Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study.

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

Development and Standardization of an Osteoradionecrosis Classification System in Head and Neck Cancer: 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 patients with head and neck cancer (HNC) treated with curative-intent intensity-modulated radiation therapy (IMRT) (≥45 Gy) from 2011 to 2017 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 with 15 existing systems for their ability to identify and predict serious ORN event (jaw fracture or requiring jaw resection). RESULTS: ORN was identified in 219 of 2,732 (8%) consecutive patients with HNC. Factors associated with high risk of ORN were oral cavity or oropharyngeal primaries, received IMRT dose ≥60 Gy, current/ex-smokers, and/or stage III to IV periodontal condition. The ORN rate for high-risk versus low-risk patients was 12.7% versus 3.1% (P < .001) with an AUC of 0.71. Existing ORN systems overclassified serious ORN events and failed to recognize maxillary ORN. A novel ORN classification system, ClinRad, was proposed on the basis of 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 on the basis of 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.

Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET).

PURPOSE: The use of stereotactic body radiation therapy for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (NCT03306680) aimed to determine the maximally tolerated dose of stereotactic body radiation therapy for ultracentral non-small cell lung carcinoma, using a time-to-event continual reassessment methodology. METHODS AND MATERIALS: Patients with T1-3N0M0 (≤6 cm) non-small cell lung carcinoma were eligible. The maximally tolerated dose was defined as the dose of radiation therapy associated with a ≤30% rate of grade (G) 3 to 5 prespecified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume; tumors with endobronchial invasion were excluded. This primary analysis occurred 2 years after completion of accrual. RESULTS: Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range, 65-87) and 17 (57%) were female. Planning tumor volume was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%), and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range, 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia. The latter had computed tomography findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% CI, 52.3%-85.3%), progression-free survival 66.1% (95% CI, 46.1%-80.2%), local control 89.6% (95% CI, 71.2%-96.5%), regional control 96.4% (95% CI, 77.2%-99.5%), and distant control 85.9% (95% CI, 66.7%-94.5%). Quality-of-life scores declined numerically over time, but the decreases were not clinically or statistically significant. CONCLUSIONS: Sixty Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the prespecified acceptability criteria and results in excellent control for ultracentral tumors.

Causes and impact of delays during the COVID-19 pandemic on head and neck cancer diagnosis.

BACKGROUND: The causes for delays during the COVID19 pandemic and their impact on head and neck cancer (HNC) diagnosis and staging are not well described. METHODS: Two cohorts were defined a priori for review and analysis-a Pre-Pandemic cohort (June 1 to December 31, 2019) and a Pandemic cohort (June 1 to December 31, 2020). Delays were categorized as COVID-19 related or not, and as clinician, patient, or policy related. RESULTS: A total of 638 HNC patients were identified including 327 in the Pre-Pandemic Cohort and 311 in the Pandemic Cohort. Patients in the Pandemic cohort had more N2-N3 category (41% vs. 33%, p = 0.03), T3-T4 category (63% vs. 50%, p = 0.002), and stage III-IV (71% vs. 58%, p < 0.001) disease. Several intervals in the diagnosis to treatment pathway were significantly longer in the pandemic cohort as compared to the Pre-Pandemic cohort. Among the pandemic cohort, 146 (47%) experienced a delay, with 112 related to the COVID-19 pandemic; 80 (71%) were clinician related, 15 (13%) were patient related, and 17 (15%) were policy related. CONCLUSIONS: Patients in the Pandemic cohort had higher stage disease at diagnosis and longer intervals along the diagnostic pathway, with COVID-19 related clinician factors being the most common cause of delay.

Telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER): A pilot study for patients treated with surgery for oral cavity carcinoma.

BACKGROUND: To address the rehabilitative barriers to frequency and precision of care, we conducted a pilot study of a biofeedback electropalatography (EPG) device paired with telemedicine for patients who underwent primary surgery +/- adjuvant radiation for oral cavity carcinoma. We hypothesized that lingual optimization followed by telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER) would further improve speech and swallowing outcomes after "standard-of-care" SOC rehabilitation. METHOD: Pilot prospective 8-week (TEBER) program following 8 weeks of (SOC) rehabilitation. RESULTS: Twenty-seven patients were included and 11 completed the protocol. When examining the benefit of TEBER independent of standard of care, "range-of-liquids" improved by +0.36 [95% CI, 0.02-0.70, p = 0.05] and "range-of-solids" improved by +0.73 [95% CI, 0.12-1.34, p = 0.03]. There was a positive trend toward better oral cavity obliteration; residual volume decreased by -1.2 [95% CI, -2.45 to 0.053, p = 0.06], and "nutritional-mode" increased by +0.55 [95% CI, -0.15 to 1.24, p = 0.08]. CONCLUSION: This pilot suggests that TEBER bolsters oral rehabilitation after 8 weeks of SOC lingual range of motion.

Exploring the Language Used to Describe Older Patients at Multidisciplinary Cancer Conferences.

Older adults with cancer often present with distinct complexities that complicate their care, yet the language used to discuss their management at multidisciplinary cancer conferences (MCCs) remains poorly understood. A mixed methods study was conducted at a tertiary cancer centre in Toronto, Canada, where MCCs spanning five tumour sites were attended over six months. For presentations pertaining to a patient aged 75 or older, a standardized data collection form was used to record their demographic, cancer-related, and non-cancer-related information, as well as the presenter's specialty and training level. Descriptive statistics and thematic analysis were employed to explore MCC depictions of older patients (n = 75). Frailty status was explicitly mentioned in 20.0% of presentations, but discussions more frequently referenced comorbidity burden (50.7%), age (33.3%), and projected treatment tolerance (30.7%) as surrogate measures. None of the presentations included mentions of formal geriatric assessment (GA) or validated frailty tools; instead, presenters tended to feature select GA domains and subjective descriptions of appearance ("looks to be fit") or overall health ("relatively healthy"). In general, MCCs appeared to rely on age-focused language that may perpetuate ageism. Further work is needed to investigate how frailty and geriatric considerations can be objectively incorporated into discussions in geriatric oncology.

Stereotactic Radiation Therapy in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease: A Nonrandomized Clinical Trial.

Importance: Patients with interstitial lung disease (ILD) and early-stage non-small cell lung cancer (NSCLC) have been reported to be at high risk of toxic effects after stereotactic ablative radiotherapy (SABR), but for many patients, there are limited alternative treatment options. Objective: To prospectively assess the benefits and toxic effects of SABR in this patient population. Design, Setting, and Participants: This prospective cohort study was conducted at 6 academic radiation oncology institutions, 5 in Canada and 1 in Scotland, with accrual between March 7, 2019, and January 12, 2022. Patients aged 18 years or older with fibrotic ILD and a diagnosis of T1-2N0 NSCLC who were not candidates for surgical resection were enrolled. Intervention: Patients were treated with SABR to a dose of 50 Gy in 5 fractions every other day. Main Outcomes and Measures: The study prespecified that SABR would be considered worthwhile if median overall survival-the primary end point-was longer than 1 year, with a grade 3 to 4 risk of toxic effects less than 35% and a grade 5 risk of toxic effects less than 15%. Secondary end points included toxic effects, progression-free survival (PFS), local control (LC), quality-of-life outcomes, and changes in pulmonary function. Intention-to-treat analysis was conducted. Results: Thirty-nine patients enrolled and received SABR. Median age was 78 (IQR, 67-83) years and 59% (n = 23) were male. At baseline, 70% (26 of 37) of patients reported dyspnea, median forced expiratory volume in first second of expiration was 80% (IQR, 66%-90%) predicted, median forced vital capacity was 84% (IQR, 69%-94%) predicted, and median diffusion capacity of the lung for carbon monoxide was 49% (IQR, 38%-61%) predicted. Median follow-up was 19 (IQR, 14-25) months. Overall survival at 1 year was 79% (95%, CI 62%-89%; P < .001 vs the unacceptable rate), and median overall survival was 25 months (95% CI, 14 months to not reached). Median PFS was 19 months (95% CI, 13-28 months), and 2-year LC was 92% (95% CI, 69%-98%). Adverse event rates (highest grade per patient) were grade 1 to 2: n = 12 (31%), grade 3: n = 4 (10%), grade 4: n = 0, and grade 5: n = 3 (7.7%, all due to respiratory deterioration). Conclusions and Relevance: In this trial, use of SABR in patients with fibrotic ILD met the prespecified acceptability thresholds for both toxicity and efficacy, supporting the use of SABR for curative-intent treatment after a careful discussion of risks and benefits. Trial Registration: ClinicalTrials.gov Identifier: NCT03485378.

RADCURE: An open-source head and neck cancer CT dataset for clinical radiation therapy insights.

PURPOSE: This manuscript presents RADCURE, one of the most extensive head and neck cancer (HNC) imaging datasets accessible to the public. Initially collected for clinical radiation therapy (RT) treatment planning, this dataset has been retrospectively reconstructed for use in imaging research. ACQUISITION AND VALIDATION METHODS: RADCURE encompasses data from 3346 patients, featuring computed tomography (CT) RT simulation images with corresponding target and organ-at-risk contours. These CT scans were collected using systems from three different manufacturers. Standard clinical imaging protocols were followed, and contours were manually generated and reviewed at weekly RT quality assurance rounds. RADCURE imaging and structure set data was extracted from our institution's radiation treatment planning and oncology information systems using a custom-built data mining and processing system. Furthermore, images were linked to our clinical anthology of outcomes data for each patient and includes demographic, clinical and treatment information based on the 7th edition TNM staging system (Tumor-Node-Metastasis Classification System of Malignant Tumors). The median patient age is 63, with the final dataset including 80% males. Half of the cohort is diagnosed with oropharyngeal cancer, while laryngeal, nasopharyngeal, and hypopharyngeal cancers account for 25%, 12%, and 5% of cases, respectively. The median duration of follow-up is five years, with 60% of the cohort surviving until the last follow-up point. DATA FORMAT AND USAGE NOTES: The dataset provides images and contours in DICOM CT and RT-STRUCT formats, respectively. We have standardized the nomenclature for individual contours-such as the gross primary tumor, gross nodal volumes, and 19 organs-at-risk-to enhance the RT-STRUCT files' utility. Accompanying demographic, clinical, and treatment data are supplied in a comma-separated values (CSV) file format. This comprehensive dataset is publicly accessible via The Cancer Imaging Archive. POTENTIAL APPLICATIONS: RADCURE's amalgamation of imaging, clinical, demographic, and treatment data renders it an invaluable resource for a broad spectrum of radiomics image analysis research endeavors. Researchers can utilize this dataset to advance routine clinical procedures using machine learning or artificial intelligence, to identify new non-invasive biomarkers, or to forge prognostic models.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

Dental Extractions Before Radiation Therapy and the Risk of Osteoradionecrosis in Patients With Head and Neck Cancer.

Importance: Patients with head and neck cancer undergo extraction of teeth with poor prognoses to minimize post-radiation therapy (RT) extractions, which are known to cause osteoradionecrosis (ORN). However, many patients are required to start RT before the extraction sites are completely healed. The role of pre-RT extractions in the development of ORN has been disputed in literature. Objective: To determine whether the timing of pre-RT dental extractions is associated with ORN development in patients with head and neck cancer. Design, Setting, and Participants: This retrospective cohort study was conducted at a single institution (Princess Margaret Cancer Centre, Toronto, Canada) between January 1, 2011, and January 1, 2018, and included 879 patients with head and neck cancer who underwent pre-RT dental extractions before curative RT of 45 Gy or greater. Patient demographic information and clinical characteristics (eg, primary cancer site, nodal involvement, chemotherapy, smoking status, dental pathology) were considered. Data analyses were performed from July to December 2022. Main outcomes and measures: Timing (number of days) from dental extractions to RT start date and pre-RT extractions categorized as healed, minor bone spicules (MBS), or ORN. Results: The study population consisted of 879 patients with a median (range) age of 62 (20-96) years, with 685 men (78%) and 194 women (22%). Of these, 847 (96.3%) healed from pre-RT dental extractions, 16 (1.8%) developed MBS, and 16 (1.8%) developed ORN. The median (range) time in number of days from pre-RT extraction(s) to start of RT was 9 (0-98) days in the healed cohort, 6 (3-23) days in the MBS cohort, and 6 (0-12) days in the ORN cohort. There was a large difference in the timing of pre-RT extractions between the healed and the MBS cohorts (mean 11.9 vs 7.4 days to radiation; difference 4.4; 95% CI, 1.5-7.3), and the healed and the ORN cohorts (mean 11.9 vs 7.1 days; difference 4.8 days; 95% CI, 2.6-7.1). Conclusion: The findings of this retrospective cohort study suggest that there was an important association between the timing of pre-RT dental extractions and ORN when extractions occurred within 7 days of the RT start date. Despite this, ORN after pre-RT extractions is relatively rare. These findings indicate that patients with head and neck cancer who are to undergo RT should not delay treatment for extractions when it might compromise oncologic control.

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.

Evaluation of clinical decision support systems in oncology: An updated systematic review.

With increasing reliance on technology in oncology, the impact of digital clinical decision support (CDS) tools needs to be examined. A systematic review update was conducted and peer-reviewed literature from 2016 to 2022 were included if CDS tools were used for live decision making and comparatively assessed quantitative outcomes. 3369 studies were screened and 19 were included in this updated review. Combined with a previous review of 24 studies, a total of 43 studies were analyzed. Improvements in outcomes were observed in 42 studies, and 34 of these were of statistical significance. Computerized physician order entry and clinical practice guideline systems comprise the greatest number of evaluated CDS tools (13 and 10 respectively), followed by those that utilize patient-reported outcomes (8), clinical pathway systems (8) and prescriber alerts for best-practice advisories (4). Our review indicates that CDS can improve guideline adherence, patient-centered care, and care delivery processes in oncology.

Multi-institutional Prognostic Modeling in Head and Neck Cancer: Evaluating Impact and Generalizability of Deep Learning and Radiomics.

Artificial intelligence (AI) and machine learning (ML) are becoming critical in developing and deploying personalized medicine and targeted clinical trials. Recent advances in ML have enabled the integration of wider ranges of data including both medical records and imaging (radiomics). However, the development of prognostic models is complex as no modeling strategy is universally superior to others and validation of developed models requires large and diverse datasets to demonstrate that prognostic models developed (regardless of method) from one dataset are applicable to other datasets both internally and externally. Using a retrospective dataset of 2,552 patients from a single institution and a strict evaluation framework that included external validation on three external patient cohorts (873 patients), we crowdsourced the development of ML models to predict overall survival in head and neck cancer (HNC) using electronic medical records (EMR) and pretreatment radiological images. To assess the relative contributions of radiomics in predicting HNC prognosis, we compared 12 different models using imaging and/or EMR data. The model with the highest accuracy used multitask learning on clinical data and tumor volume, achieving high prognostic accuracy for 2-year and lifetime survival prediction, outperforming models relying on clinical data only, engineered radiomics, or complex deep neural network architecture. However, when we attempted to extend the best performing models from this large training dataset to other institutions, we observed significant reductions in the performance of the model in those datasets, highlighting the importance of detailed population-based reporting for AI/ML model utility and stronger validation frameworks. We have developed highly prognostic models for overall survival in HNC using EMRs and pretreatment radiological images based on a large, retrospective dataset of 2,552 patients from our institution.Diverse ML approaches were used by independent investigators. The model with the highest accuracy used multitask learning on clinical data and tumor volume.External validation of the top three performing models on three datasets (873 patients) with significant differences in the distributions of clinical and demographic variables demonstrated significant decreases in model performance. Significance: ML combined with simple prognostic factors outperformed multiple advanced CT radiomics and deep learning methods. ML models provided diverse solutions for prognosis of patients with HNC but their prognostic value is affected by differences in patient populations and require extensive validation.

Individualized risk assessment of distant metastases in oral cavity carcinoma: a validated predictive-score model.

BACKGROUND: We aimed to develop and validate a risk-scoring system for distant metastases (DMs) in oral cavity carcinoma (OCC). METHODS: Patients with OCC who were treated at 4 tertiary cancer institutions with curative surgery with or without postoperative radiation/chemoradiation therapy were randomly assigned to discovery or validation cohorts (3:2 ratio). Cases were staged on the basis of tumor, node, and metastasis staging according to the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control guidelines. Predictors of DMs on multivariable analysis in the discovery cohort were used to develop a risk-score model and classify patients into risk groups. The utility of the risk classification was evaluated in the validation cohort. RESULTS: Overall, 2749 patients were analyzed. Predictors (risk score coefficient) of DMs in the discovery cohort were the following: pathological stage (p)T3-4 (0.4), pN+ (N1: 0.8; N2: 1.0; N3: 1.5), histologic grade (G) 3 (G3, 0.7), and lymphovascular invasion (0.4). The DM risk groups were defined by the sum of the following risk score coefficients: high (>1.7), intermediate (0.7-1.7), and standard risk (<0.7). The 5-year DM rates (high/intermediate/standard risk groups) were 30%/15%/4% in the discovery cohort (C-index = 0.79) and 35%/16%/5% in the validation cohort, respectively (C-index = 0.77; both P < .001). In the whole cohort, this predictive model showed excellent discriminative ability in predicting DMs without locoregional failure (29%/11%/1%), later (>2 year) DMs (11%/4%/2%), and DMs in patients treated with surgery (20%/12%/5%), postoperative radiation therapy (34%/17%/4%), and postoperative chemoradiation therapy (39%/18%/7%) (all P < .001). The 5-year overall survival rates in the overall cohort were 25%/51%/67% (P < .001). CONCLUSIONS: Patients at higher risk for DMs were identified by use of a predictive-score model for DMs that included pT3-4, pN1/2/3, G3, and lymphovascular invasion. Identified patients may be evaluated for individualized risk-adaptive treatment escalation and/or surveillance strategies.

Implication of dental insurance status on patterns of pre-radiation dental extraction and risk of osteoradionecrosis of the jaw in head-and-neck cancer patients.

Oral toxicities such as osteoradionecrosis can be minimized by dental screening and prophylactic dental care prior to head and neck (HN) radiation therapy (RT). However, limited information is available about how dental insurance interacts with prophylactic dental care and osteoradionecrosis. To address this gap in knowledge, we conducted a cohort study of 2743 consecutive adult patients treated with curative radiation for HN malignancy who underwent pre-radiation dental assessment and where required, prophylactic dental treatment. Charts were reviewed to determine patient demographics, dental findings, dental treatment and development of osteoradionecrosis following radiation. Three insurance cohorts were identified: private-insured (50.4 %), public-insured (7.3 %), being patients with coverage through government-funded disability and welfare programs, and self-pay (42.4 %). More than half the public-insured patients underwent prophylactic pre-radiation dental extractions, followed by self-pay patients (44 %) and private-insured patients (26.6 %). After a median follow-up time of 4.23 years, 6.5 % of patients developed osteoradionecrosis. The actuarial rate of osteoradionecrosis in the public-insured patients was 14.7 % at 5-years post-RT, compared to 7.5 % in private-insured patients and 6.7 % in self-pay patients. On multivariable analysis, dental insurance status, DMFS160, age at diagnosis, sex, tumor site, nodal involvement, years smoked and gross income were all significant risk factors for tooth removal prior to HN radiation. However, only public-insured status, tumor site and years smoked were significant risk factors for development of osteoradionecrosis. Our findings demonstrate that lack of comprehensive dental coverage (patients who self-pay or who have limited coverage under public-insured programs) associates strongly with having teeth removed prior to HN RT. Nearly 1 in 6 patients covered under public-insurance developed osteoradionecrosis within 5 years of completing their treatment. Well-funded dental insurance programs for HN cancer patients might reduce the number of pre-RT extractions performed in these patients, improving quality of life post-RT.

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study.

BACKGROUND: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αß, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. METHODS: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1-4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107-1×109 T4+ T-cells, administered without prior lymphodepletion. RESULTS: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. CONCLUSIONS: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

Associations between Human Papillomavirus Status, Weight Change, and Survival of Oropharyngeal Cancer Patients.

This study examined associations between HPV status and weight change in oropharyngeal cancer (OPC). OPC patients receiving concurrent chemoradiotherapy in Toronto, Canada were included. Relationships were assessed between HPV status and weight loss grade (WLG, combining weight loss and current body mass index); weight change during treatment; and HPV status and WLG/weight change on overall (OS) and cancer-specific (CSS) survival. Of 717 patients, WLG pre-radiation was less severe among HPV-positive compared to HPV-negative, though weight loss during treatment was greater. The adjusted odds ratio for greater WLG among HPV-positive versus HPV-negative was 0.47 (95%CI 0.28-0.78). Grade-4 WLG (worst category) experienced poorer OS and CSS (OS adjusted hazard ratio (aHR) 4.08; 95%CI 1.48-11.2, compared to Grade-0); and was non-significant for HPV-negative (aHR 2.34; 95%CI 0.69-7.95). Relationships between weight change before/during treatment and survival had similar direction between HPV-positive and HPV-negative, but of greater magnitude in HPV-positive patients.

Using Recurrent Neural Networks to Extract High-Quality Information From Lung Cancer Screening Computerized Tomography Reports for Inter-Radiologist Audit and Feedback Quality Improvement.

PURPOSE: Lung cancer screening programs generate a high volume of low-dose computed tomography (LDCT) reports that contain valuable information, typically in a free-text format. High-performance named-entity recognition (NER) models can extract relevant information from these reports automatically for inter-radiologist quality control. METHODS: Using LDCT report data from a longitudinal lung cancer screening program (8,305 reports; 3,124 participants; 2006-2019), we trained a rule-based model and two bidirectional long short-term memory (Bi-LSTM) NER neural network models to detect clinically relevant information from LDCT reports. Model performance was tested using F1 scores and compared with a published open-source radiology NER model (Stanza) in an independent evaluation set of 150 reports. The top performing model was applied to a data set of 6,948 reports for an inter-radiologist quality control assessment. RESULTS: The best performing model, a Bi-LSTM NER recurrent neural network model, had an overall F1 score of 0.950, which outperformed Stanza (F1 score = 0.872) and a rule-based NER model (F1 score = 0.809). Recall (sensitivity) for the best Bi-LSTM model ranged from 0.916 to 0.991 for different entity types; precision (positive predictive value) ranged from 0.892 to 0.997. Test performance remained stable across time periods. There was an average of a 2.86-fold difference in the number of identified entities between the most and the least detailed radiologists. CONCLUSION: We built an open-source Bi-LSTM NER model that outperformed other open-source or rule-based radiology NER models. This model can efficiently extract clinically relevant information from lung cancer screening computerized tomography reports with high accuracy, enabling efficient audit and feedback to improve quality of patient care.

Effect of Radiation Therapy Quality Assurance on Nasopharyngeal Carcinoma: Usage of a Novel, Web-Based Quality Assurance Application.

PURPOSE: We used a new web application for rapid review of radiation therapy (RT) target volumes to evaluate the relationship between target delineation compliance with the international guidelines and outcomes of definitive RT for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: The data set consisted of computed tomography simulation scans, RT structures, and clinical data of 354 patients with pathology-confirmed NPC treated with intensity modulated RT between 2005 and 2017. Target volumes were peer-reviewed in RT quality assurance rounds, and target contours were revised, if recommended, before treatment. We imported the contours of intermediate-risk clinical target volumes of the primary tumor (CTVp) of 332 patients into the application. Inclusion of anatomic sites within intermediate-risk CTVp was determined in accordance with 2018 international guidelines for CTV delineation for NPC and correlated with time to local failure (TTLF) using Cox regression. RESULTS: In the peer-review quality assurance analysis, local and distant control and overall survival rates were similar between peer-reviewed and nonreviewed cases and between cases with and without target contour changes. In the CTV compliance analysis, with a median follow-up of 5.6 years, 5-year TTLF and overall survival rates were 93.1% and 85.9%, respectively. The most frequently non-guideline-compliant anatomic sites were sphenoid sinus (n = 69, 20.8%), followed by cavernous sinus (n = 38, 19.3%), left and right petrous apices (n = 37 and 32, 11.1% and 9.6%), and clivus (n = 14, 4.2%). Among 23 patients with a local failure (6.9%), the number of noncompliant cases was 8 for sphenoid sinus, 7 cavernous sinus, 4 left and 3 right petrous apices, and 2 clivus. Cavernous sinus-conforming cases showed higher TTLF in comparison with nonconforming cases (93.6% vs 89.1%, P = .013). Multivariable analysis confirmed that cavernous sinus noncompliance was prognostic for TTLF. CONCLUSIONS: Our application allowed rapid quantitative review of CTVp in a large NPC cohort. Although compliance with the international guidelines was high, undercoverage of the cavernous sinus was correlated with TTLF.

The collateral impact of the COVID-19 pandemic on HPV-positive oropharyngeal cancer diagnosis.

PURPOSE: We aim to assess the potential impact of the COVID-19 pandemic on diagnostic delays in HPV-positive oropharyngeal cancer (OPC), and to describe their underlying reasons. METHODS: All HPV + OPC referred to a tertiary cancer centre and diagnosed between June-December 2019 (Pre-Pandemic cohort) vs June-December 2020 (Pandemic cohort) were reviewed. TNM classification, gross-tumor-volumes (GTV) and intervals between sign/symptom onset and treatment initiation were compared between the cohorts. Reasons for delay (>6 months from onset of signs/symptoms to a positive biopsy of the primary tumor, or a delay specifically mentioned in the patient chart) in establishing the diagnosis were recorded per clinician's documentation, and categorized as COVID-related or non-COVID-related. RESULTS: A total of 157 consecutive HPV + OPC patients were identified (Pre-Pandemic: 92; Pandemic: 65). Compared to the Pre-Pandemic cohort, Pandemic cohort patients had a higher proportion of N2-N3 (32 % vs 15 %, p = 0.019) and stage III (38 % vs 23 %, p = 0.034) disease at presentation. The differences in proportions with > 6 months delay from symptom onset to establishing the diagnosis (29 % vs 20 %, p = 0.16) or to first treatment (49 % vs 38 %, p = 0.22) were not statistically different. 47 % of diagnostic delays in the Pandemic cohort were potentially attributable to COVID-19. CONCLUSION: We observed a collateral impact of the COVID-19 pandemic on HPV + OPC care through more advanced stage at presentation and a non-significant but numerically longer interval to diagnosis. This could adversely impact patient outcomes and future resource allocation. Both COVID-19-related and unrelated factors contribute to diagnostic delays. Tailored interventions to reduce delays are warranted.