Self-reported chronic therapy use after 24-weeks of follow-up by participants who completed the simplify randomized, controlled trial.

BACKGROUND: Highly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up. METHODS: We electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations. RESULTS: After exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3-17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1-12.8) more likely to not use HS during follow-up compared to those randomized to continue. CONCLUSIONS: In healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants' post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care.

TNM 8 staging system beyond p16: Double HPV/p16 status is superior to p16 alone in predicting outcome in oropharyngeal squamous cell carcinoma.

PURPOSE: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis. METHODS: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region. RESULTS: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability. CONCLUSION: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis.

The prognostic value of image-identified extranodal extension in laryngeal and hypopharyngeal carcinoma following definitive (chemo-)radiotherapy.

OBJECTIVES: Clinical extranodal extension (cENE) is a cN modifier in TNM-8 for laryngo-hypopharygeal carcinoma (LHC). We hypothesize that image-detected ENE (iENE) can provide additional prognostic value over cENE in LHC. METHODS: Baseline CTs/MRIs of cN+ LHC patients treated with definitive (chemo-)radiotherapy between 2010-2019 were re-reviewed by a neuroradiologist using internationally accepted criteria for iENE-positive/negative (iENE+/iENE-). Overall survival (OS) was compared by iENE status. Multivariable analysis (MVA) was performed to confirm the prognostic value of iENE, adjusted for known potential confounders. RESULTS: A total of 232 LHC patients were identified, including 154 iENE-/cENE-, 60 iENE+/cENE-, and 18 iENE+/cENE+. A higher proportion of iENE+ (vs iENE-) patients had lymph node (LN) size > 3 cm [53 (67 %) vs 4 (3 %)], >=5 LNs [51 (65 %) vs 33 (21 %)], and retropharyngeal LN [12 (15 %) vs 6 (4 %)] (all p < 0.01). Median follow-up was 4.8 years. iENE+/cENE- and iENE+/cENE+patients had similarly low 5-year OS [28 % (18-44) and 29 % (13-63)] vs iENE-/cENE- [53 % (45-62)] (p < 0.001). On MVA, mortality risk was higher with iENE+vs iENE- [hazard ratio (HR) 2.22 (95 % CI 1.47-3.36)]. The prognostic value of iENE remained with MVA in larynx (n = 124) (HR 2.51 [1.35-4.68], p = 0.004] or hypopharynx (n = 108) (HR 1.87 [1.02-3.43], p = 0.04) patients, separately. CONCLUSIONS: Our study confirms the independent prognostic importance of iENE for LHC following definitive (chemo-)radiotherapy beyond TNM-8 cN status that already contains the cENE parameter. Further research is needed to explore whether iENE could replace cENE for future cN classification.

International Recommendations on Postoperative Management for Potentially Resectable Locally Recurrent Nasopharyngeal Carcinoma.

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.

Radiology-Pathology Concordance and Prognostication of Nodal Features in pN+ Oral Cavity Cancer.

BACKGROUND AND PURPOSE: The aims of our study are to evaluate the diagnostic performance and prognostic value of radiological lymph node (LN) characteristics in pN+ oral cavity squamous carcinoma (OSCC). MATERIALS AND METHODS: pN+ OSCC treated between 2012 and 2020 were included. Preoperative imaging was reviewed by a single radiologist blinded to pathologic findings for the following nodal features: imaging-positive LN (iN+), laterality and total number, and image-identified extranodal extension (iENE). The sensitivity of iN+ for pN+ was calculated. The diagnostic performance of other nodal features was evaluated in the iN+ subgroup. The association of radiologic nodal features with overall survival (OS) was evaluated. Inter-rater kappa for radiologic nodal features was assessed in 100 randomly selected cases. RESULTS: Of 406 pN+ OSCC, 288 were iN+. The sensitivity of iN+ for pN+ was 71% overall, and improved to 89% for pN+ LN >1.5 cm. Within iN+, sensitivity/specificity for LN size (>3 cm), total LN number (>4), and ENE were 0.44/0.95, 0.57/0.84, and 0.27/0.96, respectively. Sensitivity of iENE was higher in the subset, with major (>2 mm) versus minor (≤2 mm) pENE (43% vs. 13%, p = 0.001). Reduced OS was observed in iN+ versus iN- (p = 0.006), iENE+ versus iENE- (p = 0.004), LN size >3 versus ≤3 cm (p < 0.001), and higher LN number (p < 0.001). Inter-rater kappa for iN+, laterality, total LN number, and presence of iENE were 0.71, 0.57, 0.78, and 0.69, respectively. CONCLUSION: Our study shows that despite modest sensitivity of most radiological nodal features, the specificity of image-identified nodal features is high and their prognostic values are retained in pN+ OSCC. LEVEL OF EVIDENCE: Level 3 (retrospective review comparing cases and controls) Laryngoscope, 2024.

Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

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.

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.

Development and validation of a novel TNM staging N-classification of oral cavity squamous cell carcinoma.

BACKGROUND: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N-classification (TNM-8-N). METHODS: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N-classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM-8-N and two published proposals. RESULTS: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44-2.55] and 3.21 [95% CI, 2.44-4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44-2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05-1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81-1.36]). The aHR proposal provided optimal performance with these changes to TNM-8-N: 1) stratification of ENE extent, 2) elimination of N2c and 6-cm threshold, and 3) stratification of N2b by 3 cm threshold. CONCLUSION: A new N-classification improved staging performance compared to TNM-8-N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size.

Vitamin D Oral Replacement in Children With Obesity Related Asthma: VDORA1 Randomized Clinical Trial.

Children with asthma and obesity are more likely to have lower vitamin D levels, but the optimal replacement dose is unknown in this population. The objective of this study is identifying a vitamin D dose in children with obesity-related asthma that safely achieves serum vitamin D levels of ≥ 40 ng/mL. This prospective multisite randomized controlled trial recruited children/adolescents with asthma and body mass index ≥ 85% for age/sex. Part 1 (dose finding), evaluated 4 oral vitamin D regimens for 16 weeks to identify a replacement dose that achieved serum vitamin D levels ≥ 40 ng/mL. Part 2 compared the replacement dose calculated from part 1 (50,000 IU loading dose with 8,000 IU daily) to standard of care (SOC) for 16 weeks to identify the proportion of children achieving target serum 25(OH)D level. Part 1 included 48 randomized participants. Part 2 included 64 participants. In Part 1, no SOC participants achieved target serum level, but 50-72.7% of participants in cohorts A-C achieved the target serum level. In part 2, 78.6% of replacement dose participants achieved target serum level compared with none in the SOC arm. No related serious adverse events were reported. This trial confirmed a 50,000 IU loading dose plus 8,000 IU daily oral vitamin D as safe and effective in increasing serum 25(OH)D levels in children/adolescents with overweight/obesity to levels ≥ 40 ng/mL. Given the critical role of vitamin D in many conditions complicating childhood obesity, these data close a critical gap in our understanding of vitamin D dosing in children.

Predictors of prolonged treatment time intervals in oral cavity cancer.

OBJECTIVES: Delays in treatment time intervals have been associated with overall survival in oral cavity squamous cell carcinoma (OCSCC). The aim of this study was to identify bottlenecks leading to prolonged treatment intervals. MATERIAL AND METHODS: A retrospective analysis was conducted using a cohort of OCSCC patients who underwent surgery and adjuvant radiation therapy. The endpoints of interest were prolonged treatment intervals. Multivariable logistic regression was used to adjust for patient and tumour characteristics. RESULTS: Median diagnosis-to-treatment interval (DTI) and surgery to initiation of postoperative radiation therapy interval (S-PORT) were 39 days (IQR 30-54) and 64 days (IQR 54-66), respectively. Prolonged DTI was associated with older age, worse Charlson Comorbidity index scores and worse T stages. Patients with prolonged DTI had longer times to preoperative imaging reports (25 vs 9 days; P < 0.01). Time to preoperative pathology did not differ. Prolonged S-PORT was associated with longer times to pathology report (28 vs 18 days; P < 0.01), to maxillofacial consult (38 vs 15 days; P < 0.01) and to maxillofacial approval of radiation (50 vs 28 days; P < 0.01). In patients requiring medical oncology consults, those with prolonged S-PORT had longer waiting times until consultation (58 vs 38 days; P = 0.02). Multivariate analysis showed independent predictors of prolonged DTI: time to preoperative imaging; and prolonged S-PORT: time to pathology report, time to maxillofacial consult, and time to medical oncology consult. CONCLUSIONS: Strategies targeting these organizational bottlenecks may be effective for shortening treatment time intervals, hence representing potential opportunities for improving oncological outcomes in OCSCC patients.

Diagnostic challenges and prognostic implications of extranodal extension in head and neck cancer: a state of the art review and gap analysis.

Extranodal extension (ENE) is a pattern of cancer growth from within the lymph node (LN) outward into perinodal tissues, critically defined by disruption and penetration of the tumor through the entire thickness of the LN capsule. The presence of ENE is often associated with an aggressive cancer phenotype in various malignancies including head and neck squamous cell carcinoma (HNSCC). In HNSCC, ENE is associated with increased risk of distant metastasis and lower rates of locoregional control. ENE detected on histopathology (pathologic ENE; pENE) is now incorporated as a risk-stratification factor in human papillomavirus (HPV)-negative HNSCC in the eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification. Although ENE was first described almost a century ago, several issues remain unresolved, including lack of consensus on definitions, terminology, and widely accepted assessment criteria and grading systems for both pENE and ENE detected on radiological imaging (imaging-detected ENE; iENE). Moreover, there is conflicting data on the prognostic significance of iENE and pENE, particularly in the context of HPV-associated HNSCC. Herein, we review the existing literature on ENE in HNSCC, highlighting areas of controversy and identifying critical gaps requiring concerted research efforts.

Comprehensive and realistic simulation of tumour genomic sequencing data.

Accurate identification of somatic mutations and allele frequencies in cancer has critical research and clinical applications. Several computational tools have been developed for this purpose but, in the absence of comprehensive 'ground truth' data, assessing the accuracy of these methods is challenging. We created a computational framework to simulate tumour and matched normal sequencing data for which the source of all loci that contain non-reference bases is known, based on a phased, personalized genome. Unlike existing methods, we account for sampling errors inherent in the sequencing process. Using this framework, we assess accuracy and biases in inferred mutations and their frequencies in an established somatic mutation calling pipeline. We demonstrate bias in existing methods of mutant allele frequency estimation and show, for the first time, the observed mutation frequency spectrum corresponding to a theoretical model of tumour evolution. We highlight the impact of quality filters on detection sensitivity of clinically actionable variants and provide definitive assessment of false positive and false negative mutation calls. Our simulation framework provides an improved means to assess the accuracy of somatic mutation calling pipelines and a detailed picture of the effects of technical parameters and experimental factors on somatic mutation calling in cancer samples.

Pharmacokinetics of Oral Vitamin D in Children with Obesity and Asthma.

BACKGROUND AND OBJECTIVE: Vitamin D insufficiency is common in several pediatric diseases including obesity and asthma. Little data exist describing the pharmacokinetics of oral vitamin D in children or the optimal dosing to achieve therapeutic 25(OH)D targets. Describe the pharmacokinetics of oral Vitamin D in children with asthma. METHODS: This was a multi-center, randomized, open-label, oral supplementation study to describe the pharmacokinetics of vitamin D in children aged 6-17 years who have asthma and were overweight/obese. Participants had a serum 25(OH)D concentration between 10 and < 30 ng/mL at baseline. In Part 1 of the study, we assessed four 16-week dosing regimens for their ability to achieve 25(OH)D concentrations ≥ 40 ng/mL. Using serial serum 25(OH)D sampling over 28 weeks, we created a population pharmacokinetic model and performed dosing simulations to achieve 25(OH)D concentrations ≥ 40 ng/mL. In Part 2, the optimal regimen chosen from Part 1 was compared (2:1) to a standard-of-care control dose (600 international units [IU] daily) over 16 weeks. A final population pharmacokinetic model using both parts was developed to perform dosing simulations and determine important co-variates in the pharmacokinetics of vitamin D. RESULTS: Based on empiric and simulation data, the daily dose of 8000 IU and a loading dose of 50,000 IU were chosen; this regimen raised 25(OH)D concentrations above 40 ng/mL in the majority of participants while avoiding concentrations > 100 ng/mL. A 50,000-IU loading dose led to faster achievement of 25(OH)D therapeutic concentrations (≥ 40 ng/mL). The estimated median (5th-95th percentiles) apparent clearance of vitamin D from the final population pharmacokinetic model was 0.181 (0.155-0.206) L/h. The body mass index z-score was a significant covariate on apparent clearance and was associated with a significantly decreased median half-life in 25(OH)D (body mass index z-score 1.00-1.99: 97.7 days, body mass index z-score 2.00-2.99: 65.9 days, body mass index z-score ≥ 3.00: 39.1 days, p < 0.001). CONCLUSIONS: Obesity impacts vitamin D clearance and the half-life, but serum concentrations > 40 ng/mL can be reached in most children using a loading dose of 50,000 IU followed by a daily dose of 8000 IU. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03686150.

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.

The impact of surgical resection margins on outcomes for adults with head and neck osteosarcomas: A Canadian sarcoma research and Clinical Collaboration (CanSaRCC) study.

OBJECTIVE: The aim of the study is to describe the factors that influence outcome in adults with head and neck osteosarcoma (HNO) with a specific focus on the margin status. METHODS: Patients with a diagnosis of HNO between the years 1996-2021 were reviewed from the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) Database. Baseline characteristics, pathology, treatment, and outcomes were analyzed. Univariable (UVA) and multivariable (MVA) Cox regression models were performed. 5-year locoregional control rate and overall survival (OS) were estimated using Kaplan-Meier method and Log-Rank test. RESULTS: Of 50 patients with a median age of 40 years (range 16-80), 27 (54%) were male. HNO commonly involved the mandible (n = 21, 42%) followed by maxilla (n = 15, 30%). Thirteen (33.3%) had low-intermediate grade and 26 (66.6%) had high grade tumors. Three patients (6%) had negative resection margins (>5 mm), 24 (48%) had close margins (1-5 mm), 15 (30%) had positive margins (<1mm) and 7 (16%) had unknown margin status. In total, 39 (78%) received chemotherapy - 22 (44%) received neoadjuvant chemotherapy while 17 (34%) received adjuvant chemotherapy. A total of 12 (24%) patients received radiotherapy, of whom 8 (16%) had adjuvant and 3 (6%) had neo-adjuvant. Median follow-up time was 6.3 years (range 0.26-24.9). Disease recurred in 21 patients (42%), of whom 15 (30%) had local recurrence only, 4 (8%) had distant metastasis, and 2 (4%) had both local and distant recurrence. 5-year locoregional control rate and OS was 62% and 79.2% respectively. Resection margins <3 mm was associated with lower 5 years OS and locoregional control rate (Log-Rank p = 0.02, p = 0.01 respectively). CONCLUSION: Osteosarcomas of the head and neck are rare and local recurrence remains a concern. Surgical resection with negative resection margins may improve survival, and a 3 mm resection margin threshold may optimize survival. Radiotherapy and/or chemotherapy should be considered in a multidisciplinary setting based on risk-features.

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.

Incidence and predictive factors of retropharyngeal lymph node metastases in patients with oropharyngeal cancer undergoing multimodality treatment planning imaging.

BACKGROUND: We investigated the incidence and predictive factors of retropharyngeal lymph node (RPLN) metastases in patients with oropharyngeal cancer (OPC) undergoing multimodality treatment planning imaging before radiotherapy. METHODS: Consecutive patients with OPC treated with curative-intent radiotherapy from 2017 to 2019 were retrospectively analyzed. Treatment planning comprised contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose-positron emission tomography (FDG-PET) unless contraindicated. RESULTS: Of 300 patients, 66 (22%) had radiological evidence of RPLN involvement on planning images, compared to 17 (6%) on diagnostic CT alone. On multivariate analysis, RPLN involvement was statistically (p < 0.05) associated with tonsil, soft palate, and posterior pharyngeal wall primaries, and with disease extension to the soft palate or vallecula. CONCLUSIONS: Multimodality treatment planning imaging reveals a high rate of RPLN metastases from OPC compared to diagnostic CT alone. Patients with tonsil, soft palate, or posterior pharyngeal wall primaries or disease extending to the soft palate or vallecula appear at higher risk.

Are we ready for deintensification in human papillomavirus-positive oropharyngeal carcinomas?

PURPOSE OF REVIEW: Excellent outcomes following contemporary treatment of human papillomavirus (HPV)-positive oropharyngeal carcinoma (HPV+ OPC) have prompted the exploration of deintensification approaches to minimize treatment-related toxicities. This review describes the landscape of deintensification to date (up to November 2022). RECENT FINDINGS: Although several deintensification trials have been published, none are practice changing. Three phase III randomized-controlled trials studying cetuximab and radiation therapy vs. standard chemoradiotherapy all showed inferior outcomes. Although some phase II trials reported favourable outcomes, they are often single-arm trials without an adequate control arm, thereby limiting the ability to modify practice. SUMMARY: Substantial effort has been expended to explore deintensification options for selected HPV+ OPC patients aiming to avoid unnecessary toxicity. Strategies have included replacing cisplatin with cetuximab, reduced chemotherapy or radiotherapy intensity, reduction of radiotherapy volumes and risk stratification after trans-oral surgery or following induction chemotherapy. Challenges remain in the current deintensification landscape, including identifying the most suitable candidates along with a choice of most appropriate deintensification strategies. Promising selection criteria included either static baseline features or kinetic characteristics of clinical-biological parameters. Practice-changing trials remain elusive, and the search continues to attempt optimization of the therapeutic ratio for these patients.