident than those graduating two residents, and while comprising only 25% of programs and 45% of residents, produced 60% of academic careers (p < 0.02). CONCLUSION: Radiation oncology resident graduates published on average a minimum of seven manuscripts cited at least 49 times. PhD-degree graduates had significantly higher g-index scores, as did residents choosing academic over private practice careers. There was no significant gender-related difference in g-index score regardless of career choice. The majority of academic careers are produced from programs graduating at least three residents.

Outcomes of patients diagnosed with carcinoma metastatic to the neck from an unknown primary source and treated with intensity-modulated radiation therapy.

BACKGROUND: There are few published studies to guide the treatment of carcinoma metastatic to the neck from an unknown primary (CUP). In this regard, the objective of the current study was to share the authors' current experience treating patients with CUP using intensity-modulated radiation therapy (IMRT), which principally targeted both sides of the neck, the nasopharynx, and the oropharynx. METHODS: This was a retrospective study in which an institutional database search was conducted to identify patients with CUP who received IMRT. Data analysis included frequency tabulation, survival analysis, and multivariable analysis. RESULTS: Two-hundred sixty patients met inclusion criteria. The most common lymph node category was N2b (54%). IMRT volumes included the entire pharyngolaryngeal mucosa in 78 patients, the nasopharynx and oropharynx in 167 patients, and treatment limited to the involved neck in 11 patients. Eighty-four patients underwent neck dissections. The 5-year overall survival, regional control, and distant metastases-free survival rates were 84%, 91%, and 94%, respectively. Over 40% of patients had gastrostomy tubes during therapy, and 7% patients were diagnosed with chronic radiation-associated dysphagia. Higher lymph node burden was associated with worse disease-related outcomes, and in subgroup analysis, patients with human papillomavirus-associated disease had better outcomes. No therapeutic modality was statistically associated with either disease-related outcomes or toxicity. CONCLUSIONS: Comprehensive IMRT with treatment to both sides of the neck and to the oropharyngeal and nasopharyngeal mucosa results in high rates of disease control and survival. The investigators were unable to demonstrate that treatment intensification with chemotherapy or surgery added benefit or excessive toxicity. Cancer 2018;124:1415-27. © 2018 American Cancer Society.

Long-term outcomes after surgical or nonsurgical initial therapy for patients with T4 squamous cell carcinoma of the larynx: A 3-decade survey.

BACKGROUND: The current study was conducted to evaluate long-term disease control, survival, and functional outcomes after surgical and nonsurgical initial treatment for patients with T4 larynx cancer. METHODS: Demographics, disease stage, and treatment characteristics were reviewed for 221 sequential patients treated for T4 laryngeal squamous cell cancer at a single institution between 1983 and 2011. Survival and disease control outcomes were calculated. RESULTS: The median follow-up time was 47 months (71 months for patients still alive at the time of analysis). The overall 5-year and 10-year overall survival rates were 52% and 29%, respectively, and the corresponding disease-free survival rates were 57% and 48%, respectively. Overall 5-year and 10-year locoregional control rates were 78% and 67%, respectively, and the corresponding rates for freedom from distant metastasis were 76% and 74%, respectively. On both univariate and multivariate analyses, lymph node-positive disease at the time of presentation was associated with overall mortality (P<.0001). Patients treated with laryngectomy followed by postlaryngectomy radiotherapy (161 patients) achieved better initial locoregional control than patients treated with a laryngeal preservation (LP) approach (60 patients) throughout the follow-up period (log-rank P<.007) yet the median overall survival times were equal for both groups (64 months; 95% confidence interval 47-87 months and 38-87 months, respectively [P =.7]). Patients treated with an LP approach had a tracheostomy rate of 45% and an any-event aspiration rate of 23%. Rates of high-grade dysphagia at the time of last follow-up were worse for patients treated with an LP approach (P<.01). CONCLUSIONS: Surgery and postoperative radiotherapy can produce substantial long-term cancer control and survival rates for patients with T4 larynx cancer. Caution should be taken when selecting patients for initial nonsurgical treatment because of significant rates of functional impairment despite survival equivalence.

DITTO: A Visual Digital Twin for Interventions and Temporal Treatment Outcomes in Head and Neck Cancer.

Digital twin models are of high interest to Head and Neck Cancer (HNC) oncologists, who have to navigate a series of complex treatment decisions that weigh the efficacy of tumor control against toxicity and mortality risks. Evaluating individual risk profiles necessitates a deeper understanding of the interplay between different factors such as patient health, spatial tumor location and spread, and risk of subsequent toxicities that can not be adequately captured through simple heuristics. To support clinicians in better understanding tradeoffs when deciding on treatment courses, we developed DITTO, a digital-twin and visual computing system that allows clinicians to analyze detailed risk profiles for each patient, and decide on a treatment plan. DITTO relies on a sequential Deep Reinforcement Learning digital twin (DT) to deliver personalized risk of both long-term and short-term disease outcome and toxicity risk for HNC patients. Based on a participatory collaborative design alongside oncologists, we also implement several visual explainability methods to promote clinical trust and encourage healthy skepticism when using our system. We evaluate the efficacy of DITTO through quantitative evaluation of performance and case studies with qualitative feedback. Finally, we discuss design lessons for developing clinical visual XAI applications for clinical end users.

Prevention and Management of Osteoradionecrosis in Patients With Head and Neck Cancer Treated With Radiation Therapy: ISOO-MASCC-ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of osteoradionecrosis (ORN) of the jaw secondary to head and neck radiation therapy in patients with cancer. METHODS: The International Society of Oral Oncology-Multinational Association for Supportive Care in Cancer (ISOO-MASCC) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library databases were searched for randomized controlled trials and observational studies, published between January 1, 2009, and December 1, 2023. The guideline also incorporated systematic reviews conducted by ISOO-MASCC, which included studies published from January 1, 1990, through December 31, 2008. RESULTS: A total of 1,539 publications were initially identified. There were 487 duplicate publications, resulting in 1,052 studies screened by abstract, 104 screened by full text, and 80 included for systematic review evaluation. RECOMMENDATIONS: Due to limitations of available evidence, the guideline relied on informal consensus for some recommendations. Recommendations that were deemed evidence-based with strong evidence by the Expert Panel were those pertaining to best practices in prevention of ORN and surgical management. No recommendation was possible for the utilization of leukocyte- and platelet-rich fibrin or photobiomodulation for prevention of ORN. The use of hyperbaric oxygen in prevention and management of ORN remains largely unjustified, with limited evidence to support its practice.Additional information is available at www.asco.org/head-neck-cancer-guidelines.

Factors Associated With Open Access Publishing Costs in Oncology Journals: Cross-sectional Observational Study.

BACKGROUND: Open access (OA) publishing represents an exciting opportunity to facilitate the dissemination of scientific information to global audiences. However, OA publishing is often associated with significant article processing charges (APCs) for authors, which may thus serve as a barrier to publication. OBJECTIVE: In this observational cohort study, we aimed to characterize the landscape of OA publishing in oncology and, further, identify characteristics of oncology journals that are predictive of APCs. METHODS: We identified oncology journals using the SCImago Journal & Country Rank database. All journals with an OA publication option and APC data openly available were included. We searched journal websites and tabulated journal characteristics, including APC amount (in US dollars), OA model (hybrid vs full), 2-year impact factor (IF), H-index, number of citable documents, modality/treatment specific (if applicable), and continent of origin. All APCs were converted to US-dollar equivalents for final analyses. Selecting variables with significant associations in the univariable analysis, we generated a multiple regression model to identify journal characteristics independently associated with OA APC amount. An audit of a random 10% sample of the data was independently performed by 2 authors to ensure data accuracy, precision, and reproducibility. RESULTS: Of 367 oncology journals screened, 251 met the final inclusion criteria. The median APC was US $2957 (IQR 1958-3450). The majority of journals (n=156, 62%) adopted the hybrid OA publication model and were based in Europe (n=119, 47%) or North America (n=87, 35%). The median (IQR) APC for all journals was US $2957 (1958-3540). Twenty-five (10%) journals had APCs greater than US $4000. There were 10 (4%) journals that offered OA publication with no publication charge. Univariable testing showed that journals with a greater number of citable documents (P<.001), higher 2-year IF (P<.001), higher H-index (P<.001), and those using the hybrid OA model (P<.001), or originating in Europe or North America (P<.001) tended to have higher APCs. In our multivariable model, the number of citable documents (ß=US $367, SD US $133; P=.006), 2-year IF (US $1144, SD US $177; P<.001), hybrid OA publishing model (US $991, SD US $189; P<.001), and North American origin (US $838, SD US $186; P<.001) persisted as significant predictors of processing charges. CONCLUSIONS: OA publication costs are greater in oncology journals that publish more citable articles, use the hybrid OA model, have a higher IF, and are based in North America or Europe. These findings may inform targeted action to help the oncology community fully appreciate the benefits of open science.

Improving Prediction of Late Symptoms using LSTM and Patient-reported Outcomes for Head and Neck Cancer Patients.

Patient-Reported Outcomes (PRO) are collected directly from the patients using symptom questionnaires. In the case of head and neck cancer patients, PRO surveys are recorded every week during treatment with each patient's visit to the clinic and at different follow-up times after the treatment has concluded. PRO surveys can be very informative regarding the patient's status and the effect of treatment on the patient's quality of life (QoL). Processing PRO data is challenging for several reasons. First, missing data is frequent as patients might skip a question or a questionnaire altogether. Second, PROs are patient-dependent, a rating of 5 for one patient might be a rating of 10 for another patient. Finally, most patients experience severe symptoms during treatment which usually subside over time. However, for some patients, late toxicities persist negatively affecting the patient's QoL. These long-term severe symptoms are hard to predict and are the focus of this study. In this work, we model PRO data collected from head and neck cancer patients treated at the MD Anderson Cancer Center using the MD Anderson Symptom Inventory (MDASI) questionnaire as time series. We impute missing values with a combination of K nearest neighbor (KNN) and Long Short-Term Memory (LSTM) neural networks, and finally, apply LSTM to predict late symptom severity 12 months after treatment. We compare performance against clinical and ARIMA models. We show that the LSTM model combined with KNN imputation is effective in predicting late-stage symptom ratings for occurrence and severity under the AUC and F1 score metrics.

Dysphagia and shortness-of-breath as markers for treatment failure and survival in oropharyngeal cancer after radiation.

BACKGROUND: Post-treatment symptoms are a focal point of follow-up visits for head and neck cancer patients. While symptoms such as dysphagia and shortness-of-breath early after treatment may motivate additional work up, their precise association with disease control and survival outcomes is not well established. METHODS: This prospective data cohort study of 470 oropharyngeal cancer patients analyzed patient-reported swallowing, choking and shortness-of-breath symptoms at 3-to-6 months following radiotherapy to evaluate their association with overall survival and disease control. Associations between the presence of moderate-to-severe swallowing, choking and mild-to-severe shortness-of-breath and treatment outcomes were analyzed via Cox regression and Kaplan-Meier. The main outcome was overall survival (OS), and the secondary outcomes were local, regional, and distant disease control. RESULTS: The majority of patients (91.3%) were HPV-positive. Median follow-up time was 31.7 months (IQR: 21.9-42.1). Univariable analysis showed significant associations between OS and all three symptoms of swallowing, choking, and shortness-of-breath. A composite variable integrating scores of all three symptoms was significantly associated with OS on multivariable Cox regression (p = 0.0018). Additionally, this composite symptom score showed the best predictive value for OS (c-index = 0.75). Multivariable analysis also revealed that the composite score was significantly associated with local (p = 0.044) and distant (p = 0.035) recurrence/progression. Notably, the same significant associations with OS were seen for HPV-positive only subset analysis (p < 0.01 for all symptoms). CONCLUSIONS: Quantitative patient-reported measures of dysphagia and shortness-of-breath 3-to-6 months post-treatment are significant predictors of OS and disease recurrence/progression in OPC patients and in HPV-positive OPC only.

Prevalence and implications of significance testing for baseline covariate imbalance in randomised cancer clinical trials: The Table 1 Fallacy.

BACKGROUND: The 'Table 1 Fallacy' refers to the unsound use of significance testing for comparing the distributions of baseline variables between randomised groups to draw erroneous conclusions about balance or imbalance. We performed a cross-sectional study of the Table 1 Fallacy in phase III oncology trials. METHODS: From ClinicalTrials.gov, 1877 randomised trials were screened. Multivariable logistic regressions evaluated predictors of the Table 1 Fallacy. RESULTS: A total of 765 randomised controlled trials involving 553,405 patients were analysed. The Table 1 Fallacy was observed in 25% of trials (188 of 765), with 3% of comparisons deemed significant (59 of 2353), approximating the typical 5% type I error assertion probability. Application of trial-level multiplicity corrections reduced the rate of significant findings to 0.3% (six of 2345 tests). Factors associated with lower odds of the Table 1 Fallacy included industry sponsorship (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.18-0.47; multiplicity-corrected P < 0.0001), larger trial size (≥795 versus <280 patients; aOR 0.32, 95% CI 0.19-0.53; multiplicity-corrected P = 0.0008), and publication in a European versus American journal (aOR 0.06, 95% CI 0.03-0.13; multiplicity-corrected P < 0.0001). CONCLUSIONS: This study highlights the persistence of the Table 1 Fallacy in contemporary oncology randomised controlled trials, with one of every four trials testing for baseline differences after randomisation. Significance testing is a suboptimal method for identifying unsound randomisation procedures and may encourage misleading inferences. Journal-level enforcement is a possible strategy to help mitigate this fallacy.

Head and Neck Radiation Therapy Patterns of Practice Variability Identified as a Challenge to Real-World Big Data: Results From the Learning from Analysis of Multicentre Big Data Aggregation (LAMBDA) Consortium.

Purpose: Outside of randomized clinical trials, it is difficult to develop clinically relevant evidence-based recommendations for radiation therapy (RT) practice guidelines owing to lack of comprehensive real-world data. To address this knowledge gap, we formed the Learning from Analysis of Multicenter Big Data Aggregation consortium to cooperatively implement RT data standardization, develop software solutions for data analysis, and recommend clinical practice change based on real-world data analyzed. The first phase of this "Big Data" study aimed at characterizing variability in clinical practice patterns of dosimetric data for organs at risk (OARs) that would undermine subsequent use of large-scale, electronically aggregated data to characterize associations with outcomes. Evidence from this study was used as the basis for practical recommendations to improve data quality. Methods and Materials: Dosimetric details of patients with head and neck cancer treated with radiation therapy between 2014 and 2019 were analyzed. Institutional patterns of practice were characterized, including structure nomenclature, volumes, and frequency of contouring. Dose volume histogram (DVH) distributions were characterized and compared with institutional constraints and literature values. Results: Plans for 4664 patients treated to a mean plan dose of 64.4 ± 13.2 Gy in 32 ± 4 fractions were aggregated. Before implementation of TG-263 guidelines in each institution, there was variability in OAR nomenclature across institutions and structures. With evidence from this study, we identified a targeted and practical set of recommendations aimed at improving the quality of real-world data. Conclusions: Quantifying similarities and differences among institutions for OAR structures and DVH metrics is the launching point for next steps to investigate potential relationships between DVH parameters and patient outcomes.

Development and Standardization of a Classification System for Osteoradionecrosis: Implementation of a Risk-Based Model.

Purpose: Osteoradionecrosis of the jaw (ORN) can manifest in varying severity. The aim of this study is to identify ORN risk factors and develop a novel classification to depict the severity of ORN. Methods: Consecutive head-and-neck cancer (HNC) patients treated with curative-intent IMRT (≥ 45Gy) in 2011-2018 were included. Occurrence of ORN was identified from in-house prospective dental and clinical databases and charts. Multivariable logistic regression model was used to identify risk factors and stratify patients into high-risk and low-risk groups. A novel ORN classification system was developed to depict ORN severity by modifying existing systems and incorporating expert opinion. The performance of the novel system was compared to fifteen existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). Results: ORN was identified in 219 out of 2732 (8%) consecutive HNC patients. Factors associated with high-risk of ORN were: oral-cavity or oropharyngeal primaries, received IMRT dose ≥60Gy, current/ex-smokers, and/or stage III-IV periodontal disease. The ORN rate for high-risk vs low-risk patients was 12.7% vs 3.1% (p<0.001) with an area-under-the-receiver-operating-curve (AUC) of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, RadORN, was proposed based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. This system detected serious ORN events in 5.7% of patients and statistically outperformed existing systems. Conclusion: We identified risk factors for ORN, and proposed a novel ORN classification system based on vertical extent of bone necrosis and presence/absence of exposed bone/fistula. It outperformed existing systems in depicting the seriousness of ORN, and may facilitate clinical care and clinical trials.

Development and implementation of optimized endogenous contrast sequences for delineation in adaptive radiotherapy on a 1.5T MR-linear-accelerator: a prospective R-IDEAL stage 0-2a quantitative/qualitative evaluation of in vivo site-specific quality-assurance using a 3D T2 fat-suppressed platform for head and neck cancer.

Purpose: To improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T hybrid magnetic resonance imaging/linear accelerator (MR-Linac), three-dimensional (3D), T2-weighted, fat-suppressed magnetic resonance imaging sequences were developed and optimized. Approach: After initial testing, spectral attenuated inversion recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a nonsuppressed, T2-weighted sequence were acquired for five HNC patients using a 1.5T MR-Linac. MR physicists identified persistent artifacts in two of the SPAIR sequences, so the remaining three SPAIR sequences were further analyzed. The gross primary tumor volume, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated using five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences on the basis of qualitative and quantitative metrics. Results: Sequences were analyzed for the signal-to-noise ratio and the contrast-to-noise ratio and compared with fat and muscle, conspicuity, pairwise distance metrics, and segmentor assessments. In this analysis, the nonsuppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but it was superior for the pterygoid muscles. The SPAIR sequence that received the highest combined score among the analysis categories was recommended to Unity MR-Linac users for HNC radiotherapy treatment planning. Conclusions: Our study led to two developments: an optimized, 3D, T2-weighted, fat-suppressed sequence that can be disseminated to Unity MR-Linac users and a robust image quality analysis pathway that can be used to objectively score SPAIR sequences and can be customized and generalized to any image quality optimization protocol. Improved segmentation accuracy with the proposed SPAIR sequence will potentially lead to improved treatment outcomes and reduced toxicity for patients by maximizing the target coverage and minimizing the radiation exposure of organs at risk.

Association between Prior Malignancy Exclusion Criteria and Age Disparities in Cancer Clinical Trials.

Prior malignancy exclusion criteria (PMEC) are often utilized in cancer clinical trials; however, the incidence of PMEC and the association of PMEC with trial participant age disparities remain poorly understood. This study aimed to identify age disparities in oncologic randomized clinical trials as a result of PMEC. Using a comprehensive collection of modern phase III cancer clinical trials obtained via ClinicalTrials.gov, we assessed the incidence and covariates associated with trials excluding patients with prior cancers within 5+ years from registration (PMEC-5). Using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database, we further sought to determine the correlation between PMEC-5 and age disparities. PMEC-5 were used in 41% of all trials, with higher PMEC-5 utilization among industry-supported trials as well as trials evaluating a targeted therapy. Comparing trial patient median ages with population-matched median ages by disease site and time-period, we assessed the association between PMEC-5 and age disparities among trial participants. PMEC-5 were independently associated with heightened age disparities, which further worsened with longer exclusionary timeframes. Together, PMEC likely contribute to age disparities, suggesting that eligibility criteria modernization through narrower PMEC timeframes may work toward reducing such disparities in cancer clinical trial enrollment.