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Purpose: Randomized trials have found that patients with locoregionally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC) do not benefit from treatment deintensification, even among favorable risk groups. Although various methods have been used to identify candidates for treatment deintensification, the optimal approach is unknown., Methods and Materials: We conducted a multi-institutional cohort study of 444 patients with previously untreated p16+ OPSCC undergoing definitive radiation therapy with or without systemic therapy between 2009 and 2022. We compared the following 2 approaches for identifying candidates for deintensification: (1) favorable versus unfavorable risk, using NRG-HN005 eligibility criteria, and (2) low versus high relative risk of cancer events, using the Head and Neck Cancer Intergroup predictive classifier ("omega score"). We tested differences in outcomes and systemic therapy allocation by risk group using multivariable Cox models, competing event models, and logistic regression, and compared characteristics of hypothetical deintensification trials using the 2 approaches. Progression-free survival events were defined as cancer recurrence (locoregional or distant) or death from any cause., Results: Median follow-up time was 52 months; 120 patients (27.0%) were favorable risk; a different 120 patients had low omega score; 28 patients (6.3%) met both criteria; 184 patients (41.4%) had discordant classification. On ordinal logistic regression, decreasing omega score was associated with a statistically significantly lower odds of receiving intensive therapy (normalized odds ratio, 0.37 per SD; 95% CI, 0.24-0.57), with a greater magnitude than favorable risk group (odds ratio, 0.66; 95% CI, 0.44-0.99). Among patients receiving cisplatin and/or platinum-based induction (n = 374), favorable risk was associated with significantly improved progression-free survival (hazard ratio, 0.59; 95% CI, 0.36-0.99), whereas lower omega score was associated with a significantly decreased relative hazard for cancer events (relative hazard ratio, 0.18; 95% CI, 0.070-0.46). In simulations, selecting patients with low omega scores increased the efficiency of hypothetical noninferiority trials., Conclusions: Considering patients' relative risk of cancer events can help define optimal populations for treatment deintensification in p16+ OPSCC., (Published by Elsevier Inc.)

Purpose: To develop and test a method for fully automated segmentation of bony structures from whole-body computed tomography (CT) and evaluate its performance compared with manual segmentation., Methods and Materials: We developed a workflow for automatic whole-body bone segmentation using atlas-based segmentation (ABS) method with a postprocessing module (ABS PP ) in MIM MAESTRO software. Fifty-two CT scans comprised the training set to build the atlas library, and 29 CT scans comprised the test set. To validate the workflow, we compared Dice similarity coefficient (DSC), mean distance to agreement, and relative volume errors between ABS PP and ABS with no postprocessing (ABS NPP ) with manual segmentation as the reference (gold standard)., Results: The ABS PP method resulted in significantly improved segmentation accuracy (DSC range, 0.85-0.98) compared with the ABS NPP method (DSC range, 0.55-0.87; P < .001). Mean distance to agreement results also indicated high agreement between ABS PP and manual reference delineations (range, 0.11-1.56 mm), which was significantly improved compared with ABS NPP (range, 1.00-2.34 mm) for the majority of tested bony structures. Relative volume errors were also significantly lower for ABS PP compared with ABS NPP for most bony structures., Conclusions: We developed a fully automated MIM workflow for bony structure segmentation from whole-body CT, which exhibited high accuracy compared with manual delineation. The integrated postprocessing module significantly improved workflow performance., (Copyright © 2023 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: To estimate local control, survival, and toxicity associated with a 3-fraction (3F) image-guided brachytherapy (IGBT) regimen compared to longer fraction (LF) for cervical cancer., Methods: 150 patients treated between 2015-2020 with 3F (24Gy in 3 fractions) or LF (28...30 Gy in 4-5 fractions) were reviewed. The primary outcome was 2-year local failure. We compared overall survival (OS), disease-free survival (DFS), hospitalizations, and toxicity., Results: There were 32 patients in the 3F group and 118 in the LF group, with a median follow up of 22 months. The 3F had worse performance status (p = 0.01) but otherwise similar characteristics. The 2-year local failure rate was 3.6% (95% CI 0%, 10.6%) for 3F, and 7.5% (95% CI 2.4%, 12.6%) for LF. The univariable hazard ratio (HR) for local failure for 3F was 0.43 (0.05, 3.43; p = 0.43). Moreover, 2 of 32 (6.3%) 3F patients experienced Grade ...3 toxicity compared to 7 of 118 (5.9%) LF patients (p = 1.0), with no difference in hospitalization within 2 years (p = 0.66) and no treatment-related deaths., Conclusions: Local control was excellent, with long term survival and toxicity similar between the groups. These findings support consideration of 3F., (Copyright © 2023. Published by Elsevier Inc.)

Brachytherapy is a critical component of the definitive management of cervical cancer and allows for the safe delivery of about half of the total effective radiation dose needed for optimal outcomes. Moreover, the dose distribution of brachytherapy is highly conformal, allowing for a therapeutic index currently unmatched by alternative techniques. However, a modern brachytherapy program requires special equipment, infrastructure, and procedural expertise. Unfortunately, multiple lines of evidence suggest that brachytherapy is currently underutilized in the United States. In this review, we examine the importance of brachytherapy, contemporary recommendations, and avenues for growth., (Published by Elsevier Inc.)

Objective: To determine characteristics most strongly associated with risk for aspiration events among head and neck cancer (HNC) patients undergoing curative intent treatment., Materials and Methods: This was a retrospective, cross-sectional study of 106 patients with previously untreated HNC who received definitive or postoperative radiation therapy (RT) +/- systemic therapy with curative intent. Patients who received post-treatment videofluoroscopic swallow study (VFSS) between 2018-2021 were included. Using ordinal multivariable logistic regression, we modeled the effects of age (>60 years vs. ≤60 years), sex, body mass index (BMI) (>20 kg/m 2 vs. ≤20 kg/m 2 ), American Joint Committee on Cancer 8th edition stage (I-II vs. III-IVB), treatment with cisplatin (vs. other or no systemic therapy), post-operative status, primary site (oral cavity vs. P16+ oropharynx vs. P16- Mucosal Site vs. other), and quantitative VFSS measures on Penetration-Aspiration Scale (PAS) score., Results and Conclusion: On ordinal multivariable logistic regression, age >60 years (odds ratio (OR): 3.91, 95% confidence interval (CI): 1.29, 11.9), advanced stage (stage III-IVB) (OR: 3.13, 95% CI: 1.23, 7.79), pharyngeal constriction ratio (PCR) >0.25 (OR: 3.65, 95% CI: 1.14, 11.7), and bolus clearance ratio (BCR) > 0.10 (OR: 3.42, 95% CI: 1.20, 9.75) were found to be significant risk factors for higher PAS scores. Patients with ≥ 2 pre-treatment risk factors had statistically significant increased risk for post-treatment aspiration (OR 2.52, 95% CI: 1.31, 4.86) on ordinal logistic regression. This model could be useful to direct high-risk patients toward interventions designed to reduce risk of aspiration events., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify factors associated with receipt of incomplete cisplatin during chemoradiation for locally advanced cervical cancer and its impact on outcomes., Methods: Patients with locally advanced cervical cancer treated with chemoradiation at our institution between November 2015 and August 2020 were retrospectively identified. Patients who received ≤4 cycles were identified as the 'incomplete' cohort and those who received 5-6 cycles as the 'complete' cohort. The primary endpoint of incomplete chemotherapy was evaluated with multivariable logistic regression. Secondary endpoints of locoregional failure, overall survival, and distant failure were evaluated in multivariable Cox and Fine-Gray models., Results: Of 140 patients with locally advanced cervical cancer that underwent chemoradiation, 22 (15.7%) received an incomplete cisplatin regimen (8 with 0 cycles, 14 with 1-4 cycles). The most common reasons for receiving incomplete treatment were comorbidities/infections (41%), unmet laboratory parameters (27%), and cisplatin intolerance (14%). In multivariable models, only poor (2-4) Eastern Cooperative Oncology Group performance status was a significant predictor as these patients were 41 times more likely to receive incomplete chemotherapy (odds ratio (OR), 95% confidence interval (CI) 4.57 to 375.15, p<0.001). Median follow-up time was 20 months (range 4-64). In multivariable models, receipt of incomplete cisplatin was significantly associated with higher recurrence (locoregional failure hazard ratio (HR) 3.02, 95% CI 1.08 to 8.45, p=0.03; distant failure HR 2.71, 95% CI 1.13 to 6.47, p=0.02) and worse survival (overall survival HR 4.91, 95% CI 1.27 to 18.98, p=0.02)., Conclusion: Incomplete cisplatin regimen was associated with worse oncologic outcomes. Poor performance status was the only factor associated with receiving an incomplete regimen. This notable proportion of patients may be a target for better tolerated novel targeted anticancer agents in order to improve outcomes., Competing Interests: Competing interests: LKM reports research grants from Merck; consultant fees from Bayer HealthCare; and other fees from Merck and ER Squibb & Sons outside the submitted work. JM serves as a consultant for Astra Zeneca, NRG Oncology, GOG Foundation, Varian Medical Systems, Primmune, and Merck; co-chair for NRG Oncology Cervix Co-Chair; and board member for GOG Foundation outside the submitted work., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18 F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population-based sample., Methods: The authors tested nomograms for estimating progression-free survival (PFS) and overall survival (OS) in patients from the Veterans Health Administration with previously untreated locoregionally advanced OPSCC, diagnosed between 2008 and 2017, managed with definitive radiotherapy with or without adjuvant systemic therapy. Covariates were age, performance status, p16 status, T/N category, smoking history, education history, weight loss, marital status, and anemia. We used multiple imputation to handle missing data and performed sensitivity analyses on complete cases. Validation was assessed via Cox proportional hazards models, log-rank tests, and c-indexes., Results: A total of 4007 patients met inclusion criteria (658 patients had complete data). Median follow-up time was 3.20 years, with 967 progression events and 471 noncancer deaths. Each risk score was associated with poorer outcomes per unit increase (PFS score, hazard ratio [HR], 1.42 [1.37-1.47]; OS score, HR, 1.40 [1.34-1.45]). By risk score quartile, 2-year PFS estimates were 89.2%, 78.5%, 65.8%, and 48.3%; OS estimates were 92.6%, 83.6%, 73.9%, and 51.3%, respectively (P < .01 for all comparisons). C-indices for models of PFS and OS were 0.65 and 0.67, for all patients, respectively (0.69 and 0.73 for complete cases). The nomograms slightly overestimated PFS and OS in the overall cohort but exhibited high agreement in complete cases., Conclusions: NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy., (© 2022 American Cancer Society.)

Background: Chemoradiation or radiation therapy alone are curative standards for patients with locally advanced cervical cancer., Objective: To investigate factors that influence time to initiation of chemoradiation or radiation and the subsequent impact of time to treatment on recurrence and survival outcomes., Methods: Patients with locally advanced cervical cancer treated with definitive chemoradiation or radiation at our institution between November 2015 and August 2020 were retrospectively identified. Time to treatment initiation was defined as the number of days from date of diagnosis (via biopsy) to the start date of radiation. The cohort was stratified by the median time to treatment into early (<75 days) and delayed (≥75 days) cohorts. Multivariable logistic regression was conducted to examine factors associated with delayed time to treatment., Results: We identified 143 patients with locally advanced cervical cancer who underwent definitive chemoradiation or radiation. Median follow-up time was 18 months (range 2-62). A total of 71 (49.7%) patients had time to treatment <75 days and 72 (50.3%) patients had time to treatment ≥75 days. The delayed cohort had a higher proportion of Hispanic patients (51.4% vs 31.0%, p=0.04). In multivariable modeling, Hispanic women were 2.71 times more likely (p=0.04) to undergo delayed time to treatment than non-Hispanic white women. Additionally, patients with stage >IIB disease were less likely to undergo delayed time to treatment (OR 0.26, p=0.02) than patients with stage

Purpose: Cancer treatments can paradoxically appear to reduce the risk of noncancer mortality in observational studies, due to residual confounding. Here we introduce a method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding., Experimental Design: BRACE is a novel method for adjusting for bias from residual confounding in proportional hazards models. Using standard simulation methods, we compared BRACE with Cox proportional hazards regression in the presence of an unmeasured confounder. We examined estimator distributions, bias, mean squared error (MSE), and coverage probability. We then estimated treatment effects of high versus low intensity treatments in 36,630 prostate cancer, 4,069 lung cancer, and 7,117 head/neck cancer patients, using the Veterans Affairs database. We analyzed treatment effects on cancer-specific mortality (CSM), noncancer mortality (NCM), and overall survival (OS), using conventional multivariable Cox and propensity score (adjusted using inverse probability weighting) models, versus BRACE-adjusted estimates., Results: In simulations with residual confounding, BRACE uniformly reduced both bias and MSE. In the absence of bias, BRACE introduced bias toward the null, albeit with lower MSE. BRACE markedly improved coverage probability, but with a tendency toward overcorrection for effective but nontoxic treatments. For each clinical cohort, more intensive treatments were associated with significantly reduced hazards for CSM, NCM, and OS. BRACE attenuated OS estimates, yielding results more consistent with findings from randomized trials and meta-analyses., Conclusions: BRACE reduces bias and MSE when residual confounding is present and represents a novel approach to improve treatment effect estimation in nonrandomized studies., (©2022 American Association for Cancer Research.)

Purpose: To test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer., Methods and Materials: In an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m 2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS., Results: In total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ 2 P = .048) and in the combined cohort (13% vs 35%, χ 2 P = .01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P = .216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group., Conclusions: PET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Vaginal stenosis (VS) is a common late complication of radiation injury caused by cervical cancer radiotherapy. It is characterized by the narrowing or shortening of the vaginal canal, which is often detrimental to patient quality of life. To address this public health problem, an expandable vaginal dilator was designed for the prevention of VS in cervical cancer survivors. Modeling and benchtop experimentation were used to iteratively characterize the relationship among dilator pressure, expansion, and the load applied to the simulated vaginal wall. Both experimental and simulation results exhibited shared trends relating pressure, dilator expansion, applied load, and resultant displacement of the modeled vaginal walls. Future work will incorporate enhanced Mooney-Rivlin material assumptions and validation of the model with in vivo tests.Clinical Relevance- These results present a design opportunity and treatment paradigm shift to increase patient adherence to VS treatment after cervical cancer radiotherapy. Specifically, gradual expansion of the vaginal dilator increases comfort during the expansion of the vagina, while monitoring the dilator pressure enables the tracking of VS improvement and normalization of vaginal wall compliance.