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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.

Supplementary Data from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Supplementary Figure from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Supplementary Table from Bias Reduction through Analysis of Competing Events (BRACE) Correction to Address Cancer Treatment Selection Bias in Observational Data

Background Despite higher risks associated with prostate cancer, young African American men are poorly represented in prostate-specific antigen (PSA) trials, which limits proper evidence-based guidance. We evaluated the impact of PSA screening, alongside primary care provider utilization, on prostate cancer outcomes for these patients. Methods We identified African American men aged 40-55 years, diagnosed with prostate cancer between 2004 and 2017 within the Veterans Health Administration. Inverse probability of treatment-weighted propensity scores were used in multivariable models to assess PSA screening on PSA levels higher than 20, Gleason score of 8 or higher, and metastatic disease at diagnosis. Lead-time adjusted Fine-Gray regression evaluated PSA screening on prostate cancer–specific mortality (PCSM), with noncancer death as competing events. All statistical tests were 2-sided. Results The cohort included 4726 patients. Mean age was 51.8 years, with 84-month median follow-up. There were 1057 (22.4%) with no PSA screening prior to diagnosis. Compared with no screening, PSA screening was associated with statistically significantly reduced odds of PSA levels higher than 20 (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.49 to 0.63; P < .001), Gleason score of 8 or higher (OR = 0.78, 95% CI = 0.69 to 0.88; P < .001), and metastatic disease at diagnosis (OR = 0.50, 95% CI = 0.39 to 0.64; P < .001), and decreased PCSM (subdistribution hazard ratio = 0.52, 95% CI = 0.36 to 0.76; P < .001). Primary care provider visits displayed similar effects. Conclusions Among young African American men diagnosed with prostate cancer, PSA screening was associated with statistically significantly lower risk of PSA levels higher than 20, Gleason score of 8 or higher, and metastatic disease at diagnosis and statistically significantly reduced risk of PCSM. However, the retrospective design limits precise estimation of screening effects. Prospective studies are needed to validate these findings.

BACKGROUND This study was done to determine the representation of minorities, women, and the elderly in National Cancer Institute (NCI) clinical trials. METHODS This is an analysis in the NCI Clinical Data Update System. Patients were evaluated in breast, colorectal, lung, and prostate cancer trials from 2000 to 2019. Representation in a trial was determined by race/ethnicity, sex, and age. Secondarily, the change in trial participation by multivariable analysis by comparing years 2000 through 2004 to 2015 through 2019 was evaluated. RESULTS The cohort included 242,720 participants: 197,320 Non-Hispanic White (81.3%), 21,190 Black (8.7%), 11,587 Hispanic (4.8%), and 6880 Asian/Pacific Islander (2.8%). Black and Hispanic patients were underrepresented for colorectal (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001 and OR, 0.74; 95% CI, 0.64-0.87; P < .001, respectively), lung (OR, 0.83; 95% CI, 0.76-0.91; P < .001 and 0.66; 95% CI, 0.57-0.77; P < .001, respectively), and prostate cancer trials (OR, 0.85; 95% CI, 0.79-0.92; P < .001 and OR, 0.58; 95% CI, 0.51-0.66; P < .001) between 2015 and 2019. The odds of participation in 2015 to 2019 increased among Black patients in breast (OR, 2.19; 95% CI, 2.07-%2.32; P < .001), lung (OR, 1.54; 95% CI, 1.38-1.73; P < .001), and prostate cancer trials (OR, 1.14; 95% CI, 1.04-1.26; P < .001). The odds of participation in a trial among Hispanic patients increased for breast (OR, 3.32; 95% CI, 3.09-3.56; P < .001), colorectal (OR, 2.46; 95% CI, 2.04-2.96; P < .001), lung (OR, 3.88; 95% CI, 3.20-4.69; P < .001), and prostate cancer (OR, 1.70; 95% CI, 1.42-2.04; P = .005). CONCLUSIONS This study identified that Black and Hispanic patients remain underrepresented in trials, but in recent years, participation has increased. These findings indicate that minority participation has increased over time, but further efforts are needed.

PURPOSE For pelvic and abdominal treatments, excess dose to the bowel can result in acute toxicities. Current estimates of bowel toxicity are based on pre-treatment dose-volume histogram data. However, the actual dose the bowel receives depends on interfraction variations, such as patient anatomy changes. We propose a method to model bowel toxicities, incorporating in vivo patient information using transit electronic portal imaging device (EPID) images. METHODS AND MATERIALS For 63 patients treated to the lower thorax, abdomen, or pelvis on the Varian Halcyon, weekly chart review was performed to obtain incidences of grade 2 or higher toxicity, RTOG scale. Twenty patients presented with acute gastrointestinal (GI) toxicity. All patients were treated with conventional fractionation. For each treatment plan, the absolute volume dose-volume histogram of the bowel was exported and analyzed. Additionally, for each fraction of treatment, in vivo EPID images were collected and used to estimate the change in radiation transmission during the course of treatment. A logistic model was used to test correlations between acute GI toxicity and bowel dosimetric parameters as well as metrics obtained from in vivo image measurements. After performing the fit to the in vivo EPID data, the bootstrap resampling method was used to create confidence intervals. In vivo EPID image metrics from an additional 42 patients treated to the lower thorax, abdomen, or pelvis were used to validate the logistic model fit. RESULTS The incidence of toxicity versus the volume of 40 Gy to the bowel space was fitted with a logistic function, which was superior to an average model (p

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 18F-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.

OBJECTIVE Recurrence is known to predict laryngeal squamous cell cancer (LSCC) survival. Recurrence patterns in T4a LSCC are poorly characterized and represent a possible explanation for observed survival discrepancies by treatment rendered. STUDY DESIGN Retrospective database review. SETTING Veterans Affairs national database. METHODS Patients with T4a LSCC between 2000 and 2017 were identified and stratified by treatment (chemoradiotherapy [CRT] vs total laryngectomy + neck dissection + adjuvant therapy [surgical]). Primary outcomes were locoregional and distant recurrence. Secondary outcomes of overall mortality, larynx cancer mortality, and noncancer mortality were evaluated in Cox and Fine-Gray models. RESULTS A total of 1043 patients had comparable baseline demographics: 438 in the CRT group and 605 in the surgical group. Patients undergoing CRT had higher proportions of node positivity (64.6% vs 53.1%, P < .001). Locoregional and distant recurrence were less common in the surgical group (23.0% vs 37.2%, P < .001; 6.8% vs 13.3%, P < .001, respectively); however, distant metastatic rates did not differ within the N0 subgroup (P = .722). On multivariable regression, surgery demonstrated favorable locoregional recurrence (hazard ratio [HR], 0.49; 95% CI, 0.39-0.62; P < .001), distant recurrence (HR, 0.47; 95% CI, 0.31-0.71; P < .001), overall mortality (HR, 0.75; 95% CI, 0.64-0.87; P < .001), and larynx cancer mortality (HR, 0.69; 95% CI, 0.56-0.85; P < .001). CONCLUSION T4a LSCC survival discrepancies between surgical and nonsurgical treatment are influenced by varying recurrence behaviors. Surgery was associated with superior disease control and improved survival. Beyond the known benefit in locoregional control with surgery, there may be a protective effect on distant recurrence that depends on regional disease burden.

BACKGROUND The safety of active surveillance (AS) for African American men compared with non-Hispanic White (White) men with intermediate-risk prostate cancer is unclear. METHODS The authors identified patients with modified National Comprehensive Cancer Network favorable ("low-intermediate") and unfavorable ("high-intermediate") intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration database. They analyzed definitive treatment, disease progression, metastases, prostate cancer-specific mortality (PCSM), and all-cause mortality by using cumulative incidences and multivariable competing-risks (disease progression, metastasis, and PCSM) or Cox (all-cause mortality) regression. RESULTS The cohort included 1007 men (African Americans, 330 [32.8%]; Whites, 677 [67.2%]) followed for a median of 7.7 years; 773 (76.8%) had low-intermediate-risk disease, and 234 (23.2%) had high-intermediate-risk disease. The 10-year cumulative incidences of definitive treatment were not significantly different (African Americans, 83.5%; 95% confidence interval [CI], 78.5%-88.7%; Whites, 80.6%; 95% CI, 76.6%-84.4%; P = .17). Among those with low-intermediate-risk disease, there were no significant differences in the 10-year cumulative incidences of disease progression (African Americans, 46.8%; 95% CI, 40.0%-53.3%; Whites, 46.9%; 95% CI, 42.1%-51.5%; P = .91), metastasis (African Americans, 7.1%; 95% CI, 3.7%-11.8%; Whites, 10.8%; 95% CI, 7.6%-14.6%; P = .17), or PCSM (African Americans, 3.8%; 95% CI, 1.6%-7.5%; Whites, 3.8%; 95% CI, 2.0%-6.3%; P = .69). In a multivariable regression including the entire cohort, African American race was not associated with increased risks of definitive treatment, disease progression, metastasis, PCSM, or all-cause mortality (all P > .30). CONCLUSIONS Outcomes in the Veterans Affairs Health System were similar for African American and White men treated for low-intermediate-risk prostate cancer with AS.

418 Background: Chemotherapy for testicular cancer (TC) is highly effective yet associated with significant consequences on long-term health-related quality of life. We evaluate the impact of chemotherapy on anxiety, depression, and suicidality amongst TC survivors. Methods: We conducted a retrospective cohort study of US veterans diagnosed with TC in the Veterans Health Affairs database from 1990-2016. Patients with non-primary germ cell tumor histologies were excluded. Baseline disease characteristics and treatment received were ascertained from the VA Central Cancer Registry. Anxiety or depression was a composite endpoint comprised of diagnosis codes for anxiety, depression, or administration of medications used to treat these diagnoses. Incident suicidality was defined as a diagnosis code for suicidal ideation. Time to event was defined as time from diagnosis to event or censor at the time of last follow-up. Rates of outcomes were reported through cumulative incidences. Associations with outcomes and receipt of chemotherapy were assessed through multivariable Cox regression models. Results: In total, 1684 patients (1174 seminoma, 510 nonseminoma) were included in the cohort. Median age at diagnosis in the cohort was 40 years old. Median follow up time was 7.67 years for surviving patients. 1506 (89.4%) patients were white, 114 (6.8%) were African American, and 64 (3.8%) were another or unknown race. There were 1066 (63.3%) stage I patients, 191 (11.3%) stage II, 198 (11.8%) stage III, and 229 (13.6%) unknown stage patients. 579 (34.4%) patients received chemotherapy. At the time of diagnosis, 104 (6.2%) patients already experienced anxiety or depression. At 10 years, cumulative incidence of the diagnosis of anxiety or depression as 44.1% in the entire cohort. At 10 years, cumulative incidence of the diagnosis of suicidality was 5.5%. On multivariable Cox regression, factors associated with a higher risk of anxiety or depression were older age at diagnosis (Hazard Ratio (HR): 1.11 per standard deviation increase, p=0.01), being unemployed (HR: 1.25, p=0.01), and receipt of chemotherapy (HR: 1.43, p

265 Background: There is evidence that exposure to contaminated water while serving at Camp Lejeune is associated with the development of genitourinary cancers including kidney and bladder; however, there is a lack of literature regarding prostate cancer (PC). We investigated disease severity at diagnosis, overall survival, and cumulative incidence of metastases for PC patients within the Veterans Health Administration (VHA) who served at Camp Lejeune. Methods: The cohort included men diagnosed with PC between 1999 and 2022 within the VHA Database. Patients who were housed at or had one or more Military Service Episodes between August 1, 1953 and December 31, 1987 at Camp Lejeune were considered to have exposure. Camp Lejeune exposure status and baseline characteristics were ascertained through the VHA electronic health records. Logistic regressions were used to analyze associations between Camp Lejeune exposure and adverse diagnostic characteristics, adjusted for demographic covariates. The outcome of metastases was identified through natural language processing from cancer or radiology documents. Time to metastases was defined as the time from PC diagnosis to metastases, with other causes of death considered as competing risks. The hazard ratio for the association between Camp Lejeune exposure and metastatic disease was calculated with a Cox regression model, controlling for covariates. The difference in overall survival was assessed with the Kaplan-Meier method and log-rank test. Results: The cohort included 6,918 men with PC, 1,635 (23.6%) of which had Camp Lejeune exposure and 5,283 (76.4%) without. Median age at diagnosis was 65 years. Logistic regression models indicated patients with Camp Lejeune exposure have similar odds of having Gleason Score ≥8 at diagnosis (odds ratio (OR) 0.97, p=0.62) and metastasis at diagnosis (OR 1.00, p=0.997), and slightly lower odds of PSA >20 ng/mL at diagnosis (OR 0.78, p=0.02).There were 803 patients with metastatic disease, 159 of which had Camp Lejeune exposure in comparison to the 644 that did not. The 10-year cumulative incidence of metastases for those with Camp Lejeune exposure was 11.9% (CI: 9.9-13.9%), while for those without exposure it was 14.0% (CI: 12.8-15.1%). The Cox proportional hazards model indicated that those with Camp Lejeune exposure had a similar risk of developing metastases (hazard tatio (HR) 0.93, p=0.43) compared to those without exposure. The 10-year overall survival was similar for those with Camp Lejeune exposure (83.3% [CI: 80.7-85.9%]) compared to those without exposure (82.5% [CI: 81.1-83.9%]) (p=0.2). Conclusions: In contrast to kidney and bladder cancers, Camp Lejeune exposure is not associated with worse outcomes for PC. Further research should be conducted to test whether Camp Lejeune exposure affects the risk of developing PC. However, these data do not support Camp Lejeune exposure playing a large role in PC outcomes.

To determine characteristics most strongly associated with risk for aspiration events among head and neck cancer (HNC) patients undergoing curative intent treatment.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/mOn ordinal multivariable logistic regression, age60 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.

To determine the representation of women, minorities, and the elderly groups in clinical trials and whether participation has changed over time.Retrospective study in the National Cancer Institute (NCI) Clinical Data Update System and Center for Disease Control and Prevention United States Cancer Statistics 2000 to 2019. We compared cancer incidence proportion to proportion of patients enrolled in an NCI trial when stratified by race/ethnicity, sex, and age. We performed multivariable analysis to determine the odds of participating in a clinical trial in 2015 to 2019 when compared to 2000 to 2004.This study included 14,094 patients, 12,169 (86.3%) non-Hispanic White patients, 662 (4.7%) Black patients, and 660 (4.7%) Hispanic patients. There were 3,701 (26.3%) female patients and 10,393 (73.7%) male patients. For bladder cancer clinical trials, Black patients and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.57-0.88, P = 0.002) and (OR 0.69, 95%CI 0.54-0.88, P = 0.003), respectively. For kidney cancer trials, Black and Hispanic patients were underrepresented in clinical trials compared to Non-Hispanic White patients (OR 0.42, OR 0.33-0.54, P0.001) and (OR 0.68, 95% CI 0.55-0.83, P0.001), respectively. Women were underrepresented in kidney cancer trials compared to men (OR 0.80, 95% CI 0.72-0.89) and similarly for bladder cancer trials (OR 0.72, 95% CI 0.64-0.81, P0.001). For bladder cancer trials, the participation of Black patients over time (OR 1.04, P = 0.814) and female patients over time (OR 1.03, P = 0.741) were unchanged. For kidney cancer trials, the participation of Black patients over time (OR 1.17, P = 0.293) and female patients over time (OR 1.03, P = 0.663) participation was also unchanged.In this study of clinical trials in bladder and kidney cancer, we identified that Blacks, Hispanics, and females were underrepresented. Additionally, Black and female participation was unchanged over the span of 20 years.

BACKGROUND Androgen deprivation therapy (ADT) is frequently utilized in conjunction with radiotherapy (RT) in the definitive management of prostate cancer. Prior studies have suggested an association between ADT use and acute kidney injury (AKI), however, these included heterogeneous populations undergoing a variety of treatments and relied on billing codes to ascertain the incidence of AKI. METHODS We analyzed a cohort of 27,868 veterans undergoing definitive RT + /- ADT for prostate cancer between 2001 and 2015 using the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Exposure was defined as use of ADT within one year of diagnosis. The primary outcome was AKI, defined by an increase in serum creatinine to at least 1.5 times the baseline value. AKIs were classified as mild, moderate, or severe in accordance with international guidelines. A multivariate competing risks model was used to account for demographic and oncologic factors as well as medications and procedures known to influence the risk of AKI. RESULTS Most (n = 18,754) men received RT alone; 9,114 men received RT + ADT. The incidence of AKI at two years after diagnosis was 10.5% in the RT + ADT group and 7.9% in the RT group (Gray's test p

To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population-based sample.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.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.NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy.

The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about delaying treatment for localized cancer and its impact on long-term outcomes.We aimed to investigate the impact of time to chemoradiation (CRT) on recurrence and survival outcomes for patients with muscle-invasive bladder cancer (MIBC).In the national Veterans Affairs' database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 to 2018 and treated with definitive CRT. Time to treatment was defined as the number of days between date of diagnosis and start date of CRT. The cohort was stratified into90 (early) or ≥ 90 days (delayed) groups. Endpoints of locoregional failure (LRF), distant failure (DF), overall survival (OS), and bladder cancer-specific survival (BCS) were evaluated in multivariable Cox and Fine-Gray models.305 patients with MIBC underwent CRT - 190 (62.3%) received early CRT, 115 (37.7%) received delayed CRT. Multivariable analysis (including success of transurethral resection of bladder tumor and type of chemotherapy) revealed no difference in recurrence between groups - LRF HR 1.12 (95%CI 0.76-1.67, P = 0.56) and DF HR 1.03 (95%CI 0.70-1.53, P = 0.88). Similarly, there were no differences in survival outcomes. The lack of association was maintained at both earlier and later time cutoffs (60-120 days).Our findings suggest that a short-term delay in definitive therapy may not affect long-term outcomes for patients with MIBC undergoing CRT. This study does not endorse delays in therapy, but rather provides information to aid patients and clinicians navigate the unique challenges of MIBC care in both pandemic and non-pandemic times.

INTRODUCTION AND OBJECTIVE:The utility of prostate-specific antigen velocity (PSAV) to predict clinical progression in patients with localized prostate cancer (PC) on active surveillance remains un...

Purpose: Chemoradiation (CRT) is a definitive treatment option for muscle-invasive bladder cancer (MIBC). Despite its effectiveness, CRT is underused, in part owing to concerns of tolerability and the need for integrated multidisciplinary care. We investigated factors associated with and the impact of treatment discontinuation in patients with MIBC treated with CRT. Methods and Materials: In the US Veterans Affairs’ national database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 and 2018 and treated with definitive-intent CRT. The primary endpoint of discontinued radiation was evaluated in a multivariable logistic regression. Secondary endpoints of 30-day and 90-day mortality, overall mortality, and nonbladder cancer mortality were evaluated in multivariable models. Results: Of 369 veterans with MIBC who underwent CRT, 30 patients (8.1%) did not complete radiation. The most common reasons for treatment discontinuation included comorbidities or infections necessitating hospital admission (63.3%) and treatment intolerance or declining performance status (26.7%). In multivariable logistic regression, variables associated with radiation discontinuation were creatinine clearance ≤ 50 (odds ratio [OR], 3.93; 95% CI, 1.63-9.50; P = .002), incomplete transurethral resection of bladder tumor (TURBT) (OR, 3.16; 95% CI, 1.15-8.63; P = .02), and nonpreferred chemotherapy (OR, 3.31; 95% CI, 1.31-8.36; P = .01). In the cohort that discontinued radiation, 30-day mortality was 33.3% and 90-day mortality was 50.0%, with the majority of deaths attributed to nonbladder cancer causes. No patient or tumor variables were associated with either endpoint. In the cohort that completed radiation, 30-day mortality was 2.7% and 90-day mortality was 6.8%. In multivariable analysis, radiation discontinuation was associated with worse overall mortality (hazard ratio [HR], 2.48; 95% CI, 1.36-4.50; P = .003) and worse nonbladder cancer mortality (HR, 2.32; 95% CI, 1.24-4.34; P = .008). Conclusions: With a low rate of treatment discontinuation, CRT is an effective and feasible treatment option for the typically elderly and comorbid population of patients with MIBC. In addition to identified predictors of treatment discontinuation (poor renal function, incomplete TURBT, etc.), further research is required to develop evidence-based guidelines for optimal patient selection.

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.

BackgroundCancer treatments can paradoxically appear to reduce the risk of non-cancer mortality in observational studies, due to residual confounding from treatment selection bias. Here we apply a novel method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding.MethodsWe studied 36630 prostate cancer patients, 4069 lung cancer patients, and 7117 head/neck cancer patients, using the Veterans Affairs Informatics and Computing Infrastructure database. We estimated effects of intensive treatment (prostate: prostatectomy vs. radiotherapy; lung: lobectomy vs. sublobar resection or radiotherapy; head/neck: radiotherapy with concurrent cisplatin and/or multiagent induction vs. radiotherapy with or without alternative systemic therapy) on cancer-specific mortality, non-cancer mortality, and overall survival (OS), using both multivariable Cox (MVA) and propensity score (inverse probability treatment weighting (IPTW)) models. Next, we applied the BRACE method to adjust for residual confounding, based on the observed treatment effect on competing event and relative event hazards.ResultsFor each cohort, intensive treatment was associated with significantly reduced hazards for cancer-specific mortality, non-cancer mortality, and OS. Compared to the results for MVA and IPTW models, hazard ratios (95% confidence intervals) for the effect of intensive treatment on OS were attenuated in each cohort after applying BRACE: (prostate-MVA: 0.75 (0.71, 0.80), IPTW: 0.73 (0.66, 0.75), BRACE: 0.98 (0.95, 1.00); lung-0.79 (0.68, 0.91), 0.79 (0.66, 0.89), BRACE: 0.81 (0.65, 0.94); head/neck-0.71 (0.66, 0.76), 0.70 (0.66, 0.76), BRACE: 0.81 (0.76, 0.86)). BRACE estimates were similar to findings from meta-analyses and randomized trials.ConclusionsWe found evidence of residual confounding in several observational cohorts after applying standard methods, which were mitigated after applying BRACE. Application of this method could provide more reliable estimates and inferences when residual confounding is identified and represents a novel approach to improving the validity of outcomes research.

PURPOSE/OBJECTIVE(S) Despite recent guideline recommendations, the utilization of low-dose CT (LDCT) for lung cancer screening has remained low. Little is known about the driving factors behind these low rates or the effect of real-world LDCT utilization on lung cancer outcomes. We hypothesize that LDCT screening will be associated with less advanced disease at diagnosis and improved cancer survival. Furthermore, we utilize a machine learning approach to investigate predictors for receiving LDCT screening. MATERIALS/METHODS We identified patients with non-small cell lung cancer (NSCLC) within the Veterans Health Administration (VHA) diagnosed from 2015 to 2017. LDCT screening was identified using procedural codes. We calculated LDCT rates using the pre-diagnostic observation period that included up to 3 years prior to diagnosis. Multivariable logistic regression assessed the influence of LDCT usage on metastatic disease at diagnosis. Lead-time correction using published LDCT lead-times was performed. Cancer-specific mortality (CSM) was evaluated using Fine-Gray regression and non-cancer death as a competing risk. A lasso machine learning model was used to identify important predictors for receiving LDCT screening. The data were split 75%/25% into training/testing datasets. We constructed the model with training data and evaluated performance within the test data using area under the curve (AUC). An AUC of 1.0 indicated perfect prediction. RESULTS The cohort included 4,664 patients diagnosed with NSCLC at a mean age of 67.8. The pre-diagnostic period ranged from 1-3 years, median of 1 year. Median follow-up was 12 months. Overall LDCT screening rate was 1.3%. From 2015-2017, this rate increased from 0.1% to 6.6%. Compared with no screening, Patients with ≥ 1 LDCT were more likely to present with stage I disease and less likely to present with stage IV disease (Stage I: 64% vs 42%, P < 0.01; Stage IV: 10% vs 22%, P < 0.01). In multivariable models, screened patients had lower risk of metastatic disease at diagnosis (odds ratio = 0.40, 95% confidence interval (CI) = [0.22-0.74], P = 0.03) and CSM (sub-distribution hazard ratio = 0.17, 95% CI = [0.04-0.63], P < 0.01). Our lasso model achieved an AUC of 0.82 and identified year of diagnosis and regional VA site of care as the most important predictors associated with receiving LDCT screening. Non-Hispanic White patients were more likely to undergo LDCT screening. CONCLUSION Within the VHA, utilization of LDCT screening is increasing though the usage remains low. Patients undergoing LDCT were diagnosed at earlier stages and were less likely to die from cancer. While overdiagnosis and lead-time bias need to be considered, these findings are consistent with randomized data and support the need for increased utilization of LDCT screening. Availability of LDCT appeared to be the main predictor of utilization. Providing access to more patients, including those in diverse racial and ethnic groups, should be a priority to reduce lung cancer mortality.

Purpose/objective(s) Outcomes for muscle-invasive bladder cancer (MIBC) treated with definitive chemoradiation (CRT) have largely remained stagnant in recent decades. To understand how best to improve outcomes for this population, we investigated patterns of failure after CRT for MIBC within the national Veterans Affairs' (VA) database. Materials/methods In the VA database, we identified patients diagnosed between 2000 and 2018 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent CRT (defined as at least 50% of an intended definitive radiation regimen in conjunction with at least 1 cycle of chemotherapy). All patients' electronic health records were chart reviewed to obtain detailed clinical, pathologic, treatment (radiation dose, type of chemotherapy), and outcomes (dates and locations of recurrences, cause-specific death) data. Median times to recurrence are reported along with 25th-75th percentiles. Endpoints of local recurrence (LR, defined as recurrence in the bladder or upper tract), distant recurrence (DR, defined as recurrence beyond regional lymph nodes), overall mortality (OM), and bladder cancer-specific mortality (BCM) were evaluated in multivariable Cox and Fine-Gray models. Results Overall, 356 patients were included: median age 76, T2 disease 85%, lymph node positive (LN+) disease 5%. 12% of patients had carcinoma in situ, 32% had multifocal disease, and 33% had pretreatment hydronephrosis. Median follow up time was 77 months. 5-year OM was 69% (95% CI 64-74%) and 5-year BCM was 39% (95% CI 34-44%). 155 (44%) patients had no recurrence. In the 135 (38%) patients that developed DR, the median time to DR was 12.1 mo (8.0-23.4 mo). 106 (79%) patients of the DR group developed DR as a first recurrence with either DR only (n = 73) or DR and LR simultaneously (n = 33). In the 123 (35%) patients that developed LR, median time to LR was 11.1 mo (7.3-20.9 mo). Of the 92 patients who developed LR first without a simultaneous DR, 26 (28%) went on to develop DR. Median time from LR to DR in this group was 12.4 mo (3.0-27.0 mo). In multivariable models, LN+ disease, pretreatment hydronephrosis, and creatinine clearance (CrCl) ≤ 50 were associated with higher rates of DR, inferior OM, and inferior BCM. No patient, tumor, or treatment variables were associated with LR. Conclusion 44% of patients with MIBC treated with CRT had no recurrence while 35% developed LR and 38% developed DR. These results highlight the need for continued local surveillance after CRT as over a third of patients developed LR. Given the high proportion of DR and the advent of novel agents (antibody drug conjugates, immunotherapy, etc.) for advanced urothelial carcinoma, these data emphasize the need for clinical trials exploring such agents to improve outcomes for patients with MIBC undergoing definitive intent CRT. Our identified clinical markers (LN+ disease, hydronephrosis, decreased CrCl) as well as novel biomarkers (e.g., circulating tumor DNA) may help delineate populations most likely to benefit from additional therapy.

Androgen deprivation therapy (ADT) is frequently utilized in conjunction with radiotherapy (RT) in the definitive management of prostate cancer. Prior studies have suggested an association between ADT use and acute kidney injury (AKI), however, these included heterogeneous populations undergoing a variety of treatments and relied on billing codes to ascertain the incidence of AKI.We analyzed a cohort of 27,868 veterans undergoing definitive RT + /- ADT for prostate cancer between 2001 and 2015 using the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Exposure was defined as use of ADT within one year of diagnosis. The primary outcome was AKI, defined by an increase in serum creatinine to at least 1.5 times the baseline value. AKIs were classified as mild, moderate, or severe in accordance with international guidelines. A multivariate competing risks model was used to account for demographic and oncologic factors as well as medications and procedures known to influence the risk of AKI.Most (n = 18,754) men received RT alone; 9,114 men received RT + ADT. The incidence of AKI at two years after diagnosis was 10.5% in the RT + ADT group and 7.9% in the RT group (Gray's test p 0.01). Multivariate analysis confirmed ADT usage was associated with an increased risk for any AKI (SHR = 1.24, 95% CI = 1.14-1.36, p 0.01). ADT was also associated with an increased risk of mild AKI (SHR = 1.13, 95% CI = 1.01-1.27, p = 0.04) and moderate AKI (SHR = 1.45, 95% CI = 1.20-1.76, p 0.01), though not severe AKI (SHR = 1.33, 95% CI = 0.93-1.91, p = 0.11).Our findings confirm that use of ADT is associated with an increased risk of AKI in patients undergoing definitive RT for prostate cancer. Clinicians should be alert to the potential for renal dysfunction in this population.

Background: Active surveillance (AS) is a safe treatment option for men with low-risk, localized prostate cancer. However, the safety of AS for patients with intermediate-risk prostate cancer remains unclear. Patients and Methods: We identified men with NCCN-classified low-risk and favorable and unfavorable intermediate-risk prostate cancer diagnosed between 2001 and 2015 and initially managed with AS in the Veterans Health Administration. We analyzed progression to definitive treatment, metastasis, prostate cancer–specific mortality (PCSM), and all-cause mortality using cumulative incidences and multivariable competing-risks regression. Results: The cohort included 9,733 men, of whom 1,007 (10.3%) had intermediate-risk disease (773 [76.8%] favorable, 234 [23.2%] unfavorable), followed for a median of 7.6 years. The 10-year cumulative incidence of metastasis was significantly higher for patients with favorable (9.6%; 95% CI, 7.1%–12.5%; PPPPPConclusions: Compared with low-risk patients, those with favorable and unfavorable intermediate-risk prostate cancer managed with AS are at increased risk of metastasis and PCSM. AS may be an appropriate option for carefully selected patients with favorable intermediate-risk prostate cancer, though identification of appropriate candidates and AS protocols should be tested in future prospective studies.

282 Background: Active surveillance is a common management strategy for men with low-risk prostate cancer. However, there is some concern that delaying definitive therapy could lead to progressive disease and a missed opportunity to cure the cancer. We sought to study the impact of Gleason grade progression on the risk of metastases and prostate cancer-specific mortality (PCSM). We then sought to compare the risks of PCSM with the risk of competing mortality in this real-world cohort of men on active surveillance. Methods: This was a retrospective population-based cohort study using patient records from the Veterans Heath Administration Informatics and Computing Infrastructure of patients with a diagnosis of low-risk prostate cancer from January 1, 2001, to December 31, 2015, who were managed with active surveillance. Follow-up extended through March 31, 2020. Low-risk prostate cancer was defined as International Society of Urologic Pathology grade group (GG) 1, clinical tumor stage 2A or lower, PSA level of 10 ng/dL or lower. Active surveillance was defined as no definitive treatment within the first year after diagnosis with at least 1 additional re-staging biopsy after diagnostic biopsy. We identified men with pathologic upgrading to ≥GG2 and ≥GG3. We calculated the cumulative incidence of metastases, PCSM, and non-cancer mortality for men with and without pathologic upgrading. Results: The cohort included 8562 men with low-risk PC. Pathologic upgrading to ≥GG2 and ≥GG3 occurred in 3227 and 1200 men, respectively. For all patients, the 8-year cumulative incidence of metastases and PCSM was 0.8% (95% CI: 0.6-1.0%) and 0.4% (CI:0.3-0.6%), respectively. Pathologic upgrading to ≥GG2 was associated with an increased risk of metastases at 8 years (1.2% vs 0.5%, p < 0.001). Pathologic upgrading to ≥GG3 was also associated with an increased risk of metastases at 8 years (2.7% vs 0.5%, p < 0.001). In contrast, pathologic upgrading to ≥GG2 was not associated with an increased risk of PCSM at 8 years (0.5% vs 0.4%, p = 0.793). Similarly, pathologic upgrading to ≥GG3 was not associated with an increased risk of PCSM at 8 years (0.7% vs 0.4%, p = 0.82). The 8-year cumulative incidence of non-cancer mortality for all patients was 6.5% (95% CI:5.9-7.1%). Overall, the risk of non-cancer mortality was 16.25 (6.5/0.4) times higher than the risk of PCSM, regardless of upgrading status. Conclusions: For men with low-risk PC on active surveillance, pathologic upgrading was associated with a small increased risk of metastases but no increased risk of death from prostate cancer. Regardless of upgrading status, the risk of non-cancer mortality was substantially higher than the risk of PCSM. Future work is required to better tailor the intensity of follow up for surveillance protocols for men at risk of competing mortality.

27 Background: African American (AA) men with prostate cancer (PC) present with more advanced disease and have worse survival than comparable non-Hispanic White (White) men. Recent studies suggest that receiving care within an equal access setting may attenuate these disparities. We hypothesize that AA men receiving care within the Veterans Health Administration (VHA) will have improved outcomes compared to AA men receiving care in the general population as assessed by the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We identified AA men diagnosed with PC between 2004 and 2015 in the VHA and SEER. For comparisons of covariate distributions across subgroups, we used the chi-squared test with continuity correction. We analyzed the cumulative incidence (with 95% confidence intervals (CIs)) of PC specific mortality (PCSM) in the VHA and SEER. Additionally, multivariable Cox proportional hazards models controlling for demographic information were performed. Results: The cohort included 85,409 AA men (VHA: 27,415, SEER: 57,994). Median follow-up was 4.79 years in the VHA and 5.16 years in SEER. In the VHA, AA men were more likely to present with localized disease (VHA 94.7% vs SEER 86.4%, p < 0.001) and less likely to have metastatic disease (3.2% vs 4.3%, p < 0.001). The 5-year cumulative incidence of PCSM was lower for patients in the VHA (VHA: 3.8% [CI: 3.5-4.1%] vs. SEER: 5.0% [CI: 4.8-5.2%], p < 0.001). The PCSM difference was largest in men with metastatic disease. In metastatic patients, cumulative incidence of PCSM at five years was significantly lower in the VHA (VHA 52.5% [CI: 48.0-56.5%] vs. SEER 64.8% [CI: 62.3-67.1%], p < 0.001). In contrast, AA men with localized disease had similar PCSM in the VHA and SEER (VHA 2.4% [CI: 2.2-2.6%] vs. SEER 2.6% [CI: 2.4-2.7%], p = 0.09 at five years). On multivariable analysis, VHA system was associated with lower PCSM [Hazard Ratio (HR): 0.91, p < 0.001]. There was a significant interaction between VHA system and distant metastases at diagnosis [p < 0.001] indicating larger differences in PCSM by healthcare system in metastatic patients as compared to localized patients. VHA system was associated with reduced PCSM in metastatic patients [HR 0.84, p < 0.001] but not in localized patients [HR 0.96, p = 0.13]. Conclusions: AA men in the VHA had a significantly lower incidence of PCSM than those in the SEER database, especially for those who presented with distant metastases at diagnosis. Future work should examine how cost and access to care affect disparities in outcomes for AA men.

462 Background: Retrospective studies using large registries comparing outcomes between radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) to trimodality therapy (TMT), which includes transurethral resection of bladder tumor followed by chemoradiation, often cannot distinguish whether patients receiving TMT were eligible for cystectomy but declined or simply ineligible for cystectomy. The objective of this study was to compare survival outcomes of patients with MIBC receiving TMT stratified by whether they were cystectomy-eligible to patients receiving RC +/- NAC. Methods: We used the national Veterans Affairs’ (VA) database to identify patients diagnosed between 2000-2017 with urothelial histology, MIBC (T2-4a/N0-3/M0) who underwent RC or TMT. Overall survival (OS) was evaluated with multivariable Cox proportional hazards model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. We conducted a chart review of clinical notes to ascertain if patients were eligible for cystectomy. Results: Overall 2306 Veterans with MIBC were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 107 (4.6%) with TMT eligible for RC, and 221 (9.4%) with TMT ineligible for RC. Median follow up time was 4.7 years. Patients receiving RC were on average 10 years younger, had higher creatinine clearance, and fewer comorbidities than those receiving TMT. Cystectomy-eligible TMT patients had higher creatinine clearance and fewer comorbidities than those ineligible for cystectomy. On multivariable analysis, compared to RC-NAC, TMT in cystectomy-eligible patients was associated with similar OS (hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.76 - 1.28; p = 0.93) and BCSM (HR 1.02; 95% CI 0.71-1.47; p = 0.91). Compared to RC-NAC, TMT in cystectomy-ineligible patients was associated with inferior OS (HR 1.39; 95% CI 1.13 - 1.71; p = 0.002) and BCSM (HR 1.61; 95% CI 1.23 - 2.10; p < 0.001). Conclusions: There is a significant selection bias among patients with MIBC receiving TMT. Cystectomy-eligible patients receiving TMT likely have similar survival outcomes as those receiving RC. Comparisons between RC and TMT in large registry data that lack information regarding eligibility for cystectomy in the TMT arm may be unreliable.

PURPOSE/OBJECTIVE(S) Radiation treatment with concurrent chemotherapy (CRT) is a definitive treatment option for muscle-invasive bladder cancer (MIBC). Despite its effectiveness, CRT is underutilized given perceptions regarding fitness of patients for treatment and subsequent utility. Within the national Veterans Affairs' (VA) database, we investigated the factors associated with and the impact of treatment discontinuation in patients with MIBC treated with CRT. MATERIALS/METHODS In the VA database, we identified patients with urothelial histology, MIBC (T2-4a/N0-3/M0) diagnosed between 2000 and 2018 and treated with definitive intent CRT. Patients' electronic health records were chart reviewed to document if they completed definitive radiation (defined as at least 55 Gy). Preferred chemotherapy regimen was defined as containing cisplatin or combination mitomycin/5-fluorouracil. Primary endpoint of discontinued radiation was evaluated in a multivariable logistic regression. Secondary endpoints of 30/90-day mortality, overall mortality (OM), bladder cancer-specific mortality (BCM), non-bladder cancer-specific mortality (NCM), locoregional failure (LRF), and distant failure (DF) were evaluated in multivariable Cox and Fine-Gray models. RESULTS Of an identified 369 veterans with MIBC who underwent CRT, 30 (8.1%) patients did not complete definitive radiation. The most common reasons for treatment discontinuation included comorbidities/infections necessitating hospital admission (63.3%) and treatment intolerance/declining performance status (26.7%). In multivariable logistic regression, the only significant sociodemographic or clinical variables associated with radiation discontinuation were creatinine clearance (CrCl) ≤ 50 (OR 3.61, 95% CI 1.51-8.66, P < 0.01) and non-preferred chemotherapy regimen (OR 3.43, 95% CI 1.36-8.67, P = 0.01). In the discontinued radiation cohort, 30-day mortality was 33.3% and 90-day mortality was 50.0% with the majority of deaths due to non-bladder cancer-specific causes. In this cohort, no patient or tumor variables were associated with either endpoint. In the completed radiation cohort, 30-day mortality was 2.7% and 90-day mortality was 6.8%. In multivariable analysis, radiation discontinuation was significantly associated with worse OM (HR 2.50, 95% CI 1.37-4.56, P < 0.01) and worse NCM (HR 2.29, 95% CI 1.21-4.32, P = 0.01). It was not associated with inferior BCM (HR 0.56, 95% CI 0.25-1.26, P = 0.16), LRF (HR 0.93, 95% CI 0.44-1.97, P = 0.85), or DF (HR 0.60, 95% CI 0.28-1.28, P = 0.19). CONCLUSION More than 90% of patients with MIBC who undergo definitive intent CRT are able to complete their radiation course. Decreased creatinine clearance and receipt of non-preferred chemotherapy notably increased the odds of not completing radiation. Further research is required to develop evidence-based guidelines on patient selection to ensure curative therapy is offered to appropriate patients.

e18006 Background: Both chemoradiotherapy (CRT) and total laryngectomy (TL) with adjuvant therapy are curative-intent treatment options for patients with T4a larynx cancer. Disease recurrence is a known negative prognosicator, but differences in recurrence patterns and the subsequent survival associations are not well characterized. To address this knowledge gap, we present long-term recurrence and survival outcomes from a novel longitudinal data source. Methods: Retrospective study of non-metastatic T4a larynx cancer patients diagnosed between 2000-2017 who underwent curative-intent treatment (TL with adjuvant therapy or primary CRT) from the VA Informatics and Computing Infrastructure database. Adjuvant therapy consisted of either postoperative radiotherapy (RT) or CRT. Fine-Gray and Cox models were used to evaluate primary outcomes – time to locoregional recurrence and distant recurrence. Secondary outcomes included overall survival (OS), cancer-specific survival (CSS), non-cancer specific survival (NCSS), and disease-free survival (DFS). These multivariable models accounted for age, race, alcohol history, smoking status, education and income, Charlson-Deyo score, N-classification, and tumor subsite. Results: The study included 1,114 patients with a median follow-up time of 63.3 months among those alive at last follow up. In the TL group, adjuvant RT was used in 69% and adjuvant CRT was used in 31%. Median time to first recurrence was 24.4 months with overall incidence of 28.5% locoregional and 9.5% distant recurrence. Primary CRT patients had higher rates of locoregional (37.2 vs. 22.9%) and distant recurrence (13.3 vs. 7.0%) (p < 0.0001). Median OS was 27.3 months for CRT (95% CI: 23.6-32.4 months) and 47.5 months (95% CI: 39.6-52.1 months) for TL. Median DFS was 14.1 months for CRT (95% CI:12.5-17.2 months) and 37.9 months (95% CI 31.2-47.5 months) for TL. On multivariable analysis compared to CRT, TL was associated with longer time to locoregional (HR 0.50, 95% CI:0.40-0.61) and distant recurrence (HR 0.50, 95% CI:0.34-0.73). Having N+ disease increased risk of distant recurrence (HR 2.20, 95% CI:1.42-3.41). TL was associated with improved OS (HR 0.78, 95% CI:0.67 – 0.91), CSS (HR 0.73, 95% CI:0.59 – 0.89), and DFS (HR 0.58, 95% CI 0.49-0.69) compared to CRT; NCSS was equivalent between groups (HR 1.09, 95% CI:0.88-1.35). Of the CRT patients with locoregional failures, 67/163 (41.1%) were salvaged with surgery. Conclusions: In this cohort of T4a larynx cancer patients, surgical management demonstrated favorable recurrence and survival results. TL with adjuvant therapy was associated with significantly lower incidence of both locoregional and distant recurrence and increased OS, CSS and DFS compared to CRT. Lower probability of disease recurrence, in addition to a survival advantage, should be considered as an important advantage to up-front surgery.

Key Points Question Is prostate-specific antigen velocity associated with clinical progression in patients with low-risk prostate cancer treated with active surveillance, and are there differences between African American and non-Hispanic White patients? Findings In this population-based cohort study of 5296 patients with low-risk prostate cancer, prostate-specific antigen velocity was associated with clinical progression to more advanced disease. Compared with non-Hispanic White patients, African American patients were more likely to experience disease progression at lower prostate-specific antigen velocity thresholds. Meaning This study suggests that prostate-specific antigen velocity is a useful clinical tool for all patients treated with active surveillance, and African Americans may require closer attention to follow-up., Importance The association of prostate-specific antigen velocity (PSAV) with clinical progression in patients with localized prostate cancer managed with active surveillance remains unclear and, to our knowledge, has not been studied in African American patients. Objectives To test the hypothesis that PSAV is associated with clinical progression in patients with low-risk prostate cancer treated with active surveillance and to identify differences between African American and non-Hispanic White patients. Design, Setting, and Participants This was a retrospective population-based cohort study using patient records from the Veterans Heath Administration Informatics and Computing Infrastructure on 5296 patients with a diagnosis of localized prostate cancer from January 1, 2001, to December 31, 2015, who were managed with active surveillance. Follow-up extended through March 31, 2020. Low-risk prostate cancer was defined as International Society of Urologic Pathology grade group (GG) 1 clinical tumor stage 2A or lower, PSA level of 10 ng/dL or lower, active surveillance, and no definitive treatment within the first year after diagnosis with at least 1 additional staging biopsy after diagnostic biopsy. Exposures Prostate-specific antigen testing. Main Outcomes and Measures The primary outcome was GG progression detected after repeated biopsy or prostatectomy, defined as GG2 or higher or GG3 or higher. The secondary outcome was incident metastases. Cumulative incidence functions and multivariable Cox proportional hazards regression models were used to test associations between PSAV and outcomes. Results The final cohort (n = 5296) included 3919 non-Hispanic White men (74.0%; mean [SD] age, 65.7 [5.8] years) and 1377 African American men (26.0%; mean [SD] age, 62.8 [6.6] years). Compared with African American patients, non-Hispanic White patients were older (mean [SD] age, 65.7 [5.8] years vs 62.8 [6.6] years; P, This cohort study evaluates whether prostate-specific antigen velocity is associated with clinical progression in patients with low-risk prostate cancer treated with active surveillance and identifies differences between African American and non-Hispanic White patients.

196 Background: The utility of prostate-specific antigen velocity (PSAV) to predict clinical progression in patients with localized prostate cancer (PC) on active surveillance remains unclear, and in African American (AA) patients on active surveillance remains undefined. Methods: We performed a cohort analysis using the national US Veterans Affairs Informatics and Computing Infrastructure (VINCI). We identified 5296 patients diagnosed with localized prostate cancer (PC) from 2001 to 2015 managed with active surveillance. Follow-up extended through March 31, 2020. We defined low-risk PC as ISUP grade group 1 (GG1) clinical tumor stage ≤ 2A, and PSA level ≤ 10 ng/dl; and active surveillance as no definitive treatment within the first year after diagnosis with at least one additional staging biopsy after diagnostic biopsy. The primary outcome was grade progression on repeat biopsy/prostatectomy defined as GG2 or GG3. The secondary outcome was incident metastases. Cumulative incidence functions and multivariable Cox proportional hazards models were used to test associations between PSAV and outcomes. Results: The final cohort included 3919 Non-Hispanic White patients (NHW) (74%) and 1377 AA (26%) patients. GG2 progression on repeat biopsy occurred in 2062 (38.9%) patients, with a cumulative incidence (CI) of 43.2 % and GG3 progression occurred in 728 (13.7%) patients, with a CI of 18% at seven years. Fifty-four (0.8%) patients developed metastases, with a CI of 1.4% at ten years. In unadjusted analyses, compared to NHW patients, AA patients were significantly more likely to progress to GG2 (52.8% vs 39.8%, p

IMPORTANCE: There is concern that African American men with low-risk prostate cancer may harbor more aggressive disease than non-Hispanic White men. Therefore, it is unclear whether active surveillance is a safe option for African American men. OBJECTIVE: To compare clinical outcomes of African American and non-Hispanic White men with low-risk prostate cancer managed with active surveillance. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study in the US Veterans Health Administration Health Care System of African American and non-Hispanic White men diagnosed with low-risk prostate cancer between January 1, 2001, and December 31, 2015, and managed with active surveillance. The date of final follow-up was March 31, 2020. EXPOSURES: Active surveillance was defined as no definitive treatment within the first year of diagnosis and at least 1 additional surveillance biopsy. MAIN OUTCOMES AND MEASURES: Progression to at least intermediate-risk, definitive treatment, metastasis, prostate cancer–specific mortality, and all-cause mortality. RESULTS: The cohort included 8726 men, including 2280 African American men (26.1%) (median age, 63.2 years) and 6446 non-Hispanic White men (73.9%) (median age, 65.5 years), and the median follow-up was 7.6 years (interquartile range, 5.7-9.9; range, 0.2-19.2). Among African American men and non-Hispanic White men, respectively, the 10-year cumulative incidence of disease progression was 59.9% vs 48.3% (difference, 11.6% [95% CI, 9.2% to 13.9%); P

Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up regulation in AH livers and a 26-fold up regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Over expression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH.

Purpose: Breast glandular tissue architecture complicates mammographyimage interpretation due to superposition. We have built a dedicated breast CT (BCT) scanner to produce volumetric images of the breast and begun a preliminary clinical trial in volunteers and selected patients. The purpose of this study was to evaluate visualization and identification of breast landular tissue patterns in BCT volume data and its potential to improve lesion detection compared to mammography.Method and Materials: A dedicated BCT scanner was constructed and previously described. Volunteer and patient imaging was performed using 80 kVp at doses comparable to a standard 2‐view mammogram and reconstructed using a modified Feldkamp algorithm. BCT data of 512^3 voxels have an approximately isotropic resolution of 300 μm. Volume data were analyzed and viewed on a specially designed volume workstation and were displayed using blending, maximum‐intensity‐projection (MIP) and summation projection algorithms. Interactive review was possible for the entire volume. Breast glandular structures were identified based on CT number, voxel histograms and structural features. Results: BCT images showed impressive breast parenchyma and glandular structure detail with excellent contrast resolution. Volume rendering, especially summation projection, and thick slices provided optimization of viewing of ductal structures. Multi‐planar slices permitted rapid scrolling through slices. Voxel CT numbers, histograms and architectural features were effective in differentiating glandular from fat, skin and connective tissues. MIP images clearly demonstrated calcifications. Conclusion: BCT provides high‐quality volume data that enhanced visualization of breast glandular tissue and architecture compared to other breast imaging methods. Voxel CT numbers plus direct interactive viewing provided the mammographer clear views of breast architecture and glandular tissues. Workstation display flexibility presented data appearing similar to mammograms plus additional tomographic slices further enhancing conspicuity of breast architecture. A small number of mammographically demonstrated cancers were readily identified in BCT data.

Purpose: To develop and innovative Volumetric Ultrasound guided Online Adaptive Partial Breast Irradiation system (VUSABI) for the improvement of the precision of the delivery of prescribed radiationdose to the target volume while sparing the adjunct normal breast tissues.Method and Materials: The VUSABI system consists of a volumetric breast ultrasound (VBUS) scanning system and an online adaptive replanning system. The VBUS system developed for early breast cancer detection is a non‐ionizing radiation, non‐compression, and operator‐free imagingsystem. It can provide real‐time, high quality volumetric breast images in pendulant position with low cost. A GPU‐based innovative supercomputing online adaptive replanning environment (SCORE) was developed for general‐purpose online adaptive radiotherapy(ART). The major components of SCORE system are: image registration,dose calculation, plan re‐optimization, and treatment plan user interface. We are integrating VBUS and SCORE into the whole VUSABI system by hardware integration and software adaptation. In this paper, we report on our progress of the VUSABI system development. Results: The performance of VBUS system was evaluated with both breast phantoms and patients. With the VBUS scanner, a 3D ultrasound breast image can be acquired in ∼18 sec and reconstructed in ∼ 5 sec. the overall performance are satisfactory. The initial PBI treatment plan was generated with Eclipse planning system. The major components of SCORE system were developed and evaluated with digital phantom data and clinical patient data. The whole replanning process can be accomplished in ∼10 second using a NVIDIA Tesla C1060 GPU platform. Conclusion: We are in the progress of developing VUSABI system. According to the initial results, the VUSABI system will be able to produce an optimized treatment plan based on a VBUS scan within 2 minutes when considering human intervention such as contour modification.

Purpose: To evaluate the ability of a prototype breast CT scanner to detect micro‐calcifications, and to understand the influence that tube potential and radiation dose have on this. Method and Materials: Commercially available micro‐calcifications (μCa) of various sizes (200 to 425 μm) were embedded inside a 12.7 mm polyethylene tube filled with gelatin (to simulate glandular tissue). The gelatin tube was then placed inside a 14 cm diameter adipose equivalent cylindrical phantom and scanned using various tube potentials (60 to 100 kVp) and tube currents. CTimages were reconstructed with both Ramp and Shepp‐Logan filters, with a reconstructed voxel size of about 320×320×200 μm. The μCa were then evaluated quantitatively using signal‐to‐noise ratio (SNR) metric, and subjective appraisals were made as well. A dedicated breast CT visualization workstation was used for subjective evaluation. Results: Results for 250–280 mm μCa imaged at 80 kVp shown that the μCa are clearly visible when the rod is scanned by itself, but extremely difficult to locate when placed inside the 14 cm phantom. The visualization of the μCa improved overall for larger μCa, and overall visualization improves as the radiation levels are increased, as expected. Conclusion: These initial results suggested that the pixel size may not be a critical factor when determining the ability of the prototype system to visual micro‐calcifications, as the current objects scanned are only about 48% of the reconstructed voxel size. Maximum intensity projection (MIP) display for thick‐slice imaging was found to be most useful for subjective viewing of micro‐calcification clusters.