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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.

The standard of care for the definitive treatment of locoregionally advanced cervical cancer is external beam radiation therapy (EBRT) with concurrent chemotherapy followed by a brachytherapy boost. Historically, EBRT was delivered via a two-dimensional technique based primarily on bony landmarks. This gave way to three-dimensional conformal radiation therapy, which allows for dose calculation and adjustment based on individual tumour and patient anatomy. Further technological advances have established intensity-modulated radiation therapy (IMRT) as a standard treatment modality, given the ability to maintain tumoricidal doses to target volumes while reducing unwanted radiation dose to nearby critical structures, thereby reducing toxicity. Routine image guidance allows for increased confidence in patient alignment prior to treatment, and the ability to visualise the daily position of the targets and organs at risk has been instrumental in allowing safe reductions in treated volumes. Additional EBRT technologies, including proton therapy and stereotactic body radiation therapy, may further improve the therapeutic index. In the realm of brachytherapy, a shift from point-based dose planning to image-guided brachytherapy has been associated with improved local control and reduced toxicity, with additional refinement ongoing. Here we will discuss these advances, the supporting data and future directions., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Maximum standardized uptake value (SUV max ) on PET imaging is prognostic in cervical cancer. It was recently demonstrated that low pretreatment SUV max is associated with superior prognosis and is correlated with decreased inflammatory signaling and myeloid-derived cell infiltration into the tumor microenvironment, potentially identifying susceptibility to targeted therapies. See related article by Floberg et al., p. 4245 ., (©2021 American Association for Cancer Research.)

Radiation therapy exerts a tumoricidal local effect as well as both local and systemic immunomodulation. Immune checkpoint blockade has become a widely used treatment modality across cancer types with a rapidly growing list of agents and US Food and Drug Administration-approved indications. Moreover, there may be synergy between radiation therapy and immune checkpoint blockade. Various strategies have been used, but the optimal sequencing of these therapies is unclear. In this review, the authors discuss the major mechanisms of available immune checkpoint inhibitors and explore the available preclinical and clinical evidence regarding treatment sequencing. They also review safety considerations and conclude with possible future directions., (© 2021 American Cancer Society.)

Purpose: Sparing active bone marrow (ABM) can reduce acute hematologic toxicity in patients undergoing chemoradiotherapy for cervical cancer, but ABM segmentation based on positron emission tomography/computed tomography (PET/CT) is costly. We sought to develop an atlas-based ABM segmentation method for implementation in a prospective clinical trial., Methods and Materials: A multiatlas was built on a training set of 144 patients and validated in 32 patients from the NRG-GY006 clinical trial. ABM for individual patients was defined as the subvolume of pelvic bone greater than the individual mean standardized uptake value on registered 18 F-fluorodeoxyglucose PET/CT images. Atlas-based and custom ABM segmentations were compared using the Dice similarity coefficient and mean distance to agreement and used to generate ABM-sparing intensity modulated radiation therapy plans. Dose-volume metrics and normal tissue complication probabilities of the two approaches were compared using linear regression., Results: Atlas-based ABM volumes (mean [standard deviation], 548.4 [88.3] cm 3 ) were slightly larger than custom ABM volumes (535.1 [93.2] cm 3 ), with a Dice similarity coefficient of 0.73. Total pelvic bone marrow V 20 and D mean were systematically higher and custom ABM V 10 was systematically lower with custom-based plans (slope: 1.021 [95% confidence interval (CI), 1.005-1.037], 1.014 [95% CI, 1.006-1.022], and 0.98 [95% CI, 0.97-0.99], respectively). We found no significant differences between atlas-based and custom-based plans in bowel, rectum, bladder, femoral heads, or target dose-volume metrics., Conclusions: Atlas-based ABM segmentation can reduce pelvic bone marrow dose while achieving comparable target and other normal tissue dosimetry. This approach may allow ABM sparing in settings where PET/CT is unavailable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m 2 . We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 10 3 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity., (Copyright © 2020 Vitzthum, Heide, Park, Williamson, Sheridan, Huynh-Le, Sirak, Wei, Tarnawski, Mahantshetty, Nguyen, Mayadev, Yashar, Sacco and Mell.)

Background: To test the hypothesis that atlas-based active bone marrow (ABM)-sparing intensity modulated radiation therapy (IMRT) yields similar dosimetric results compared to custom ABM-sparing IMRT for cervical cancer patients., Methods: We sampled 62 cervical cancer patients with pre-treatment FDG-PET/CT in training (n=32) or test (n=30) sets. ABM was defined as the subvolume of the pelvic bone marrow (PBM) with standardized uptake value (SUV) above the mean on the average FDG-PET image (ABM Atlas ) vs. the individual's PET (ABM Custom ). Both were deformed to the planning CT. Overlap between the two subvolumes was measured using the Dice coefficient. Three IMRT plans designed to spare PBM, ABM Atlas , or ABM Custom were compared for 30 test patients. Dosimetric parameters were used to evaluate plan quality., Results: ABM Atlas and ABM Custom volumes were not significantly different (p=0.90), with a mean Dice coefficient of 0.75, indicating good agreement. Compared to IMRT plans designed to spare PBM and ABM Custom , ABM Atlas -sparing IMRT plans achieved excellent target coverage and normal tissue sparing, without reducing dose to ABM Custom (mean ABM Custom dose 29.4Gy vs. 27.1Gyvs. 26.9Gy, respectively; p=0.10); however, PTV coverage and bowel sparing were slightly reduced., Conclusions: Atlas-based ABM sparing IMRT is clinically feasible and may obviate the need for customized ABM-sparing as a strategy to reduce hematologic toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To quantify longitudinal changes in active bone marrow (ABM) distributions within unirradiated (extrapelvic) and irradiated (pelvic) bone marrow (BM) in cervical cancer patients treated with concurrent chemoradiation therapy (CRT)., Methods and Materials: We sampled 39 cervical cancer patients treated with CRT, of whom 25 were treated with concurrent cisplatin (40 mg/m 2 ) and 14 were treated with cisplatin (40 mg/m 2 ) plus gemcitabine (50-125 mg/m 2 ) (C/G). Patients underwent 18 F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and 1.5 to 6.0 months after treatment. ABM was defined as the subvolume of bone with standardized uptake value (SUV) above the mean SUV of the total bone. The primary aim was to measure the compensatory response, defined as the change in the log of the ratio of extrapelvic versus pelvic ABM percentage from baseline to after treatment. We also quantified the change in the proportion of ABM and mean SUV in pelvic and extrapelvic BM using a 2-sided paired t test., Results: We observed a significant increase in the overall extrapelvic compensatory response after CRT (0.381; 95% confidence interval [CI]: 0.312, 0.449) and separately in patients treated with cisplatin (0.429; 95% CI: 0.340, 0.517) and C/G (0.294; 95% CI: 0.186, 0.402). We observed a trend toward higher compensatory response in patients treated with cisplatin compared with C/G (P=.057). Pelvic ABM percentage was reduced after CRT both in patients receiving cisplatin (P<.001) and in those receiving C/G (P<.001), whereas extrapelvic ABM percentage was increased in patients receiving cisplatin (P<.001) and C/G (P<.001). The mean SUV in pelvic structures was lower after CRT with both cisplatin (P<.001) and C/G (P<.001). The mean SUV appeared lower in extrapelvic structures after CRT in patients treated with C/G (P=.076) but not with cisplatin (P=.942). We also observed that older age and more intense chemotherapy regimens were correlated with a decreased compensatory response on multivariable analysis. In patients treated with C/G, mean pelvic bone marrow dose was found to be negatively correlated with the compensatory response., Conclusion: Patients have differing subacute compensatory responses after CRT, owing to variable recovery in unirradiated marrow. Intensive chemotherapy regimens appear to decrease the extrapelvic compensatory response, which may lead to increased hematologic toxicity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer., Methods and Materials: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life., Results: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ 2 P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25)., Conclusions: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events., Methods: We identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion., Results: In each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8., Conclusion: Compared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)

Purpose: To quantify changes in bone marrow fat fraction and determine associations with peripheral blood cell counts., Methods and Materials: In this prospective study, 19 patients received either highly myelotoxic treatment (radiation therapy plus cisplatin, 5-fluorouracil mitomycin C [FU/MMC], or cisplatin/5-FU/cetuximab) or less myelotoxic treatment (capecitabine-radiation therapy or no concurrent chemotherapy). Patients underwent MR imaging and venipuncture at baseline, midtreatment, and posttreatment visits. We performed mixed effects modeling of the mean proton density fat fraction (PDFF[%]) by linear time, treatment, and vertebral column region (lumbar [L]4-sacral [S]2 vs thoracic [T]10-L3 vs cervical[C]3-T9), while controlling for cumulative mean dose and other confounders. Spearman rank correlations were performed by white blood cell (WBC) counts versus the differences in PDFF(%) before and after treatment., Results: Cumulative mean dose was associated with a 0.43% per Gy (P=.004) increase in PDFF(%). In the highly myelotoxic group, we observed significant changes in PDFF(%) per visit within L4-S2 (10.1%, P<.001) and within T10-L3 (3.93%, P=.01), relative to the reference C3-T9. In the less myelotoxic group, we did not observe significant changes in PDFF(%) per visit according to region. Within L4-S2, we observed a significant difference between treatment groups in the change in PDFF(%) per visit (5.36%, P=.04). Rank correlations of the inverse log differences in WBC versus the differences in PDFF(%) overall and within T10-S2 ranged from 0.69 to 0.78 (P<.05). Rank correlations of the inverse log differences in absolute neutrophil counts versus the differences in PDFF(%) overall and within L4-S2 ranged from 0.79 to 0.81 (P<.05)., Conclusions: Magnetic resonance imaging fat quantification is sensitive to marrow composition changes that result from chemoradiation therapy. These changes are associated with peripheral blood cell counts. This study supports a rationale for bone marrow-sparing treatment planning to reduce the risk of hematologic toxicity., (Published by Elsevier Inc.)

Unlabelled: Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met., Significance: This report examines the mechanism of increased tumor aggressiveness after anti-VEGF therapy and presents evidence for roles of vascular pruning, hypoxia, and c-Met activation. The results show that simultaneous inhibition of c-Met and VEGF signaling not only slows tumor growth but also reduces invasion and metastasis., (©2012 AACR.)

Angiogenesis inhibitors that block VEGF receptor (VEGFR) signaling slow the growth of many types of tumors, but eventually the disease progresses. Multiple strategies are being explored to improve efficacy by concurrent inhibition of other functionally relevant receptor tyrosine kinases (RTK). XL880 (foretinib, GSK1363089) and XL184 (cabozantinib) are small-molecule inhibitors that potently block multiple RTKs, including VEGFR and the receptor of hepatocyte growth factor c-Met, which can drive tumor invasion and metastasis. This study compared the cellular effects of XL880 and XL184 with those of an RTK inhibitor (XL999) that blocks VEGFR but not c-Met. Treatment of RIP-Tag2 mice with XL999 resulted in 43% reduction in vascularity of spontaneous pancreatic islet tumors over 7 days, but treatment with XL880 or XL184 eliminated approximately 80% of the tumor vasculature, reduced pericytes and empty basement membrane sleeves, caused widespread intratumoral hypoxia and tumor cell apoptosis, and slowed regrowth of the tumor vasculature after drug withdrawal. Importantly, XL880 and XL184 also decreased invasiveness of primary tumors and reduced metastasis. Overall, these findings indicate that inhibition of c-Met and functionally related kinases amplifies the effects of VEGFR blockade and leads to rapid, robust, and progressive regression of tumor vasculature, increased intratumoral hypoxia and apoptosis, and reduced tumor invasiveness and metastasis., (©2011 AACR.)