Functional imaging guided stereotactic ablative body radiotherapy (SABR) with focal dose escalation and bladder trigone sparing for intermediate and high-risk prostate cancer: study protocol for phase II safo trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment alternative for patients with localized low and intermediate risk prostate cancer patients. As already explored by some authors in the context of conventional moderate hypofractionated radiotherapy, focal boost of the index lesion defined by magnetic resonance imaging (MRI) is associated with an improved biochemical outcome. The objective of this phase II trial is to determine the effectiveness (in terms of biochemical, morphological and functional control), the safety and impact on quality of life, of prostate SABR with MRI guided focal dose intensification in males with intermediate and high-risk localized prostate cancer. METHODS: Patients with intermediate and high-risk prostate cancer according to NCCN definition will be treated with SABR 36.25 Gy in 5 fractions to the whole prostate gland with MRI guided simultaneous integrated focal boost (SIB) to the index lesion (IL) up to 50 Gy in 5 fractions, using a protocol of bladder trigone and urethra sparing. Intra-fractional motion will be monitored with daily cone beam computed tomography (CBCT) and intra-fractional tracking with intraprostatic gold fiducials. Androgen deprivation therapy (ADT) will be allowed. The primary endpoint will be efficacy in terms of biochemical and local control assessed by Phoenix criteria and post-treatment MRI respectively. The secondary endpoints will encompass acute and late toxicity, quality of life (QoL) and progression-free survival. Finally, the subgroup of high-risk patients will be involved in a prospective study focused on immuno-phenotyping. DISCUSSION: To the best of our knowledge, this is the first trial to evaluate the impact of post-treatment MRI on local control among patients with intermediate and high-risk prostate cancer undergoing SABR and MRI guided focal intensification. The results of this trial will enhance our understanding of treatment focal intensification through the employment of the SABR technique within this specific patient subgroup, particularly among those with high-risk disease, and will help to clarify the significance of MRI in monitoring local responses. Hopefully will also help to design more personalized biomarker-based phase III trials in this specific context. Additionally, this trial is expected to be incorporated into a prospective radiomics study focused on localized prostate cancer treated with radiotherapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL SPONSOR: IRAD/SEOR (Instituto de Investigación de Oncología Radioterápica / Sociedad Española de Oncología Radioterápica). STUDY SETTING: Clinicaltrials.gov identifier: NCT05919524; Registered 17 July 2023. TRIAL STATUS: Protocol version number and date: v. 5/ 17 May-2023. Date of recruitment start: August 8, 2023. Date of recruitment completion: July 1, 2024.

Dosimetric impact of bone marrow sparing for robustly optimized IMPT for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: To investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC). MATERIALS AND METHODS: Twenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated. RESULTS: A total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7-21.6] GyRBE , which reduced to 12.0 [10.0-14.0] GyRBE with maximum BMS. The mean OAR dose [range] increased modestly for 1 GyRBE BMS: 0.2 [0.0 - 0.6] GyRBE for bladder, 0.3 [-0.2 - 0.7] GyRBE for rectum, 0.4 [0.1 - 0.8] GyRBE for small bowel, and 0.2 [-0.2 - 0.4] GyRBE for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 - 6.7] GyRBE for bladder, 5.8 [1.8 - 12.4] GyRBE for rectum, 3.9 [1.6 - 5.9] GyRBE for small bowel, and 2.7 [0.6 - 5.9] GyRBE for sigmoid. CONCLUSION: Achieving 1 GyRBE BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Predictive Factors for Toxicity After Primary Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

PURPOSE: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. METHODS AND MATERIALS: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. RESULTS: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm3, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. CONCLUSIONS: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use.

The effects of radiation on myeloid lineage immune cells within the rodent urinary bladder: a systematic review.

PURPOSE: Radiotherapy is a prominent therapy for many malignant and non-malignant disorders, though it can cause side effects such as radiation-induced cystitis. Current research has highlighted a role for mast cells and macrophages in the prognosis of such radiation-induced toxicities. However, the prognostic value of these immune cells in the pathophysiology of radiation-induced cystitis is not clear. As such, a systematic review was conducted to assess myeloid-lineage immune cells for their prognostic value in radiation-induced cystitis to address this gap in literature. METHODS: The protocol was registered in PROSPERO, and searches were performed in PubMed, Embase and Web of Science databases for pre-clinical rodent studies on radiation-induced cystitis. RESULTS: After de-duplication, 153 articles were screened for relevancy by title and abstract. Title and abstract screening deemed 64 studies irrelevant. The remaining 85 studies were full-text screened, yielding seven unique articles for data extraction. Most included studies had an unclear risk of bias. The findings of this systematic review suggest that the prognostic value of myeloid-lineage immune cells in radiation-induced cystitis is still unclear, indicating a need for further research in this field. CONCLUSION: Although the studies reviewed provide some insight into the role of these immune cells in disease pathology, the limited number of studies and unclear risk of bias further highlights a need for additional, high-quality research in this area. In summary, this systematic review highlights a need to understand the involvement of immune cells in radiation-induced cystitis pathophysiology and lay the groundwork for further research in this area. TRIAL REGISTRATION: PROSPERO registration: CRD42022345960.

Differences in Quality of Life and Toxicity for Male and Female Patients following Chemo(radiotherapy) for Bladder Cancer.

AIMS: BC2001, a randomised trial of treatment for muscle-invasive bladder cancer, demonstrated no difference in health-related quality of life (HRQoL) or late toxicity between patients receiving radical radiotherapy with and without chemotherapy. This secondary analysis explored sex-based differences in HRQoL and toxicity. MATERIALS AND METHODS: Participants completed the Functional Assessment of Cancer Therapy Bladder (FACT-BL) HRQoL questionnaires at baseline, end of treatment, 6 months and annually until 5 years. Clinicians assessed toxicity with the Radiation Therapy Oncology Group (RTOG) and Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM) scoring systems at the same timepoints. The impact of sex on patient-reported HRQoL was evaluated using multivariate analyses of change in FACT-BL subscores from baseline to the timepoints of interest. For clinician-reported toxicity, differences were compared by calculating the proportion of patients with grade 3-4 toxicities occurring over the follow-up period. RESULTS: For both males and females, all FACT-BL subscores had a reduction in HRQoL at the end of treatment. For males, the mean bladder cancer subscale (BLCS) score remained stable through to year 5. For females, there was a decline in BLCS from baseline at years 2 and 3 with a return to baseline at year 5. At year 3, females had a statistically significant and clinically meaningful worsening of mean BLCS score (-5.18; 95% confidence interval -8.37 to -1.99), which was not seen in males (0.24; -0.76 to 1.23). RTOG toxicity was more frequent in females than males (27% versus 16%, P = 0.027). CONCLUSION: Results suggest that female patients treated with radiotherapy ± chemotherapy for localised bladder cancer report worse treatment-related toxicity in post-treatment years 2 and 3 than males.

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril.

PURPOSE: Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury. METHODS AND MATERIALS: C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy × 3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells. RESULTS: SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P = .0428) and negatively correlated with number of voids (P = .028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. CONCLUSIONS: This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed.

Bladder filling volume variation between the first and second day of planning computed tomography for prostate cancer radiation therapy and correlation with renal function.

AIM: During radiation therapy (RT) for prostate cancer, bladder filling helps exclude the organ from irradiation and reduces adverse effects. For RT planning, we performed computed tomography (CT) for 2 consecutive days to evaluate inter-day variations in organs such as the bladder. However, the patient factors that are associated with large intra-patient variations in bladder filling volume prior to RT are not known. METHODS: This was a retrospective study of 97 prostate cancer patients who underwent CT for 2 consecutive days for RT planning between March 2015 and March 2020 and with confirmed water intake volume before the scans. Patients consumed 500 ml of water immediately after urination and underwent CT 30 min after the start of water intake; CT was performed under similar conditions over 2 consecutive days. Patient information was collected from the medical records taken before CT. RESULTS: The median bladder filling volume was 102.8 cm3 (range: 31.7-774.0), and the median intra-patient bladder filling volume variation was 23.4 cm3 (range: 0.4-277.7). Univariate analysis revealed that the intra-patient variation was significantly larger in patients with an eGFR higher than the median (p = 0.003). No other factor showed correlations with the variation. As the larger bladder filling volume of the 2 consecutive days in patients increased (median 121.5 cm3 , range: 47.8-774.0), the intra-patient variation also increased. CONCLUSION: Patients with a higher eGFR show greater variation in bladder filling volume, and caution should be exercised when applying RT in these patients.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Dosimetric impact of rectum and bladder anatomy and intrafractional prostate motion on hypofractionated prostate radiation therapy

Objective The objective of this study was to evaluate the dosimetric impact on hypofractionated prostate radiation therapy of two geometric uncertainty sources: rectum and bladder filling and intrafractional prostate motion.Materials and methodsThis prospective study included 544 images (375 pre-treatment cone-beam CT [CBCT] and 169 post-treatment CBCT) from 15 prostate adenocarcinoma patients. We recalculated the dose on each pre-treatment CBCT once the positioning errors were corrected. We also recalculated two dose distributions on each post-treatment CBCT, either using or not intrafractional motion correction. A correlation analysis was performed between CBCT-based dose and rectum and bladder filling as well as intrafraction prostate displacements.ResultsNo significant differences were found between administered and planned rectal doses. However, we observed an increase in bladder dose due to a lower bladder filling in 66% of treatment fractions. These differences were reduced at the end of the fraction since the lower bladder volume was compensated by the filling during the treatment session. A statistically significant reduction in target volume coverage was observed in 27% of treatment sessions and was correlated with intrafractional prostate motion in sagittal plane > 4 mm.ConclusionsA better control of bladder filling is recommended to minimize the number of fractions in which the bladder volume is lower than planned. Fiducial mark tracking with a displacement threshold of 5 mm in any direction is recommended to ensure that the prescribed dose criteria are met. (AU)

Voiding defects in acute radiation cystitis driven by urothelial barrier defect through loss of E-cadherin, ZO-1 and Uroplakin III.

Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4-8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell-cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.

Mitigation on bowel loops daily variations by 1.5-T MR-guided daily-adaptive SBRT for abdomino-pelvic lymph-nodal oligometastases.

PURPOSE: We report preliminary dosimetric data concerning the use of 1.5-T MR-guided daily-adaptive radiotherapy for abdomino-pelvic lymph-nodal oligometastases. We aimed to assess the impact of this technology on mitigating daily variations for both target coverage and organs-at-risk (OARs) sparing. METHODS: A total of 150 sessions for 30 oligometastases in 23 patients were analyzed. All patients were treated with MR-guided stereotactic body radiotherapy (SBRT) for a total dose of 35 Gy in five fractions. For each fraction, a quantitative analysis was performed for PTV volume, V35Gy and Dmean. Similarly, for OARs, we assessed daily variations of volume, Dmean, Dmax. Any potential statistically significant change between baseline planning and daily-adaptive sessions was assessed using the Wilcoxon signed-rank test, assuming a p value < 0.05 as significant. RESULTS: Average baseline PTV, bowel, bladder, and single intestinal loop volumes were respectively 8.9 cc (range 0.7-41.2 cc), 1176 cc (119-3654 cc), 95 cc (39.7-202.9 cc), 18.3 cc (9.1-37.7 cc). No significant volume variations were detected for PTV (p = 0.21) bowel (p = 0.36), bladder (p = 0.47), except for single intestinal loops, which resulted smaller (p = 0.026). Average baseline V35Gy and Dmean for PTV were respectively 85.6% (72-98.8%) and 35.6 Gy (34.6-36.1 Gy). We recorded a slightly positive trend in favor of daily-adaptive strategy vs baseline planning for improved target coverage, although not reaching statistical significance (p = 0.11 and p = 0.18 for PTV-V35Gy and PTV-Dmean). Concerning OARs, a significant difference was observed in favor of daily-adapted treatments in terms of single intestinal loop Dmax [23.05 Gy (13.2-26.9 Gy) at baseline vs 20.5 Gy (12.1-24 Gy); p value = 0.0377] and Dmean [14.4 Gy (6.5-18 Gy) at baseline vs 13.0 Gy (6.7-17.6 Gy); p value = 0.0003]. Specifically for bladder, the average Dmax was 18.6 Gy (0.4-34.3 Gy) at baseline vs 18.3 Gy (0.7-34.3 Gy) for a p value = 0.28; the average Dmean was 7.0 Gy (0.2-16.6 Gy) at baseline vs 6.98 Gy (0.2-16.4 Gy) for a p value = 0.66. Concerning the bowel, no differences in terms of Dmean [4.78 Gy (1.3-10.9 Gy) vs 5.6 Gy (1.4-10.5 Gy); p value = 0.23] were observed between after daily-adapted sessions. A statistically significant difference was observed for bowel Dmax [26.4 Gy (7.7-34 Gy) vs 25.8 Gy (7.8-33.1 Gy); p value = 0.0086]. CONCLUSIONS: Daily-adaptive MR-guided SBRT reported a significantly improved single intestinal loop sparing for lymph-nodal oligometastases. Also, bowel Dmax was significantly reduced with daily-adaptive strategy. A minor advantage was also reported in terms of PTV coverage, although not statistically significant.

Development of in-house fully residual deep convolutional neural network-based segmentation software for the male pelvic CT.

BACKGROUND: This study aimed to (1) develop a fully residual deep convolutional neural network (CNN)-based segmentation software for computed tomography image segmentation of the male pelvic region and (2) demonstrate its efficiency in the male pelvic region. METHODS: A total of 470 prostate cancer patients who had undergone intensity-modulated radiotherapy or volumetric-modulated arc therapy were enrolled. Our model was based on FusionNet, a fully residual deep CNN developed to semantically segment biological images. To develop the CNN-based segmentation software, 450 patients were randomly selected and separated into the training, validation and testing groups (270, 90, and 90 patients, respectively). In Experiment 1, to determine the optimal model, we first assessed the segmentation accuracy according to the size of the training dataset (90, 180, and 270 patients). In Experiment 2, the effect of varying the number of training labels on segmentation accuracy was evaluated. After determining the optimal model, in Experiment 3, the developed software was used on the remaining 20 datasets to assess the segmentation accuracy. The volumetric dice similarity coefficient (DSC) and the 95th-percentile Hausdorff distance (95%HD) were calculated to evaluate the segmentation accuracy for each organ in Experiment 3. RESULTS: In Experiment 1, the median DSC for the prostate were 0.61 for dataset 1 (90 patients), 0.86 for dataset 2 (180 patients), and 0.86 for dataset 3 (270 patients), respectively. The median DSCs for all the organs increased significantly when the number of training cases increased from 90 to 180 but did not improve upon further increase from 180 to 270. The number of labels applied during training had a little effect on the DSCs in Experiment 2. The optimal model was built by 270 patients and four organs. In Experiment 3, the median of the DSC and the 95%HD values were 0.82 and 3.23 mm for prostate; 0.71 and 3.82 mm for seminal vesicles; 0.89 and 2.65 mm for the rectum; 0.95 and 4.18 mm for the bladder, respectively. CONCLUSIONS: We have developed a CNN-based segmentation software for the male pelvic region and demonstrated that the CNN-based segmentation software is efficient for the male pelvic region.

Dosimetric impact of dwell time deviation constraint on inverse brachytherapy treatment planning and comparison with conventional optimization method for interstitial brachytherapy implants.

PURPOSE: High-dose rate remote afterloading brachytherapy machine and advanced treatment planning system help in getting optimum dose to tumor and low dose to normal structures. Inverse planning simulated annealing (IPSA) optimization technique has a unique feature of dwell time deviation constraint (DTDC). In this study, six IPSA-based plans having different DTDC values with routinely practiced geometric plus graphical optimization (GO + GrO) have been compared using various dosimetric parameters. MATERIALS AND METHODS: For this retrospective study, we have generated IPSA-optimized interstitial brachytherapy plans for ten cancer cervix patients. Routinely practiced GO + GrO-based plans were compared with six different IPSA plans having varying DTDC values from 0.0 to 1.0 using different dosimetric indices. RESULTS: Conformity index and homogeneity index (HI) were higher in GO + GrO plans, compared to IPSA-optimized plans. However, HI of IPSA plans was increasing with increasing DTDC values. High-dose volumes were well controllable using DTDC parameter in IPSA-optimized plans. Dose to the rectum and bladder was smaller for IPSA-optimized plans than GO + GrO plans. CONCLUSIONS: One of the benefits of applying DTDC in IPSA-optimized plan is that it reduces high-dose volumes. Another advantage is the reduction in rectum and bladder dose.

Radiation cystitis: A late effect of radiotherapy in a patient with cervical rhabdomyosarcoma.

We report the case of a 22-year old female presenting with an embryonal rhabdomyosarcoma of the cervix that was successfully treated by surgery followed by adjuvant radiation therapy and chemotherapy. She subsequently developed radiation cystitis after 10 years of follow-up. She was successfully treated with cystoscopic fulguration. In this report, we discuss a review of management strategies for cervical rhabdomyosarcoma and also throw some light on incidence and management of radiation cystitis after pelvic radiotherapy. We discuss the dose independence of radiation cystitis, which can be seen after as low as 4500 cGy of pelvic radiation.

Analysis of the Influence of Peripheral Anatomical Changes for CBCT-Guided Prostate Cancer Radiotherapy.

PURPOSE: To analyze the influence of the bladder and rectum filling and the body contour changes on the prostate target dose. METHODS: A total of 190 cone-beam CT (CBCT) image data sets from 16 patients with prostate cancer were used in this study. Dose reconstruction was performed on the virtual CT generated by the deformable planning CT. Then, the effects of the bladder filling, rectal filling, and the patient's body contour changes of the PCTV1 (the prostate area, B1) and PCTV2 (the seminal vesicle area, B2) on the target dose were analyzed. Correlation analysis was performed for the ratio of bladder and rectal volume variation and the variation of the bladder and rectal dose. RESULTS: The mean Dice coefficients of B1, B2, bladder, and rectum were 0.979, 0.975, 0.888 and 0.827, respectively, and the mean Hausdorff distances were 0.633, 1.505, 2.075, and 1.533, respectively. With the maximum volume variations of 142.04 ml for the bladder and 40.50 ml for the rectum, the changes of V100, V95, D2, and D98 were 1.739 ± 1.762 (%), 0.066 ± 0.169 (%), 0.562 ± 0.442 (%), and 0.496 ± 0.479 (%) in PCTV1 and 1.686 ± 1.051 (%), 0.240 ± 0.215 (%), 1.123 ± 0.925 (%), and 0.924 ± 0.662 (%) in PCTV2, respectively. With a 10% increase in the volume of the bladder and rectum, the V75, V70, and V65 of rectum increased at 0.73 (%), 0.71 (%), and 1.18 (%), and the V75, V70, and V65 of bladder changed at -0.21 (%), -0.32 (%), and -0.39 (%), respectively. CONCLUSION: Significant correlations were observed between the volume variation and the dose variation of the bladder and rectum. However, when a bladder and rectal filling protocol was adopted, the target dose coverage can be effectively ensured based on CBCT guidance to correct the prostate target position.

Dosimetric impact of rectum and bladder anatomy and intrafractional prostate motion on hypofractionated prostate radiation therapy.

OBJECTIVE: The objective of this study was to evaluate the dosimetric impact on hypofractionated prostate radiation therapy of two geometric uncertainty sources: rectum and bladder filling and intrafractional prostate motion. MATERIALS AND METHODS: This prospective study included 544 images (375 pre-treatment cone-beam CT [CBCT] and 169 post-treatment CBCT) from 15 prostate adenocarcinoma patients. We recalculated the dose on each pre-treatment CBCT once the positioning errors were corrected. We also recalculated two dose distributions on each post-treatment CBCT, either using or not intrafractional motion correction. A correlation analysis was performed between CBCT-based dose and rectum and bladder filling as well as intrafraction prostate displacements. RESULTS: No significant differences were found between administered and planned rectal doses. However, we observed an increase in bladder dose due to a lower bladder filling in 66% of treatment fractions. These differences were reduced at the end of the fraction since the lower bladder volume was compensated by the filling during the treatment session. A statistically significant reduction in target volume coverage was observed in 27% of treatment sessions and was correlated with intrafractional prostate motion in sagittal plane > 4 mm. CONCLUSIONS: A better control of bladder filling is recommended to minimize the number of fractions in which the bladder volume is lower than planned. Fiducial mark tracking with a displacement threshold of 5 mm in any direction is recommended to ensure that the prescribed dose criteria are met.

Effect of irradiation on the expression of E-cadherin and ß-catenin in early and late radiation sequelae of the urinary bladder and its modulation by NF-κB inhibitor thalidomide.

PURPOSE: In a previous study we have shown in a mouse model that administration of nuclear factor-kappa B (NF-κB) inhibitor thalidomide has promising therapeutic effects on early radiation cystitis (ERC) and late radiation sequelae (LRS) of the urinary bladder. The aim of this study was to evaluate in the same mice the effect of thalidomide on adherens junction (AJ) proteins in ERC and LRS. METHODS: Urothelial expressions of E­cadherin and ß­catenin were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) bladder specimens over 360 days post single-dose irradiation on day 0. First, the effect of irradiation on AJ expression and then effects of thalidomide on irradiation-induced AJ alterations were assessed using three different treatment times. RESULTS: Irradiation provoked a biphasic upregulation of E­cadherin and ß­catenin in the early phase. After a mild decrease of E­cadherin and a pronounced decrease of ß­catenin at the end of the early phase, both increased again in the late phase. Early administration of thalidomide (day 1-15) resulted in a steeper rise in the first days, an extended and increased expression at the end of the early phase and a higher expression of ß­catenin alone at the beginning of the late phase. CONCLUSION: Upregulation of AJ proteins is an attempt to compensate irradiation-induced impairment of urothelial barrier function. Early administration of thalidomide improves these compensatory mechanisms by inhibiting NF-κB signaling and its interfering effects.

Therapeutic effect of Low intensity Extracorporeal Shock Wave Therapy (Li-ESWT) on diabetic bladder dysfunction in a rat model.

Objectives: Low intensity extracorporeal shock wave therapy (Li-ESWT) has proven to be effective and safe for the treatment of various urological disorders including erectile dysfunction and chronic pelvic pain syndrome. In this study, we elucidated the therapeutic effect and possible mechanisms of Li-ESWT on diabetic bladder dysfunction (DBD) in a rat model. Materials and Methods: In all, thirty-two female Sprague-Dawley rats were divided into three groups: normal control (NC), diabetes mellitus (DM) control, and DM Li-ESWT. The two DM groups were given high fat diets for one month, followed by 2 intraperitoneal injections of streptozotocin (STZ) 30 mg/kg separated by one week. Body weight and fasting blood glucose were monitored every week. Only rats with fasting blood glucose 140 mg/dL or more were considered diabetic and used in the subsequent portions of the study. The Li-ESWTs were applied toward the pelvis of the rats twice a week for 4 weeks with energy flux density (EFD) 0.02 mJ/mm2, 500 shocks, at 3Hz. All rats underwent plasma insulin tolerance test, conscious cystometry, leak-point pressure (LPP) assessment, and immunohistochemical studies. Results: DM groups had significantly lower insulin sensitivity and higher body weight. Conscious cystometry also revealed voiding dysfunctions. In the DM Li-ESWT group, the rats had significantly improved voiding functions that were reflected in longer micturition intervals and higher LPP compared to DM control. Immunofluorescence in DM control groups showed increased tyrosine hydroxylase (TH) expression and decreased neuronal nitric oxide synthase (nNOS) expression in the longitudinal urethral smooth muscles. Besides, rats had dilations and deformities of suburothelium capillary network of the bladder, revealing the deterioration of the nerve function of the urethra and destruction of the vascularization of the bladder. However, the DM Li-ESWT group exhibited recovery of the nerve expression of the urethra and vascularization of bladder. Conclusions: Li-ESWT ameliorates the bladder dysfunction and urinary continence in the DBD rat model, reflected in restoration of the nerve expression of the urethra and the vascularization of the bladder. Non-invasive Li-ESWT could be an alternative therapeutic option for DBD.

[Dosimetric impact of hydrogel spacer use for stereotactic body radiotherapy of localised prostate cancer]. / Impact dosimétrique de la pose d'un espaceur rectal dans le traitement de cancer de la prostate localisé par irradiation en conditions stéréotaxiques.

PURPOSE: Stereotactic body radiotherapy (SBRT) of prostate cancer is associated with rectal toxicities, which can be reduced by using a hydrogel spacer. The object of this retrospective study was to show the feasibility of spacer placement under local anesthesia and utility of hydrogel spacer to reduce the dose to the rectal wall. MATERIAL AND METHODS: We collected data from all patients with localised prostate cancer treated with SBRT (40Gy in 5 fractions) between 2018 and 2020. A hydrogel spacer (SpaceOAR®) was placed depending on the availability of the product. We collected dosimetric data for target volumes and organs at risk. We calculated mean values, which were compared using non-parametric tests. RESULTS: Among 35 patients, mean age was 75 years. Seventeen had a spacer placed, with a mean space created of 10mm. No complication was reported during the intervention. High doses to the rectal wall were significantly lower in spacer group (V38: 0.39 cm3 vs. 0.72 cm3; P=0.02). PTV were better covered in spacer group (P=0.07). Doses to the bladder wall were similar in both groups. CONCLUSION: Spacer procedure under local anesthesia was well tolerated. Hydrogel spacer allowed to reduce doses to the rectum while improving PTV coverage.