Toxicity In Prostate Cancer Patients Research Articles

Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126

The objective of this study was to characterize the conditional risk of developing a grade 2+ urinary or gastrointestinal toxicity for patients treated with external beam radiotherapy on RTOG 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and later points of follow up. 1,532 patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1,499 were eligible and included in data analysis with a median follow up of 8.4 years (range 0.02-13). Patients were treated with either 3DCRT or IMRT according to institutional practice without the addition of androgen deprivation and randomized to receive either standard dose radiotherapy of 70.2 Gy or dose escalated radiotherapy of 79.2 Gy of radiotherapy to the prostate only with standard fractionation. UVA and MVA analyses were determine if initial factors were predictive of late toxicity at time of treatment and at later timepoints. As patients proceed further from completion of radiotherapy without the development of toxicity, the subsequent risk of both grade 2+ GU and GI toxicity decreased with time. At time of enrollment the risk of developing a grade 2+ toxicity over the next 5 years was 9.57 and 17.89% respectively. After five years of toxicity free survival, the risk of developing a grade 2+ GU or GI toxicity in the subsequent five years was 3.02% and 1.54% respectively. Baseline treatment and patient related factors predicted late toxicity both at trial enrollment and after two years of toxicity free survivorship. Baseline urinary dysfunction and dose escalated radiotherapy were associated with increased late GU toxicity. Acute GI toxicity and dose escalated radiotherapy were associated with increased risk of late GI toxicity. Treatment with IMRT was associated with reduced risk of either toxicity. The conditional risk of grade 2+ toxicities decrease as patients proceed further from treatment with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Exploring the Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Genitourinary Toxicities in Prostate Cancer Patients Undergoing Radiation Therapy: A Case Study and Discussion

Radiation therapy is a common treatment modality offered to patients with localized prostate cancer. It can be associated with early radiation-induced toxicities including dysuria, nocturia, frequency, urgency, spasm, and, rarely, hematuria. Early toxicities usually resolve once the treatment period has ended. Chronic toxicities are less common, and rarely, patients may experience radiation-induced hemorrhagic cystitis and hematuria months or years after radiation. We herein describe the case of a 65-year-old man with a past medical history of type-2 diabetes mellitus who experienced hemorrhagic cystitis for months following his radiation therapy. The patient was on sodium-glucose cotransporter-2 inhibitor therapy (empagliflozin), which we highlight as a potential risk factor for hemorrhagic cystitis. After cessation of Jardiance and initiation of semaglutide (GLP-1 agonist), his urinary symptoms significantly improved. To the best of our knowledge, this is the first such case reported.

Abstract 1128: Association between gut microbial change and acute gastrointestinal toxicity in patients with prostate cancer undergoing definitive radiation therapy

Abstract Purpose: This prospective cohort study investigated the association between gut microbial changes and acute gastrointestinal toxicities in prostate cancer patients undergoing definitive radiation therapy (RT). Methods: Seventy-nine fecal samples were analyzed. Stool samples were collected at the following timepoints: pre-RT (prRT), 2 weeks after the start of RT (RT-2w), 5 weeks after the start of RT (RT-5w), 1 month after completion of RT (poRT-1m), and 3 months after completion of RT (poRT-3m). We computed the microbial community polarization index (MCPI) as an indicator of RT-induced dysbiosis. Results: Patients experiencing toxicity had lower alpha diversity, especially at RT-2w (P=0.037) and RT-5w (P=0.003). Compared to patients without toxicity, the MCPI in those experiencing toxicities was significantly elevated (P=0.019). In terms of predicted metabolic pathways, we found linearly decreasing pathways including carbon fixation pathways in prokaryotes (P=0.035) and the bacterial secretion system (P=0.005), in patients who experienced toxicities. Conclusions: We showed RT-induced dysbiosis among patients who experienced toxicities. Reduced diversity and elevated RT-related MCPI could be helpfully used for developing individualized RT approaches. Citation Format: Bum-Sup Jang, Dong Soo Lee. Association between gut microbial change and acute gastrointestinal toxicity in patients with prostate cancer undergoing definitive radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1128.

Carbon ion irradiation exerts antitumor activity by inducing cGAS-STING activation and immune response in prostate cancer-bearing mice.

As an advanced radiotherapy technique, carbon ion radiotherapy has demonstrated good efficacy and low toxicity for prostate cancer patients, but the radiobiological mechanism of killing tumor cells has not been fully elucidated. This study aims to explore the antitumor effects of carbon ion irradiation (CIR) through investigating the immune response induced by CIR in prostate cancer-bearing mice and the underlying molecular mechanism. We established subcutaneous transplantation tumor models of prostate cancer to evaluate the tumor inhibition effect of CIR. Investigation of immunophenotype alterations were assessed by flow cytometry. Immunofluorescence, western blot, and real-time quantitative PCR was employed to analyze the activation of cGAS-STING pathway. CIR showed more powerful tumor growth control than photon irradiation in immunocompetent syngeneic C57BL/6 mice. CIR exerts antitumor effect by triggering immune response, characterized by increased CD4+ T cells and macrophages in tumor, enhanced CD8+ T cells and T effector memory cells in spleen, improved IFN-γ production of CD8+ tumor-infiltrating lymphocytes, and reduced exhausted T cells in tumor and spleen. Additionally, production of cytoplasmic double-stranded DNA, protein levels of p-TBK1 and p-IRF3 in the cGAS-STING pathway, and gene expression levels of downstream interferon-stimulated genes were significantly increased after CIR in a dose-dependent manner. Treatment of RM1 tumor-bearing mice with the STING inhibitor C-176 impaired the antitumor effect of CIR. The excellent antitumor activity of CIR in immunocompetent prostate cancer-bearing C57BL/6 mice may be attributed to stronger induction of antitumor immune response and higher activation of cGAS-STING pathway.

Unraveling the safety of adjuvant radiotherapy in prostate cancer: impact of older age and hypofractionated regimens on acute and late toxicity - a multicenter comprehensive analysis.

The objective of this study was to assess the impact of age and other patient and treatment characteristics on toxicity in prostate cancer patients receiving adjuvant radiotherapy (RT). This observational study (ICAROS-1) evaluated both acute (RTOG) and late (RTOG/EORTC) toxicity. Patient- (age; Charlson's comorbidity index) and treatment-related characteristics (nodal irradiation; previous TURP; use, type, and duration of ADT, RT fractionation and technique, image-guidance systems, EQD2 delivered to the prostate bed and pelvic nodes) were recorded and analyzed. A total of 381 patients were enrolled. The median EQD2 to the prostate bed (α/β=1.5) was 71.4 Gy. The majority of patients (75.4%) were treated with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Acute G3 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 0.5% and 1.3%, respectively. No patients experienced >G3 acute toxicity. The multivariable analysis of acute toxicity (binomial logistic regression) showed a statistically significant association between older age (> 65) and decreased odds of G≥2 GI acute toxicity (OR: 0.569; 95%CI: 0.329-0.973; p: 0.040) and decreased odds of G≥2 GU acute toxicity (OR: 0.956; 95%CI: 0.918-0.996; p: 0.031). The 5-year late toxicity-free survival rates for G≥3 GI and GU toxicity were 98.1% and 94.5%, respectively. The only significant correlation found (Cox's regression model) was a reduced risk of late GI toxicity in patients undergoing hypofractionation (HR: 0.38; 95% CI: 0.18-0.78; p: 0.008). The unexpected results of this analysis could be explained by a "response shift bias" concerning the protective effect of older age and by treatment in later periods (using IMRT/VMAT) concerning the favorable effect of hypofractionation. However, overall, the study suggests that age should not be a reason to avoid adjuvant RT and that the latter is well-tolerated even with moderately hypofractionated regimens.

KDM3B Single-Nucleotide Polymorphisms Impact Radiation Therapy Toxicity Through Circular RNA-Mediated KDM3B Expression and Inflammatory Responses

PurposeGenome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with radiotherapy (RT) toxicities in prostate cancer patients. SNP rs17599026 in intron 21 of KDM3B is significantly associated with the development of late urinary toxicity, specifically in the increase in urinary frequency two years after RT compared with pre-treatment conditions. The present study aimed to provide mechanistic insights for this association. Methods and MaterialsUsing 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. ResultsKDM3B rs17599026 lies in a motif important for circular RNA expression which is responsible for sponging miRNAs to regulate KDM3B expression. Using a murine model with heterozygous deletion of 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 non-invasive ultrasound imaging. ConclusionsKDM3B SNPs can impact its expression through regulating noncoding (nc) 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.

P084 - Clinical and dosimetric correlation of acute and late toxicities in prostate cancer patients treated with hypofractionated radiotherapy

P084 - Clinical and dosimetric correlation of acute and late toxicities in prostate cancer patients treated with hypofractionated radiotherapy

Association between gut microbial change and acute gastrointestinal toxicity in patients with prostate cancer receiving definitive radiation therapy.

This prospective study investigated the association between gut microbial changes and acute gastrointestinal toxicities in prostate cancer patients receiving definitive radiation therapy (RT). Seventy-nine fecal samples were analyzed. Stool samples were collected at the following timepoints: pre-RT (prRT), 2 weeks after the start of RT (RT-2w), 5 weeks after the start of RT (RT-5w), 1 month after completion of RT (poRT-1 m), and 3 months after completion of RT (poRT-3 m). We computed the microbial community polarization index (MCPI) as an indicator of RT-induced dysbiosis. Patients experiencing toxicity had lower alpha diversity, especially at RT-2w (p = 0.037) and RT-5w (p = 0.003). Compared to patients without toxicity, the MCPI in those experiencing toxicities was significantly elevated (p = 0.019). In terms of predicted metabolic pathways, we found linearly decreasing pathways, including carbon fixation pathways in prokaryotes (p = 0.035) and the bacterial secretion system (p = 0.005), in patients who experienced toxicities. We showed RT-induced dysbiosis among patients who experienced toxicities. Reduced diversity and elevated RT-related MCPI could be helpfully used for developing individualized RT approaches.

Association between Gut Microbial Change and Acute Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Definitive Radiation Therapy: A Prospective Pilot Analysis.

The gut microbiome is an emerging biomarker that is known to have a pivotal role in the development of diverse human diseases. This prospective cohort study aimed to investigate the association between gut microbial changes and acute gastrointestinal (GI) toxicities in prostate cancer patients receiving definitive radiation therapy (RT). Seventy-nine fecal samples from 16 prostate cancer patients were analyzed. Stool samples were collected at the following timepoints: pre-RT (prRT), 2 weeks after the start of RT (RT-2w), 5 weeks after the start of RT (RT-5w), 1 month after completion of RT (poRT-1m), and 3 months after completion of RT (poRT-3m). Total RT doses were 69.6‒74.4 Gy at 2.4 Gy per fraction in the high-dose area and 45‒50.4 Gy at 1.8 Gy per fraction in the low-dose area. Alpha- and beta-diversity were estimated. We computed the microbial community polarization index (MCPI) as an indicator of RT-induced dysbiosis. A linear mixed effect model was adopted to evaluate time effects after RT. Metabolic pathway abundances were inferred using bioinformatics tools. Seven patients experienced ≥ grade 1 acute GI toxicities. Patients experiencing toxicity had lower alpha diversity, especially at RT-2w (P = 0.037) and RT-5w (P = 0.003), with the microbiota enriched in Fusobacteria, Fusobacterium, and Bacteroides fragilis. Patients receiving a large RT field had a trend of lower alpha diversity, particularly at poRT-1m (P = 0.027), with the microbiota enriched in Propionibacteriaceae, Cutibacterium, and Prevotella stercorea. Compared with the MCPI at prRT, the MCPI observed at poRT-1m in patients experiencing toxicities was significantly elevated (P = 0.007). In terms of predicted metabolic pathways, we found linearly decreasing pathways, including carbon fixation pathways in prokaryotes (P = 0.035) and the bacterial secretion system (P = 0.005), in patients who experienced toxicities. Regarding the RT field, no linear trend of functional pathways was found across timepoints. We showed RT-induced dysbiosis in the gut microbiome among patients with prostate cancer who experienced toxicities or received a large RT field. Reduced diversity and elevated RT-related MCPI could be helpful for developing individualized RT approaches. Longitudinal analysis revealed dynamic changes in several microbes and metabolic pathways, which should be validated in a whole metagenome sequencing study.

Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126

Patients with localized prostate cancer (PCA) treated with RT alone have excellent outcomes, making quality of life and minimization of toxicities of great concern. The risk of developing toxicity may evolve with time from treatment which is of interest to patients seen in follow up. The primary objective of this study is to determine the conditional risk of grade 2+ GI or GU toxicity for patients treated with RT. A secondary objective is to determine risk factors associated with the development of late toxicities. We performed a post-hoc analysis of RTOG 0126, which enrolled patients with intermediate risk PCa who were randomized to receive standard dose RT of 70.2 Gy in 39 fractions vs dose escalated dose RT (DE-RT) of 79.2 Gy in 44 fractions. Cumulative incidence was used to calculate risk of grade 2+ GU and grade 2+ GI toxicity at initial time points, as well as for patients who survived 2 years and 5 years without respective grade 2+ toxicity. Risk factors of age, race, urinary incontinence, baseline urinary frequency, acute GU toxicity, treatment arm, RT method (3DCRT vs IMRT), and OAR contouring protocol violation were analyzed using univariate and multivariate Cox proportional hazards modeling for late GU toxicity. Risk factors of age, race, RT method, acute GI toxicity, DE-RT, RT method, and OAR contouring protocol violation were analyzed for late GI toxicity. One thousand four hundred ninety-nine patients with a median follow up of 8.4 years (range 0.02-13 years) were included for analysis. The conditional cumulative 5-year risk of late grade 2+ GI toxicity at enrollment, 2-, and 5-years of grade 2+GI toxicity free survivorship was 14.7%, 6.2%, and 1.8% respectively. The cumulative 5-year risk of late grade 2+ GU toxicity at enrollment, 2-, and 5-years of late grade 2+ GU toxicity free survivorship was 7.9%, 4.7%, and 2.7% respectively. Initially DE-RT (HR 1.401, 95% CI 1.099-1.787; p = 0.0066), acute GI toxicity (HR 1.962, 95% CI 1.271-2.616; P<0.0001), and black race (HR 0.630, 95% CI 0.4-0.993; p<0.0463) were predictive of late GI toxicity. After two years of 2+ GI toxicity free survivorship, only acute GI toxicity (HR 2.015, 95% CI 1.238-3.279, p<0.0048) remained predictive of late GI toxicity on MVA. DE-RT (HR 1.616, 95% CI 1.187-2.2, p<0.0023), IMRT (HR 0.559, 95% CI 0.389-0.804, p = 0.0017), and urinary frequency at baseline (HR 1.377, 95% CI 1-1.895 p<0.0498) were predictive of late GU toxicity at enrollment. This data suggests that as patients proceed further from completion of EBRT, the conditional risk of late toxicity decreases. The majority of grade 2+ GI and GU toxicities occur in the first two years of treatment and patients who have not had a grade 2+ GU or GI toxicity within the first five years are likely to remain toxicity free. Factors such as presence of baseline urinary dysfunction, presence of acute toxicities, DE-RT, and radiation modality predict for late toxicity. These findings are of relevance for clinicians and patients in the post treatment setting.

5-Years Analysis of Effectivity and Toxicity of Ultra-Hypofractionated Proton Radiotherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer-A Retrospective Analysis.

We retrospectively analyzed the 5-year biochemical disease-free survival (bDFS) and occurrence of late toxicity in prostate cancer patients treated with pencil beam scanning (PBS) proton radiotherapy. In the period from January 2013 to June 2018, 853 patients with prostate cancer were treated with an ultra-hypofractionated schedule (36.25 GyE/five fractions). The mean PSA value was 6.7 (0.7-19.7) µg/L. There were 318 (37.3%), 314 (36.8%), and 221 (25.9%) patients at low (LR), favorable intermediate (F-IR), and unfavorable intermediate risk (U-IR), respectively. Neoadjuvant hormonal therapy was administered to 197 (23.1%) patients, and 7 (0.8%) patients had adjuvant hormonal therapy. The whole group of patients reached median follow-up time at 62.7 months, and their mean age was 64.8 (40.0-85.7) years. The bDFS rates and late toxicity profile were evaluated. Median treatment time was 10 (7-38) days. Estimated 5-year bDFS rates were 96.5%, 93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk groups, respectively. Cumulative late toxicity (CTCAE v4.0) of G2+ was as follows: gastrointestinal (GI)-G2: 9.1%; G3: 0.5%; genitourinary (GU)-G2: 4.3%, and no G3 toxicity was observed. PSA relapse was observed in 58 (6.8%) patients: 16 local, 22 lymph node, 4 bone recurrences, and 10 combined sites of relapse were detected. Throughout the follow-up period, 40 patients (4.7%) died, though none due to prostate cancer. Ultra-hypofractionated proton beam radiotherapy is an effective treatment for low- and favorable intermediate-risk prostate cancer, with long-term bDFS rates comparable to other techniques. It is promising for unfavorable intermediate-risk prostate cancer and has acceptable long-term GI and favorable GU toxicity.

State of the art and future challenges of urethra-sparing stereotactic body radiotherapy for prostate cancer: a systematic review of literature

PurposeDoses delivered to the urethra have been associated with an increased risk to develop long-term urinary toxicity in patients undergoing stereotactic body radiotherapy (SBRT) for prostate cancer (PCa). Aim of the present systematic review is to report on the role of urethra-sparing SBRT (US-SBRT) techniques for prostate cancer, with a focus on outcome and urinary toxicity.MethodA systematic review of the literature was performed on the PubMed database on May 2023. Based on the urethra-sparing technique, 13 studies were selected for the analysis and classified in the two following categories: “urethra-steering” SBRT (restriction of hotspots to the urethra) and “urethra dose-reduction” SBRT (dose reduction to urethra below the prescribed dose).ResultsBy limiting the urethra Dmax to 90GyEQD2 (α/β = 3 Gy) with urethra-steering SBRT techniques, late genitourinary (GU) grade 2 toxicity remains mild, ranging between 12.1% and 14%. With dose-reduction strategies decreasing the urethral dose below 70 GyEQD2, the risk of late GU toxicity was further reduced (< 8% at 5 years), while maintaining biochemical relapse-free survival rates up to 93% at 5 years.ConclusionUS-SBRT techniques limiting maximum doses to urethra below a 90GyEQD2 (α/β = 3 Gy) threshold result in a low rate of acute and late grade ≥ 2 GU toxicity. A better understanding of clinical factors and anatomical substructures involved in the development of GU toxicity, as well as the development and use of adapted dose constraints, is expected to further reduce the long-term GU toxicity of prostate cancer patients treated with SBRT.

Comprehensive geriatric assessment predicts radiation-induced acute toxicity in prostate cancer patients.

The purpose of the present prospective study was to evaluate the significance of geriatric conditions measured by acomprehensive geriatric assessment (GA) for the prediction of the risk of high-grade acute radiation-induced toxicity. Atotal of 314 prostate cancer patients (age ≥ 65years) undergoing definitive radiotherapy at atertiary academic center were included. Prior to treatment, patients underwent aGA. High-grade toxicity was defined as acute toxicity grade ≥ 2 according to standard RTOG/EORTC criteria. To analyze the predictive value of the GA, univariable and multivariable logistic regression models were applied. A total of 40 patients (12.7%) developed acute toxicity grade ≥ 2; high grade genitourinary was found in 37patients (11.8%) and rectal toxicity in 8patients (2.5%), respectively. Multivariable analysis revealed asignificant association of comorbidities with overall toxicity grade ≥ 2 (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.260-5.502; p = 0.010) as well as with high-grade genitourinary and rectal toxicity (OR 2.169, 95%CI1.017-4.625; p = 0.045 and OR 7.220, 95%CI 1.227-42.473; p = 0.029, respectively). Furthermore, the Activities of Daily Living score (OR 0.054, 95%CI 0.004-0.651; p = 0.022), social status (OR 0.159, 95%CI 0.028-0.891; p = 0.036), and polypharmacy (OR 4.618, 95%CI 1.045-20.405; p = 0.044) were identified as independent predictors of rectal toxicity grade ≥ 2. Geriatric conditions seem to be predictive of the development of high-grade radiation-induced toxicity in prostate cancer patients treated with definitive radiotherapy.

Radiomics based predictive modeling of rectal toxicity in prostate cancer patients undergoing radiotherapy: CT and MRI comparison.

Rectal toxicity is one of the common side effects after radiotherapy in prostate cancer patients. Radiomics is a non-invasive and low-cost method for developing models of predicting radiation toxicity that does not have the limitations of previous methods. These models have been developed using individual patients' information and have reliable and acceptable performance. This study was conducted by evaluating the radiomic features of computed tomography (CT) and magnetic resonance (MR) images and using machine learning (ML) methods to predict radiation-induced rectal toxicity. Seventy men with pathologically confirmed prostate cancer, eligible for three-dimensional radiation therapy (3DCRT) participated in this prospective trial. Rectal wall CT and MR images were used to extract first-order, shape-based, and textural features. The least absolute shrinkage and selection operator (LASSO) was used for feature selection. Classifiers such as Random Forest (RF), Decision Tree (DT), Logistic Regression (LR), and K-Nearest Neighbors (KNN) were used to create models based on radiomic, dosimetric, and clinical data alone or in combination. The area under the curve (AUC) of the receiver operating characteristic curve (ROC), accuracy, sensitivity, and specificity were used to assess each model's performance. The best outcomes were achieved by the radiomic features of MR images in conjunction with clinical and dosimetric data, with a mean of AUC: 0.79, accuracy: 77.75%, specificity: 82.15%, and sensitivity: 67%. This research showed that as radiomic signatures for predicting radiation-induced rectal toxicity, MR images outperform CT images.

OC-0597 Gut Microbiota is Predictive of Radio-induced Gastrointestinal Toxicity in Prostate Cancer Patients

OC-0597 Gut Microbiota is Predictive of Radio-induced Gastrointestinal Toxicity in Prostate Cancer Patients

Machine-learning with region-level radiomic and dosimetric features for predicting radiotherapy-induced rectal toxicities in prostate cancer patients

Background and purposeThis study aims to build machine learning models to predict radiation-induced rectal toxicities for three clinical endpoints and explore whether the inclusion of radiomic features calculated on radiotherapy planning computerised tomography (CT) scans combined with dosimetric features can enhance the prediction performance. Materials and methods183 patients recruited to the VoxTox study (UK-CRN-ID-13716) were included. Toxicity scores were prospectively collected after 2 years with grade ≥ 1 proctitis, haemorrhage (CTCAEv4.03); and gastrointestinal (GI) toxicity (RTOG) recorded as the endpoints of interest. The rectal wall on each slice was divided into 4 regions according to the centroid, and all slices were divided into 4 sections to calculate region-level radiomic and dosimetric features. The patients were split into a training set (75%, N = 137) and a test set (25%, N = 46). Highly correlated features were removed using four feature selection methods. Individual radiomic or dosimetric or combined (radiomic + dosimetric) features were subsequently classified using three machine learning classifiers to explore their association with these radiation-induced rectal toxicities. ResultsThe test set area under the curve (AUC) values were 0.549, 0.741 and 0.669 for proctitis, haemorrhage and GI toxicity prediction using radiomic combined with dosimetric features. The AUC value reached 0.747 for the ensembled radiomic-dosimetric model for haemorrhage. ConclusionsOur preliminary results show that region-level pre-treatment planning CT radiomic features have the potential to predict radiation-induced rectal toxicities for prostate cancer. Moreover, when combined with region-level dosimetric features and using ensemble learning, the model prediction performance slightly improved.

Salvage high-dose-rate interventional radiotherapy (brachytherapy) for locally relapsed prostate cancer after radical prostatectomy and subsequent external irradiation.

To report the use of high-dose-rate (HDR) interventional radiotherapy (brachytherapy, IRT) as a salvage treatment for macroscopic histologically confirmed local relapse of prostatic cancer after prostatectomy and subsequent external irradiation. A retrospective study of patients with prostate adenocarcinoma, treated with HDR-IRT for an isolated local relapse after prostatectomy and external irradiation at our institution (2010-2020). Treatment results and treatment related-toxicity were recorded. Clinical outcomes were analyzed. Ten patients were identified. The median age was 63 years (range, 59-74 years), and the median follow-up time was 34 months (range, 10-68 months). Four patients had a biochemical relapse, and the mean time to prostate specific antigen (PSA) increase was 13 months. One-year biochemical failure-free survival (bFFS), 3-year bFFS, and 4-year bFFS were 80%, 60%, and 60%, respectively. Most of the treatment-related toxicities were grade 1-2. Two patients experienced grade 3 late genitourinary toxicity. HDR-IRT seems to be an effective treatment option showing acceptable toxicity for prostate cancer patients with isolated macroscopic histologically confirmed local relapse after prostatectomy and subsequent external irradiation.

Dose to the Bladder Trigone and Acute Urinary Toxicity after Prostate SBRT in a Randomized Phase 3 Trial

<h3>Purpose/Objective(s)</h3> The bladder trigone is physiologically the most densely innervated region of the bladder, owing to its prominent role in detrusor overactivity. Radiotherapy (RT) dose to the bladder trigone has been previously associated with increased genitourinary (GU) toxicity in prostate cancer patients treated with conventionally fractionated RT. However, there is little data exploring dosimetric parameters to the bladder trigone after prostate stereotactic body radiotherapy (SBRT). Herein, we assessed the potential association of bladder trigone dose-volume parameters and acute GU toxicity in prostate cancer patients treated with SBRT in a phase 3 clinical trial. <h3>Materials/Methods</h3> We included patients treated with prostate SBRT in an ongoing international, prospective randomized phase 3 trial (NCT01794403) between April 2013 and January 2022. Patients received 36.25 Gy to the prostate and proximal seminal vesicles, in 5 fractions, 3x week. The bladder trigone volumes were contoured retrospectively. GU toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0) and International Prostate Symptom Score (IPSS). Dose-volume histograms of the urethra, whole bladder, bladder trigone, and bladder minus trigone were examined. The primary endpoint was physician-reported CTCAE GU acute toxicity ≥2 and/or patient-reported IPSS increase of ≥10 from baseline within 3 months from treatment. Univariate and multivariate analyses were performed via logistic regression models. <h3>Results</h3> A total of 56 patients were eligible for analysis. Twenty-nine patients developed GU acute toxicity ≥2 and/or an IPSS increase of ≥10 within three months from starting treatment. The bladder trigone maximal dose, V20, V30, and V40 (p=0.475, 0.228, 0.155, 0.115, respectively) were not significantly associated with GU acute toxicity ≥2 and/or IPSS increase of ≥10 on univariate analysis. However, the maximal dose to the bladder trigone showed a trend towards a statistically significant association with an IPSS increase ≥10 (p=0.052). The urethra mean dose, V20, V25, and V30 (p=0.041, 0.020, 0.019, 0.021, respectively) were significantly associated with GU acute toxicity ≥2 and/or IPSS increase of ≥10 on univariate analysis. On multivariate analysis, the urethra V25 (p=0.024) was significantly associated with GU acute toxicity ≥2 and/or IPSS increase of ≥10. <h3>Conclusion</h3> In an ongoing phase 3 clinical trial assessing prostate SBRT, we confirm previously reported relationships of urethral dose and GU toxicity. There is also a trend in the association of maximal dose to the bladder trigone with patient-reported outcomes, suggesting that attention should be paid to this subvolume. Further investigation in larger studies on the dosimetric impact to urinary tract subvolumes in prostate SBRT is warranted.

Accumulated bladder wall dose is correlated with patient-reported acute urinary toxicity in prostate cancer patients treated with stereotactic, daily adaptive MR-guided radiotherapy

Background and purposeMagnetic resonance (MR)-guided linear accelerators (MR-Linac) enable accurate estimation of delivered doses through dose accumulation using daily MR images and treatment plans. We aimed to assess the association between the accumulated bladder (wall) dose and patient-reported acute urinary toxicity in prostate cancer (PCa) patients treated with stereotactic body radiation therapy (SBRT). Materials and methodsOne-hundred-and-thirty PCa patients treated on a 1.5 T MR-Linac were included. Patients filled out International Prostate Symptom Scores (IPSS) questionnaires at baseline, 1 month, and 3 months post-treatment. Deformable image registration-based dose accumulation was performed to reconstruct the delivered dose. Dose parameters for both bladder and bladder wall were correlated with a clinically relevant increase in IPSS (≥ 10 points) and/or start of alpha-blockers within 3 months using logistic regression. ResultsThirty-nine patients (30%) experienced a clinically relevant IPSS increase and/or started with alpha-blockers. Bladder D5cm3, V10–35Gy (in %), and Dmean and Bladder wall V10–35Gy (cm3 and %) and Dmean were correlated with the outcome (odds ratios 1.04–1.33, p-values 0.001–0.044). Corrected for baseline characteristics, bladder V10–35Gy (in %) and Dmean and bladder wall V10–35Gy (cm3 and %) and Dmean were still correlated with the outcome (odds ratios 1.04–1.30, p-values 0.001–0.028). Bladder wall parameters generally showed larger AUC values. ConclusionThis is the first study to assess the correlation between accumulated bladder wall dose and patient-reported urinary toxicity in PCa patients treated with MR-guided SBRT. The dose to the bladder wall is a promising parameter for prediction of patient-reported urinary toxicity and therefore warrants prospective validation and consideration in treatment planning.

Radiotherapy-induced toxicity in prostate cancer patients with hip prostheses

IntroductionAcute and late toxicity was analysed for prostate cancer patients with bilateral hip prostheses, who received fixed field intensity modulated radiotherapy (IMRT). The aims were (1) to establish whether toxicity rates differed from those of a control group with normal hips, (2) to develop a volumetric modulated arc therapy (VMAT) approach for patients with prostheses and (3) to compare doses to bladder and rectum for the control group, prostheses group and VMAT replans for the prostheses group.MethodsGenitourinary (GU) and gastrointestinal (GI) toxicity was scored using Common Terminology Criteria for Adverse Events version 5.0. The incidence of grade 2 or worse (G2+) toxicity was compared using Fisher’s exact test. Dose volume histograms (DVHs) and mean doses to organs at risk (OARs) were compared using signed rank tests.ResultsThere were 17 patients in the prostheses group and 50 in the control group. Acute and late GU toxicity was similar. G2+ late GI toxicity incidence was 31% for the prostheses group and 14% for the control group (p = 0.14). Significant differences (p < 0.05) were seen between the OAR DVHs of the prostheses group who had IMRT and the control group for a range of intermediate doses. The rectum mean dose was significantly different (p < 0.001), but no difference was seen for the bladder mean dose (p = 0.08).ConclusionsNo significant differences were seen in GU and GI toxicity incidence between patients with bilateral hip prostheses and a control group. The DVHs for bladder and rectum were significantly higher for patients with prostheses planned with IMRT. Replanning using a VMAT technique significantly reduced doses to the OARs, whilst maintaining good planning target volume coverage.