Factors Associated With Cardiac Radiation Dose Reduction After Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium.

PURPOSE: Limiting cardiac radiation dose is important for minimizing long-term cardiac toxicity in patients with left-sided early-stage breast cancer. METHODS AND MATERIALS: Prospectively collected dosimetric data were analyzed for patients undergoing moderately hypofractionated radiation therapy to the left breast within the Michigan Radiation Oncology Quality Consortium from 2016 to 2022. The mean heart dose (MHD) goal was progressively tightened from ≤2 Gy in 2016 to MHD ≤ 1.2 Gy in 2018. In 2021, a planning target volume (PTV) coverage goal was added, and the goal MHD was reduced to ≤1 Gy. Multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goals in 2016 to 2020 and the combined MHD/PTV coverage goal in 2021 to 2022. RESULTS: In total, 4165 patients were analyzed with a median age of 64 years. Overall average cardiac metric compliance was 91.7%. Utilization of motion management increased from 41.8% in 2016 to 2020 to 46.5% in 2021 to 2022. Similarly, use of prone positioning increased from 12.2% to 22.2% in these periods. On multivariate analysis in the 2016 to 2020 cohort, treatment with motion management (odds ratio [OR], 5.20; 95% CI, 3.59-7.54; P < .0001) or prone positioning (OR, 3.21; 95% CI, 1.85-5.57; P < .0001) was associated with meeting the MHD goal, while receipt of boost (OR, 0.25; 95% CI, 0.17-0.39; P < .0001) and omission of hormone therapy (OR, 0.65; 95% CI, 0.49-0.88; P = .0047) were associated with not meeting the MHD goal. From 2021 to 2022, treatment with motion management (OR, 1.89; 95% CI, 1.12-3.21; P = .018) or prone positioning (OR, 3.71; 95% CI, 1.73-7.95; P = .0008) was associated with meeting the combined MHD/PTV goal, while larger breast volume (≥1440 cc; OR, 0.34; 95% CI, 0.13-0.91; P = .031) was associated with not meeting the combined goal. CONCLUSIONS: In our statewide consortium, high rates of compliance with aggressive targets for limiting cardiac dose were achievable without sacrificing target coverage.

External Beam Radiation Therapy With or Without Brachytherapy Boost in Men With Very-High-Risk Prostate Cancer: A Large Multicenter International Consortium Analysis.

PURPOSE: Very-high-risk (VHR) prostate cancer (PC) is an aggressive subgroup with high risk of distant disease progression. Systemic treatment intensification with abiraterone or docetaxel reduces PC-specific mortality (PCSM) and distant metastasis (DM) in men receiving external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT). Whether prostate-directed treatment intensification with the addition of brachytherapy (BT) boost to EBRT with ADT improves outcomes in this group is unclear. METHODS AND MATERIALS: This cohort study from 16 centers across 4 countries included men with VHR PC treated with either dose-escalated EBRT with ≥24 months of ADT or EBRT + BT boost with ≥12 months of ADT. VHR was defined by National Comprehensive Cancer Network (NCCN) criteria (clinical T3b-4, primary Gleason pattern 5, or ≥2 NCCN high-risk features), and results were corroborated in a subgroup of men who met Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials inclusion criteria (≥2 of the following: clinical T3-4, Gleason 8-10, or PSA ≥40 ng/mL). PCSM and DM between EBRT and EBRT + BT were compared using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression. RESULTS: Among the entire cohort, 270 underwent EBRT and 101 EBRT + BT. After a median follow-up of 7.8 years, 6.7% and 5.9% of men died of PC and 16.3% and 9.9% had DM after EBRT and EBRT + BT, respectively. There was no significant difference in PCSM (sHR, 1.47 [95% CI, 0.57-3.75]; P = .42) or DM (sHR, 0.72, [95% CI, 0.30-1.71]; P = .45) between EBRT + BT and EBRT. Results were similar within the STAMPEDE-defined VHR subgroup (PCSM: sHR, 1.67 [95% CI, 0.48-5.81]; P = .42; DM: sHR, 0.56 [95% CI, 0.15-2.04]; P = .38). CONCLUSIONS: In this VHR PC cohort, no difference in clinically meaningful outcomes was observed between EBRT alone with ≥24 months of ADT compared with EBRT + BT with ≥12 months of ADT. Comparative analyses in men treated with intensified systemic therapy are warranted.

Predictors of Definitive Treatment Interruptions of Long-Course Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Introduction To identify predictors of definitive treatment interruptions (DTI) of the neoadjuvant long-course radiotherapy (LCRT) in locally advanced rectal cancer (LARC), and to determine their impact on clinical outcomes. Methods Patients with stage II-III LARC treated between 2009-2018 were retrospectively analyzed (n=101, median FU 49.5 months). Logistic regression models evaluated the impact of relevant clinical variables on grade 3 or greater (G3+) acute toxicity, definitive treatment interruption (DTI), pCR, and definitive ostomy (dOST) rates. The secondary outcomes were LRC, MFS, PFS, CSS, and OS. Results The incidences of grade 3 and 4 toxicities were 25.3%, and 1.1%, respectively. The most common G3+ toxicities were peri-anal dermatitis (14.7%) and diarrhea (7.4%), which were more frequent in females (p=0.040) and tumors close to the anal verge (p=0.019). In this study, 11 patients (10.9%) developed DTI, which was associated with these G3+ events (p<0.001). Resection occurred after 7.1 weeks (median, IQR:6.1-8.9). Downstaging occurred in 57.4% (17.8% pCR), 88% achieved negative margins and the dOST rate was 56.4%. The five-year LRC, MFS, PFS, CSS and OS were: 94.4%, 78.9%, 74.7%, 85.2% and 81.6%, respectively. DTI events did not impact any outcome. The factors associated with loco-regional failure were close/positive margins (p<0.001) and stage ypIII (p=0.002). Conclusions: Tumors close to the anal verge and female sex were associated with increased G3+ toxicity, which was predictive of DTI. The resultant partial/complete omission of the planned boost, however, dose did not increase the chance of LR. Further studies to clarify the benefit and optimal timing to deliver the boost are warranted, especially for positive margins.

Mediators of Racial Disparities in Heart Dose Among Whole Breast Radiotherapy Patients.

BACKGROUND: Racial disparities in survival of patients with cancer motivate research to quantify treatment disparities and evaluate multilevel determinants. Previous research has not evaluated cardiac radiation dose in large cohorts of breast cancer patients by race nor examined potential causes or implications of dose disparities. METHODS: We used a statewide consortium database to consecutively sample 8750 women who received whole breast radiotherapy between 2012 and 2018. We generated laterality- and fractionation-specific models of mean heart dose. We generated patient- and facility-level models to estimate race-specific cardiac doses. We incorporated our data into models to estimate disparities in ischemic cardiac event development and death. All statistical tests were 2-sided. RESULTS: Black and Asian race independently predicted higher mean heart dose for most laterality-fractionation groups, with disparities of up to 0.42 Gy for Black women and 0.32 Gy for Asian women (left-sided disease and conventional fractionation: 2.13 Gy for Black women vs 1.71 Gy for White women, P < .001, 2-sided; left-sided disease and accelerated fractionation: 1.59 Gy for Asian women vs 1.27 Gy for White women, P = .002). Patient clustering within facilities explained 22%-30% of the variability in heart dose. The cardiac dose disparities translated to estimated excesses of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women vs White women. CONCLUSIONS: Depending on laterality and fractionation, Asian women and Black women experience higher cardiac doses than White women. This may translate into excess radiation-associated ischemic cardiac events and deaths. Solutions include addressing inequities in baseline cardiac risk factors and facility-level availability and use of radiation technologies.

Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer: A Patient-Level Data Analysis of 3 Cohorts.

IMPORTANCE: Radiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain. OBJECTIVE: To determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTINGS, AND PARTICIPANTS: This was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021. EXPOSURES: High-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs). MAIN OUTCOMES AND MEASURES: The primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months). RESULTS: This cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to <6, 6 to <18, and ≥18 months). Natural cubic spline analysis identified minimum duration thresholds of 26.3 months (95% CI, 25.4-36.0 months) for EBRT and 12 months (95% CI, 4.9-36.0 months) for EBRT+BT for optimal effect on DMFS. In RADAR, the prolongation of ADT for patients receiving only EBRT was not associated with significant improvements in DMFS (hazard ratio [HR], 1.01; 95% CI, 0.65-1.57); however, for patients receiving EBRT+BT, a longer duration was associated with improved DMFS (DMFS HR, 0.56; 95% CI, 0.36-0.87; P = .01). For patients receiving EBRT alone (DART), 28 months of ADT was associated with improved DMFS compared with 18 months (RADAR HR, 0.37; 95% CI, 0.17-0.80; P = .01). CONCLUSIONS AND RELEVANCE: These cohort study findings suggest that the optimal minimum ADT duration for treatment with high-dose EBRT alone is more than 18 months; and for EBRT+BT, it is 18 months or possibly less. Additional studies are needed to determine more precise minimum durations.

Comparative Effectiveness Analysis of 3D-Conformal Radiation Therapy Versus Intensity Modulated Radiation Therapy (IMRT) in a Prospective Multicenter Cohort of Patients With Breast Cancer.

PURPOSE: Simple intensity modulation of radiation therapy reduces acute toxicity compared with 2-dimensional techniques in adjuvant breast cancer treatment, but it remains unknown whether more complex or inverse-planned intensity modulated radiation therapy (IMRT) offers an advantage over forward-planned, 3-dimensional conformal radiation therapy (3DCRT). METHODS AND MATERIALS: Using prospective data regarding patients receiving adjuvant whole breast radiation therapy without nodal irradiation at 23 institutions from 2011 to 2018, we compared the incidence of acute toxicity (moderate-severe pain or moist desquamation) in patients receiving 3DCRT versus IMRT (either inverse planned or, if forward-planned, using ≥5 segments per gantry angle). We evaluated associations between technique and toxicity using multivariable models with inverse-probability-of-treatment weighting, adjusting for treatment facility as a random effect. RESULTS: Of 1185 patients treated with 3DCRT and conventional fractionation, 650 (54.9%) experienced acute toxicity; of 774 treated with highly segmented forward-planned IMRT, 458 (59.2%) did; and of 580 treated with inverse-planned IMRT, 245 (42.2%) did. Of 1296 patients treated with hypofractionation and 3DCRT, 432 (33.3%) experienced acute toxicity; of 709 treated with highly segmented forward-planned IMRT, 227 (32.0%) did; and of 623 treated with inverse-planned IMRT, 164 (26.3%) did. On multivariable analysis with inverse-probability-of-treatment weighting, the odds ratio for acute toxicity after inverse-planned IMRT versus 3DCRT was 0.64 (95% confidence interval, 0.45-0.91) with conventional fractionation and 0.41 (95% confidence interval, 0.26-0.65) with hypofractionation. CONCLUSIONS: This large, prospective, multicenter comparative effectiveness study found a significant benefit from inverse-planned IMRT compared with 3DCRT in reducing acute toxicity of breast radiation therapy. Future research should identify the dosimetric differences that mediate this association and evaluate cost-effectiveness.

Disease Control After Hypofractionation Versus Conventional Fractionation for Triple Negative Breast Cancer: Comparative Effectiveness in a Large Observational Cohort.

PURPOSE: Questions remain about whether moderately hypofractionated whole-breast irradiation is appropriate for patients with triple-negative breast cancer. METHODS AND MATERIALS: Using the prospective database of a multicenter, collaborative quality improvement consortium, we identified patients with node-negative, triple-negative breast cancer who received whole-breast irradiation with either moderate hypofractionation or conventional fractionation. Using inverse probability of treatment weighting (IPTW), we compared outcomes using the Kaplan-Meier product-limit estimation method with Cox regression models estimating the hazard ratio for time-to-event endpoints between groups. RESULTS: The sample included 538 patients treated at 18 centers in 1 state in the United States, of whom 307 received conventionally fractionated whole-breast irradiation and 231 received moderately hypofractionated whole-breast irradiation. The median follow-up time was 5.0 years (95% confidence interval [CI], 4.77-5.15 years). The 5-year IPTW estimates for freedom from local recurrence were 93.6% (95% CI, 87.8%-96.7%) in the moderate hypofractionation group and 94.4% (95% CI, 90.3%-96.8%) in the conventional fractionation group. The hazard ratio was 1.05 (95% CI, 0.51-2.17; P = .89). The 5-year IPTW estimates for recurrence-free survival were 87.8% (95% CI, 81.0%-92.4%) in the moderate hypofractionation group and 88.4% (95% CI 83.2%-92.1%) in the conventional fractionation group. The hazard ratio was 1.02 (95% CI, 0.62-1.67; P = .95). The 5-year IPTW estimates for overall survival were 96.6% (95% CI, 92.0%-98.5%) in the moderate hypofractionation group and 93.4% (95% CI, 88.7%-96.1%) in the conventional fractionation group. The hazard ratio was 0.65 (95% CI, 0.30-1.42; P = .28). CONCLUSIONS: Analysis of outcomes in this large observational cohort of patients with triple-negative, node-negative breast cancer treated with whole-breast irradiation revealed no differences by dose fractionation. This adds evidence to support the use of moderate hypofractionation in patients with triple-negative disease.

Performance of a Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography-Derived Risk-Stratification Tool for High-risk and Very High-risk Prostate Cancer.

Importance: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect low-volume, nonlocalized (ie, regional or metastatic) prostate cancer that was occult on conventional imaging. However, the long-term clinical implications of PSMA PET/CT upstaging remain unclear. Objectives: To evaluate the prognostic significance of a nomogram that models an individual's risk of nonlocalized upstaging on PSMA PET/CT and to compare its performance with existing risk-stratification tools. Design, Setting, and Participants: This cohort study included patients diagnosed with high-risk or very high-risk prostate cancer (ie, prostate-specific antigen [PSA] level >20 ng/mL, Gleason score 8-10, and/or clinical stage T3-T4, without evidence of nodal or metastatic disease by conventional workup) from April 1995 to August 2018. This multinational study was conducted at 15 centers. Data were analyzed from December 2020 to March 2021. Exposures: Curative-intent radical prostatectomy (RP), external beam radiotherapy (EBRT), or EBRT plus brachytherapy (BT), with or without androgen deprivation therapy. Main Outcomes and Measures: PSMA upstage probability was calculated from a nomogram using the biopsy Gleason score, percentage positive systematic biopsy cores, clinical T category, and PSA level. Biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall survival (OS) were analyzed using Fine-Gray and Cox regressions. Model performance was quantified with the concordance (C) index. Results: Of 5275 patients, the median (IQR) age was 66 (60-72) years; 2883 (55%) were treated with RP, 1669 (32%) with EBRT, and 723 (14%) with EBRT plus BT; median (IQR) PSA level was 10.5 (5.9-23.2) ng/mL; 3987 (76%) had Gleason grade 8 to 10 disease; and 750 (14%) had stage T3 to T4 disease. Median (IQR) follow-up was 5.1 (3.1-7.9) years; 1221 (23%) were followed up for at least 8 years. Overall, 1895 (36%) had BCR, 851 (16%) developed DM, and 242 (5%) died of prostate cancer. PSMA upstage probability was significantly prognostic of all clinical end points, with 8-year C indices of 0.63 (95% CI, 0.61-0.65) for BCR, 0.69 (95% CI, 0.66-0.71) for DM, 0.71 (95% CI, 0.67-0.75) for PCSM, and 0.60 (95% CI, 0.57-0.62) for PCSM (P < .001). The PSMA nomogram outperformed existing risk-stratification tools, except for similar performance to Staging Collaboration for Cancer of the Prostate (STAR-CAP) for PCSM (eg, DM: PSMA, 0.69 [95% CI, 0.66-0.71] vs STAR-CAP, 0.65 [95% CI, 0.62-0.68]; P < .001; Memorial Sloan Kettering Cancer Center nomogram, 0.57 [95% CI, 0.54-0.60]; P < .001; Cancer of the Prostate Risk Assessment groups, 0.53 [95% CI, 0.51-0.56]; P < .001). Results were validated in secondary cohorts from the Surveillance, Epidemiology, and End Results database and the National Cancer Database. Conclusions and Relevance: These findings suggest that PSMA upstage probability is associated with long-term, clinically meaningful end points. Furthermore, PSMA upstaging had superior risk discrimination compared with existing tools. Formerly occult, PSMA PET/CT-detectable nonlocalized disease may be the main driver of outcomes in high-risk patients.

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown. Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment. Design, Setting, and Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT). Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models. Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001). Conclusions and Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Efficacy and Incontinence Rates After Urethroplasty for Radiation-induced Urethral Stenosis: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the efficacy of urethroplasty and rates of de novo stress urinary incontinence (SUI) in the specific setting of radiation-induced urethral stenosis. METHODS: A systematic search of databases (PubMed and EMBASE) was performed between 1980-2019 (CRD42020144845). Inclusion criteria were: (1) prior pelvic radiotherapy; (2) surgical urethroplasty; (3) rates of successful treatment and/or SUI development and (4) total case number provided. The pooled summary of stenosis resolution rate and SUI were calculated using the random-effects model weighted by the inverse variance. Accessory analyses were performed by reconstructive technique and type of RT. RESULTS: Ninety-six studies were identified, of which 8 retrospective studies met inclusion criteria, comprising 256 patients. The proportion of cases treated with external beam RT (EBRT), brachytherapy (BT), or combination (EBRT+BT) were 52%, 33%, and 15%, respectively, of studies that specified modality. Most strictures involved the bulbomembranous region (n = 212; 83%). Sixty-one percent of cases (n = 157) entailed primary anastomosis, while the remainder underwent augmentation reconstruction (graft or flap). The mean follow-up time after urethroplasty varied from 10 to 50.5 months. The pooled stenosis resolution rate was 80% (95% CI: 74%-86%). There were no significant associations between stenosis resolution rate and reconstructive technique (rho=0.20, P = .74) or RT modality (rho=-0.31, P = .53). Fifty-three cases developed subsequent SUI, with a pooled complication rate of 19% (95% CI: 10%-31%). CONCLUSIONS: Urethroplasty after radiation-induced urethral stenosis is effective for 80% of cases, independent of prior RT modality or urethroplasty technique; however, 1 out of every 5 patients develops SUI post-procedure.

Clinical effects of morning and afternoon radiotherapy on high-grade gliomas.

Initial clinical reports comparing the delivery of radiotherapy (RT) at distinct times of the day suggest that this strategy might affect toxicity and oncologic outcomes of radiation for multiple human tissues, but the clinical effects on high-grade gliomas (HGG) are unknown. The present study addresses the hypothesis that radiotherapy treatment time of the day (RT-TTD) influences outcome and/or toxic events in HGG. Patients treated between 2009-2018 were reviewed (n = 109). Outcomes were local control (LC), distant CNS control (DCNSC), progression-free survival (PFS), and overall survival (OS). RT-TTD was classified as morning if ≥50% of fractions were delivered before 12:00 h (n = 70) or as afternoon (n = 39) if after 12:00 h. The average age was 62.6 years (range: 14.5-86.9) and 80% were glioblastoma. The median follow-up was 10.9 months (range: 0.4-57.2). The 1y/3y LC, DCNSC, and PFS were: 61.3%/28.1%, 86.8%/65.2%, and 39.7%/10.2%, respectively. Equivalent PFS was found between morning and afternoon groups (HR 1.27; p = .3). The median OS was 16.5 months. Patients treated in the afternoon had worse survival in the univariate analysis (HR 1.72; p = .05), not confirmed after multivariate analysis (HR 0.92, p = .76). Patients with worse baseline performance status and treatment interruptions showed worse PFS and OS. The proportion of patients that developed grade 3 acute toxicity, pseudo progression, and definitive treatment interruptions were 10.1%, 9.2%, and 7.3%, respectively, and were not affected by RT-TTD. In conclusion, for patients with HGG, there was no difference in PFS and OS between patients treated in the morning or afternoon. Of note, definitive treatment interruptions adversely affected outcomes and should be avoided, especially in patients with low performance status. Based on these clinical findings, high-grade glioma cells may not be the best initial model to be irradiated in order to study the effects of chronotherapy.

Risk of in-hospital death associated with Covid-19 lung consolidations on chest computed tomography - A novel translational approach using a radiation oncology contour software.

PURPOSE: To determine whether the percentage of lung involvement at the initial chest computed tomography (CT) is related to the subsequent risk of in-hospital death in patients with coronavirus disease-2019 (Covid-19). MATERIALS AND METHODS: Using a cohort of 154 laboratory-confirmed Covid-19 pneumonia cases that underwent chest CT between February and April 2020, we performed a volumetric analysis of the lung opacities. The impact of relative lung involvement on outcomes was evaluated using multivariate logistic regression. The primary endpoint was the in-hospital mortality rate. The secondary endpoint was major adverse hospitalization events (intensive care unit admission, use of mechanical ventilation, or death). RESULTS: The median age of the patients was 65 years: 50.6 % were male, and 36.4 % had a history of smoking. The median relative lung involvement was 28.8 % (interquartile range 9.5-50.3). The overall in-hospital mortality rate was 16.2 %. Thirty-six (26.3 %) patients were intubated. After adjusting for significant clinical factors, there was a 3.6 % increase in the chance of in-hospital mortality (OR 1.036; 95 % confidence interval, 1.010-1.063; P = 0.007) and a 2.5 % increase in major adverse hospital events (OR 1.025; 95 % confidence interval, 1.009-1.042; P = 0.002) per percentage unit of lung involvement. Advanced age (P = 0.013), DNR/DNI status at admission (P < 0.001) and smoking (P = 0.008) also increased in-hospital mortality. Older (P = 0.032) and male patients (P = 0.026) had an increased probability of major adverse hospitalization events. CONCLUSIONS: Among patients hospitalized with Covid-19, more lung consolidation on chest CT increases the risk of in-hospital death, independently of confounding clinical factors.

Outcomes and toxicity after salvage radiotherapy for vaginal relapse of endometrial cancer.

OBJECTIVES: Studies of salvage radiotherapy in locally recurrent endometrial cancer remain limited. The aim of this study was to evaluate the efficacy of salvage radiotherapy for vaginal relapse of endometrial cancer and to explore prognostic factors associated with outcomes. METHODS: We evaluated 30 patients treated with salvage external-beam radiotherapy and/or vaginal brachytherapy for vaginal relapses of endometrial cancer between 2009 and 2018. The inclusion criteria were: pathologically-confirmed recurrence; loco-regional relapse (in absence of distant metastases); and salvage treatment including external-beam radiotherapy and/or vaginal brachytherapy. Outcomes were evaluated via Kaplan-Meier, with the log-rank test employed to compare differences among various groups and identify prognostic factors. RESULTS: 30 patients developed vaginal recurrence at a median time of 20.6 months (range 2-219) post-hysterectomy. The most common site of recurrence was the vaginal apex (60%), followed by the distal vagina (10%). Salvage radiotherapy entailed combination external-beam radiotherapy and vaginal brachytherapy (n=24) or single modality treatment (n=6), along with concurrent chemotherapy in 20 cases. At a median follow-up of 4.4 years (range 0.1-130) post-radiotherapy, the 5 year rates of local control, regional control, metastasis-free interval, disease-free interval, and overall survival were 89%, 91.5%, 75.5%, 69%, and 83%, respectively. Factors associated with improved disease-free interval included: endometrioid histology (p=0.03), isolated vaginal relapse (p=0.003), late recurrence (>9 months) (p=0.007), and combined modality radiotherapy (p=0.001). The only factor associated with overall survival was isolated vaginal relapse (in the absence of other recurrent disease) (p=0.02). Regarding toxicity, 18% of patients experienced acute grade ≥3 events (most commonly gastrointestinal). The 5 year rates of rectal bleeding, small bowel obstruction, and pelvic fracture were 31%, 18%, and 13%, respectively. CONCLUSIONS: Salvage radiotherapy imparts excellent loco-regional control for vaginal relapses of endometrial cancer and should entail combination external-beam radiotherapy and vaginal brachytherapy. Patients should be closely monitored for late gastrointestinal toxicity following salvage radiotherapy.

The Role of Facility Variation on Racial Disparities in Use of Hypofractionated Whole Breast Radiation Therapy.

PURPOSE: Hypofractionated radiation therapy is a less burdensome and less costly approach that is efficacious for most patients with early-stage breast cancer. Concerns about racial disparities in adoption of medical advances motivate investigation of the use of hypofractionated radiation in diverse populations. The goal of our study was to determine whether hypofractionated whole breast radiation therapy after breast-conserving surgery was being similarly used across racial groups in the state of Michigan. METHODS AND MATERIALS: A prospectively collected statewide quality consortium database from 25 institutions was queried for patients with breast cancer who completed hypofractionated (HF) or conventionally fractionated whole breast radiation therapy from January 2012 to December 2018. We used patient-level multivariable modeling to evaluate associations between HF use and race, controlling for patient and facility factors, and multilevel modeling to account for patient clustering within facilities. RESULTS: Of 9634 patients analyzed, 81% self-reported race as white, 17% as black, and 2% as Asian, similar to statewide and national distributions. In addition, 31.7% of whites were treated at teaching centers compared with 66.7% of blacks and 64.8% of Asians. In 2018, HF was used in 72.7% of whites versus 56.7% of blacks and 67.6% of Asians (P = .0411). On patient-level multivariable analysis, black and Asian races were significantly associated with a lower likelihood of HF receipt (P < .001), despite accounting for treatment year, age, laterality, body mass index, breast volume, comorbidities, stage, triple-negative status, intensity modulated radiation therapy use, teaching center treatment, and 2011 American Society for Radiation Oncology Hypofractionation Guideline eligibility. On multilevel analysis, race was no longer significantly associated with HF receipt. CONCLUSIONS: We observed that black and Asian patients receive hypofractionated whole breast radiation therapy less often than whites, despite more frequent treatment at teaching centers. Multilevel modeling eliminated this disparity, suggesting that differences in facility-specific HF use appear to have contributed. Further inquiry is needed to determine whether reduction of facility-level variation may reduce disparities in accessing HF treatment.

Prostate-only Versus Whole-pelvis Radiation with or Without a Brachytherapy Boost for Gleason Grade Group 5 Prostate Cancer: A Retrospective Analysis.

BACKGROUND: The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases. OBJECTIVE: To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTING, AND PARTICIPANTS: We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment. RESULTS AND LIMITATIONS: A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS). CONCLUSIONS: WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted. PATIENT SUMMARY: When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.

Application of a Prognostic Stratification System for High-risk Prostate Cancer to Patients Treated With Radiotherapy: Implications for Treatment Optimization.

OBJECTIVES: We applied an established prognostic model to high-risk prostate cancer (HRPC) patients treated with radiotherapy (RT) and evaluated the influence of clinical and treatment variables on treatment outcomes. METHODS: In total, 1075 HRPC patients undergoing definitive radiotherapy (RT) between 1995 and 2010 were retrospectively reviewed. Median follow-up was 62.3 months. Patients received either dose-escalated external beam radiotherapy (n=628, EBRT) or combined-modality radiotherapy (n=447, pelvic RT and low-dose rate brachytherapy boost, CMRT). 82.9% received androgen-deprivation therapy (ADT). A prognostic model stratified patients into predefined groups (good, intermediate, and poor). Kaplan-Meier methods and Cox proportional hazards regressions assessed biochemical failure (BF), distant metastasis (DM), prostate cancer-specific mortality (PCSM) and overall mortality (OM). C-indices analyzed predictive value. RESULTS: The model was prognostic; C-indices for BF, DM, PCSM and OM were: 0.62, 0.64, 0.61, and 0.57. On multivariate analysis, CMRT and longer ADT (≥24 mo) were associated with improved BF, DM, and PCSM. Gleason score (GS) 9-10 was the strongest predictor of PCSM. C-indices for BF, DM, PCSM, and OM using a 4-compartment model incorporating GS 9-10 were: 0.62, 0.65, 0.68, and 0.56. In poor-prognosis patients (GS 8-10+additional risk factors), CMRT+LTADT (>12 mo) had 10-year PCSM (3.7%±3.6%), comparing favorably to 25.8%±9.2% with EBRT+LTADT. CONCLUSIONS: The model applies to high-risk RT patients; GS 9-10 remains a powerful predictor of PCSM. Comparing similar prognosis patients, CMRT is associated with improved disease-specific outcomes relative to EBRT. In poor-prognosis patients, CMRT+LTADT yields superior 10-year PCSM, potentially improving RT treatment personalization for those with HRPC.

Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results From a Multi-institutional Consortium Study.

PURPOSE: Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. METHODS AND MATERIALS: The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. RESULTS: The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P < .01 by χ2 test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048). CONCLUSIONS: To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.