Radiation therapy (RT) cures many patients with localized prostate cancer, but late urinary toxicity impairs quality of life and can limit dose escalation for better RT efficacy. Understanding the mechanistic bases of radiation toxicity is critical for designing effective treatment strategies to benefit prostate cancer survivors. Genome-wide association studies (GWAS) have shown that genetic susceptibility can influence toxicity risk. A GWAS of reduced urinary stream two years after RT identified rs7720298 tagging a risk locus, but the mechanism through which this SNP acts is unclear. We performed integrative bioinformatics and molecular studies that identified a nearby long non-coding RNA, LncDNAH5, whose expression is influenced by rs7720298 in human tissues, and we hypothesized it mediates RT responses. In cultured cells, LncDNAH5 suppressed the DNA repair factor TP53BP1, thus favoring homologous recombination (HR) over non-homologous end joining (NHEJ). Mechanistically, LncDNAH5 enhanced MDM2-dependent ubiquitination and degradation of TP53BP1 by promoting formation of an MDM2-TP53BP1 complex; MDM2 antagonist Nutlin-3 attenuated these effects. In vivo, a bladder-specific LncDNAH5 overexpression mouse model exhibited exacerbated RT-induced inflammatory and fibrotic responses, consistent with a heightened urothelial radiosensitivity. Together, these data support a rs7720298/LncDNAH5/MDM2/TP53BP1 axis that modulates DNA repair choice and tissue response to radiation. Clinically, LncDNAH5 expression and rs7720298 genotype may serve as complementary biomarkers to identify patients at risk for late urinary toxicity and to guide early intervention and personalized radioprotective strategies for better patient outcomes.

BACKGROUND:NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT-Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). METHODS:Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease-free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6-8 weeks post-CRT; one-sided α = 0.05, using a χ2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5-, 2-, and 2-point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. RESULTS:From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6-8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6-8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different (p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non-pCR patients, respectively, having improved 1-year ECS scores. CONCLUSIONS:The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

PURPOSE:NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial. METHODS:Patients with limited-stage small cell lung cancer (LS-SCLC), stage Tx-IV, N0-3, and M0 with Eastern Cooperative Group performance status (PS) 0-2 received one cycle of chemotherapy (platinum/etoposide) before study registration and were randomly assigned to CRT alone versus CRT plus concurrent and adjuvant atezolizumab, 1,200 mg once daily, every 3 weeks until investigator-assessed progression or intolerable side effects for a maximum of 17 cycles. Patients were stratified by choice of chemotherapy (cisplatin v carboplatin), radiation fractionation schedule (66 Gy once daily v 45 Gy twice daily), sex, and PS (0/1 v 2). The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate, local control, and distant-metastasis-free survival (DMFS). RESULTS:patients were randomly assigned from May 2019 to December 2023. The median OS was 36.1 months (95% CI, 28.1 to 42.5) for the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) for the CRT + atezolizumab arm, respectively (hazard ratio [HR], 1.03 [95% CI, 0.80 to 1.32]). The median PFS was 11.4 months (95% CI, 10.3 to 13.2) for the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) for the CRT + atezolizumab arm, respectively (HR, 0.98 [95% CI, 0.79 to 1.22]). The median DMFS was 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezolizumab arm (HR, 0.96 [95% CI, 0.76 to 1.21]). No unexpected safety signals with concurrent atezolizumab were observed. CONCLUSION:Concurrent and adjuvant atezolizumab with chemoradiation did not improve survival in patients with LS-SCLC.

Purpose Genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) linked to radiation therapy (RT)-induced toxicities in patients with prostate cancer. SNP rs17599026, located in intron 21 of the KDM3B gene, has been associated with late-onset urinary toxicity, with an increased frequency of urination observed 2 years post-RT compared with pretreatment conditions. This study aimed to explore the underlying mechanisms driving this association. Methods and Materials A clustered regularly interspaced short palindromic repeats-dead Cas9 prime editing system was used to mimic KDM3B genetic variants in prostate stromal cell lines. Murine models with wild-type and heterozygous Kdm3b genotypes were used to assess fibrosis following radiation. RNA immunoprecipitation, transcript stability assays, and protein analysis elucidated the role of N6-methyladenosine (m6A) modification in regulating lysyl oxidase (LOX) expression. α-ketoglutarate (α-KG) supplementation was tested for its effects on KDM3B protein stability, LOX expression, and fibrosis mitigation. Results The rs17599026 SNP reduced KDM3B protein expression via circular RNA and microRNA-mediated mechanisms, leading to decreased m6A modification and increased stability of LOX messenger RNA. Elevated LOX expression promoted collagen cross-linking and fibrosis in prostate stroma. α-KG supplementation restored KDM3B protein levels, reduced LOX expression, and mitigated fibrosis in vitro and in vivo. Conclusions KDM3B genetic variations influence radiation-induced fibrosis through posttranscriptional regulation of LOX. Dietary α-KG supplementation may serve as a mechanism-based strategy to alleviate radiation toxicity in patients with prostate cancer, offering a potential therapeutic pathway to improve treatment outcomes.

Background/Objectives: Cone-beam computed tomography (CBCT)-guided online adaptive radiotherapy (oART) represents a significant advancement in radiation oncology, enabling on-couch plan adaptation to account for daily anatomical changes. While this automation improves precision and workflow efficiency, it also introduces new failure modes (FMs) and workflow irregularities. This study aimed to systematically evaluate the clinical and technical challenges associated with CBCT-guided oART implementation. Methods: We retrospectively analyzed over 1000 CBCT-guided oART sessions for pelvic malignancies performed at our institution. A multidisciplinary team conducted a comprehensive review to identify and classify FMs, followed by root cause analysis (RCA) to evaluate their impact on treatment safety, efficacy, and workflow robustness. Results: In addition to session-terminating FMs, we identified recurring failure modes across three major domains: (1) system-driven issues, such as rigid target localization and software-driven irregularities; (2) patient-driven challenges, including interfractional and intrafractional anatomical variations; and (3) treatment planning and execution failures, including excessive dose hotspots from field-of-view limitations. The system’s closed-loop automation, while streamlining processes, introduced rigid constraints in plan adaptation and fallback plan execution, occasionally leading to unintended dose discrepancies. Conclusions: This study provides a comprehensive clinical practice-based evaluation of CBCT-guided oART, highlighting system-specific failure modes and their implications. Addressing these challenges requires structured quality assurance processes, multidisciplinary collaboration, and continuous workflow refinement. Our findings contribute to the development of safer and more robust adaptive radiotherapy platforms and clinical workflows.

PURPOSE:We investigated the efficacy and toxicity of thoracic radiation therapy (RT) plus concurrent and consolidation carboplatin with either solvent-based paclitaxel (sb-paclitaxel) or solvent-free nanoparticle albumin-bound paclitaxel (nab-paclitaxel). METHODS AND MATERIALS:This multicenter phase 1/2 randomized trial included patients with inoperable stage IIIA/B nonsmall cell lung cancer (AJCC 7) and an Eastern Cooperative Oncology Group performance status of 0-1. In phase 1, 6 patients received weekly nab-paclitaxel (50 mg/m²) and carboplatin (AUC 2) with concurrent thoracic RT (60 Gy in 30 fractions), followed by nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 and carboplatin (AUC 6) on day 1 for two 21-day cycles. In phase 2, 92 patients were randomly assigned to weekly sb-paclitaxel (50 mg/m²) or nab-paclitaxel (40 mg/m²) with concurrent RT, followed by consolidation therapy with sb-paclitaxel or nab-paclitaxel and carboplatin for 2 cycles. RESULTS:Two phase 1 patients had dose-limiting toxicities, setting the phase 2 nab-paclitaxel dose at 40 mg/m². For the phase 2 cohort, 2-year overall survival was 67% for sb-paclitaxel and 56% for nab-paclitaxel (P = .10), with progression-free survival of 44% and 27%, respectively (P = .14). Fewer patients completed consolidation with nab-paclitaxel (26%) versus sb-paclitaxel (58%) (P = .005). Grade 3 and higher adverse events were more frequent with nab-paclitaxel (56%) than with sb-paclitaxel (30%) (P = .029). CONCLUSIONS:Nab-paclitaxel was associated with higher toxicity and numerically lower efficacy than sb-paclitaxel when used with thoracic radiation in locally advanced nonsmall cell lung cancer.

Table S3 shows bivariate associations of patient, cancer, and treatment factors with hematuria

BACKGROUND:Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively affects survivors. Few risk factors are known beyond the radiation dose and volume of bladder exposed. A polygenic risk score (PRS) could identify susceptible patients. METHODS:A PRS was built using genome-wide association results from the Radiogenomics Consortium (N = 3,988) and then tested in the prospective REQUITE and URWCI studies (N = 2,034). The primary outcome was time to patient-reported gross [grade ≥2, (≥G2)] hematuria, analyzed using Cox proportional hazards regression. Secondary outcomes were ≥G2 urinary retention and frequency. The PRS was externally validated for clinically diagnosed irradiation cystitis in the UK Biobank (N = 8,430). A gene-burden test evaluated rare coding variants. RESULTS:A 115-variant PRS was associated with a significantly increased risk of ≥G2 hematuria [hazard ratio (HR) per SD = 1.22; P = 0.009] as well as urinary retention (HR per SD = 1.18; P = 0.016) and frequency (HR per SD = 1.14; P = 0.036). When binarized, men in the upper decile (PRShigh) had a >2-fold increased risk of hematuria after adjusting for clinical risk factors [HR = 2.12; P = 0.002; Harrel's concordance index = 0.71 (95% confidence interval, 0.65-0.76)]. A similar effect size was seen in the UK Biobank for clinically diagnosed irradiation cystitis [odds ratio (OR) = 2.15; P = 0.026]. The burden test identified BOD1L1 as a putative novel radiosensitivity gene. CONCLUSIONS:This PRS identifies susceptible patients and could guide the selection of those needing reoptimized treatment plans that spare the bladder beyond currently recommended constraints. IMPACT:PRS-guided treatment planning in radiation oncology could lower the incidence of clinically relevant bladder toxicity and reduce the impact of this outcome on prostate cancer survivors.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI ( P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773 ).

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (PD35)1 May 2024PD35-11 NEUTROPHIL-RELATED URINARY EXTRACELLULAR VESICLE PROTEIN SIGNATURES MAY PREDICT LATE RADIATION CYSTITIS RISK IN PROSTATE CANCER PATIENTS Ryan D. Molony, M. Mahmudul Hasan Akash, Sarah L. Kerns, Brian Marples, Emmanuel Oshodi, YuhChyau Chen, and Yi-Fen Lee Ryan D. MolonyRyan D. Molony , M. Mahmudul Hasan AkashM. Mahmudul Hasan Akash , Sarah L. KernsSarah L. Kerns , Brian MarplesBrian Marples , Emmanuel OshodiEmmanuel Oshodi , YuhChyau ChenYuhChyau Chen , and Yi-Fen LeeYi-Fen Lee View All Author Informationhttps://doi.org/10.1097/01.JU.0001009396.21455.74.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: After undergoing radiotherapy (RT), ∼15% of prostate cancer (PCa) patients develop late radiation cystitis (RC), presenting principally as hematuria, but the mechanisms underlying this pathological outcome remain poorly characterized. Membrane-enclosed extracellular vesicles (EVs) are released from tumor and non-tumor cells at baseline, and their composition can change markedly in response to stimuli. We recently found that elevated post-RT PCa patient urinary EV concentrations can predict RC incidence 6+ months after sample collection, suggesting a possible role for these EVs as biomarkers and/or functional mediators of RC incidence. Here, we sought to characterize the composition of pre- and post-RT urinary EVs from PCa patients to understand their association with bladder tissue toxicity. METHODS: Urinary EV cargo proteins in pre- and post-RT PCa patient samples for patients that did and did not develop late hematuria were analyzed and compared by LC-MS/MS. Proteomic analyses were used to identify enriched proteins (≥10-fold change in abundance) between donors that did and did not develop RC. ELISAs were used to measure the levels of myeloperoxidase (MPO) and inflammatory cytokines (TNF-α, IL-6, IL-1β) in PCa patient samples. RESULTS: Relative to patients who did not develop RC, the post-RT urinary EVs of PCa patients who eventually developed RC harbored significantly elevated levels of 40 RT-enriched proteins, including a high number of neutrophil-associated marker and effector proteins with potential pro-inflammatory and deleterious functions. Strikingly, an intrinsically enriched 20-protein signature was also detected in the pre-RT urinary EVs of PCa patients who went on to develop post-RT hematuria, and this signature was dominated by neutrophil proteins, including MPO. ELISAs confirmed the presence of higher MPO and inflammatory cytokine levels in urine samples from PCa patients who later developed hematuria. CONCLUSIONS: These data highlight a potential role for neutrophil EVs present in urine as biomarkers and/or mediators of late hematuria and RC incidence in PCa patients. While further large-scale validation of these results will be essential, the intrinsically enriched 20-protein signature established herein may provide an opportunity for PCa patient risk stratification before treatment, while the 40-protein RT-enriched protein signature may support post-RT monitoring, enabling treatment modification or other interventions that can abrogate decisional regret and improve quality of life. Source of Funding: Funded by the Department of Urology Research Fund © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e729 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Ryan D. Molony More articles by this author M. Mahmudul Hasan Akash More articles by this author Sarah L. Kerns More articles by this author Brian Marples More articles by this author Emmanuel Oshodi More articles by this author YuhChyau Chen More articles by this author Yi-Fen Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

In men with favorable-risk prostate cancer, long-term disease-free survival is non-inferior with 70 Gy in 28 fractions compared to 73.8 Gy in 41 fractions. The risk of BR is reduced with moderate hypofractionation. No differences in late Grade ≥3 GI/GU toxicity were observed between the arms. (ClinicalTrials.gov identifier: NCT00331773).

Abstract Objective: To summarize articles reporting on burnout and well-being among attending and resident radiation oncologists in the United States in a narrative review. Methods: PubMed was searched for peer-reviewed articles from 2010 through 2023 reporting on burnout and well-being among radiation oncologists in the United States. Each study was critically reviewed and included if it reported primary data utilizing a validated tool to measure burnout among radiation oncologists. A subset of high-quality studies was included. Results: There are limited studies regarding burnout among radiation oncologists in the United States, especially when compared with data from other countries. Despite these limitations, there is a prevalence of burnout among radiation oncologists of all career stages, with rates of burnout ranging from 30% to 63%. A few smaller studies have explored interventions to decrease burnout and enhance professional fulfillment among radiation oncologists. Best practices to enhance professional fulfillment for radiation oncologists include optimizing support structures to alleviate physicians of administrative duties; including physicians in departmental decisions that affect their work; providing dedicated time for research; promoting work-life balance and job satisfaction; providing support for trainees, including psychological tool-focused approaches and humanities exercises; and encouraging mindfulness. Conclusions: A large cross-sectional study is warranted to further explore modern burnout rates and causes among radiation oncologists in the United States. This may inform areas of advocacy to improve professional fulfillment among radiation oncologists.

Objectives Head and neck cancer is a common malignancy frequently treated with chemotherapy and radiotherapy. Studies have shown an increased risk of stroke with the receipt of radiotherapy, but data on stroke-related mortality are limited, particularly in the modern era. Evaluating stroke mortality related to radiotherapy is vital given the curative nature of head and neck cancer treatment and the need to understand the risk of severe stroke in this population. Methods We analyzed the risk of stroke death among 122,362 patients (83,651 patients who received radiation and 38,711 patients who did not) with squamous cell carcinoma of the head and neck (HNSCC) diagnosed between 1973 and 2015 in the SEER database. Patients in radiation vs. no radiation groups were matched using propensity scores. Our primary hypothesis was that radiotherapy would increase the hazard of death from stroke. We also examined other factors impacting the hazard of stroke death, including whether radiotherapy was performed during the modern era when IMRT and modern stroke care were available as well as increased HPV-mediated cancers of the head and neck. We hypothesized that the hazard of stroke death would be less in the modern era. Results There was an increased hazard of stroke-related death in the group receiving radiation therapy (HR 1.203, p = 0.006); however, this was a very small absolute increase, and the cumulative incidence function of stroke death was significantly reduced in the modern era (p < 0.001), cohorts with chemotherapy (p=0.003), males (p=0.002), younger cohorts (p<0.001) and subsites other than nasopharynx (p=0.025). Conclusions While radiotherapy for head and neck cancer increases the hazard of stroke death, this is reduced in the modern era and remains a very small absolute risk.

Purpose:Advancing equity, diversity, and inclusion in the physician workforce is essential to providing high-quality and culturally responsive patient care and has been shown to improve patient outcomes. To better characterize equity in the field of radiation oncology, we sought to describe the current academic radiation oncology workforce, including any contemporary differences in compensation and rank by gender and race/ethnicity. Methods and Materials:We conducted a retrospective cohort study using data from the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) 2018 Financial Survey. Multivariable logistic regression models were used to identify factors associated with associate or full professor rank. Compensation was compared by gender and race/ethnicity overall and stratified by rank and was further analyzed using multivariable linear regression models. Results:Of the 858 academic radiation oncologists from 63 departments in the United States in the sample, 33.2% were female, 65.2% were White, 27.2% were Asian, and 7.6% were underrepresented in medicine (URiM). There were 44.0% assistant professors, 32.0% associate professors, and 22.8% full professors. Multivariable logistic regression analysis for factors associated with associate or full professor rank did not reveal statistically significant associations between gender or race/ethnicity with academic rank (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.56-1.32; P = .48 for gender; OR, 0.81; 95% CI, 0.5-1.30; P = .37 for Asian vs White; and OR, 0.69; 95% CI, 0.31-1.55; P = .37 for URiM vs White), but CIs were wide due to sample size, and point estimates were <1. Similarly, multivariable linear regression analysis modeling the log relative total compensation did not detect statistically significant differences between radiation oncologists by gender (-1.7%; 95% CI, -6.8% to 3.4%; P = .51 for female vs male) or race/ethnicity (-1.6%; 95% CI, -7.3% to 4.0%; P = .57 for Asian vs White and -3.0%; 95% CI, -12.1% to 6.0%; P = .51 for URiM vs White). Conclusions:The low numbers of women and faculty with URiM race/ethnicity in this radiation oncology faculty sample limits the ability to compare career trajectory and compensation by those characteristics. Given that point estimates were <1, our findings do not contradict larger multispecialty studies that suggest an ongoing need to monitor equity.

PURPOSE:Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with radiation therapy (RT) toxicities in patients with prostate cancer. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency 2 years after RT compared with pretreatment conditions. The present study aimed to provide mechanistic insights for this association. METHODS AND MATERIALS:Using human tissues and cell lines, we examined the protein expression of KDM3B and molecular mechanisms underlying the SNP modulation by variants of KDM3B SNP alleles. In animals with normal and heterozygous expressions of Kdm3b, we examined the relationship between Kdm3b expression and radiation toxicity. RESULTS:KDM3B rs17599026 lies in a motif important for circular RNA expression that is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of the Kdm3b gene, we found that lower Kdm3b expression is associated with altered pattern of urination after bladder irradiation, which is related to differential degrees of tissue inflammation as measured by analyses of gene expression, lymphocyte infiltration, and noninvasive ultrasound imaging. CONCLUSIONS:KDM3B SNPs can impact its expression through regulating noncoding RNA expression. Differential KDM3B expression underlies radiation toxicity through tissue inflammation at the molecular and physiological level. Our study outcome offers a foundation for mechanism-based mitigation for radiation toxicity for prostate cancer survivors.