Bladder Toxicity Research Articles

GSOR08 Presentation Time: 12:05 PM: Relationship between Late Bladder Toxicity & Dose to Bladder Sub-Volumes in Locally Advanced Cervical Cancer Treated with Interstitial Brachytherapy: A Prospective Study

GSOR08 Presentation Time: 12:05 PM: Relationship between Late Bladder Toxicity & Dose to Bladder Sub-Volumes in Locally Advanced Cervical Cancer Treated with Interstitial Brachytherapy: A Prospective Study

The Clinical Course of the Late Toxicity of Definitive Radiotherapy in Cervical Cancer.

Background and Objectives: This study aimed to investigate the clinical course and characteristics of late toxicity over time following the completion of definitive radiotherapy (RT) in patients with cervical cancer. Materials and Methods: We retrospectively reviewed the medical records of 60 patients with cervical cancer who underwent pelvic external beam radiotherapy followed by intracavitary brachytherapy. Late toxicity was assessed for the lower gastrointestinal (GI) tract and bladder organ at 6, 12, 24, 36, and >36 months post-RT. We examined the onset and prevalence of late toxicity at each time point. Clinical remission and interventions for managing late toxicity were also investigated. Results: The peak onset of lower GI toxicity occurred 12 months after RT completion, with a median symptom duration of 9.9 months (range, 0.1-26.3 months), and exhibited its highest prevalence rate of 15.5% at 24 months post-RT. Most GI toxicities developed and resolved within three years post-RT, with a prevalence rate of 8.1% at three years, followed by a decreasing trend. Bladder toxicity first peaked at 24 months post-RT and continued to occur beyond 36 months, showing the re-increasing pattern in the prevalence rate after 36 months (23.5%). In terms of clinical remission, 66.7% of lower GI toxicities (12 of 18 patients) and 60% of bladder toxicities (9 of 15 patients) achieved complete remission by the last follow-up date. Conclusions: Late toxicities of the GI and bladder following definitive RT in cervical cancer are partially reversible and exhibit distinct patterns of onset and prevalence over time. A systematic follow-up strategy should be established for the early detection and timely intervention of late toxicity by understanding these clinical courses.

Radiotherapy Related Bowel and Bladder Toxicity after Prostate Cancer Irradiation

Background: Pelvic radiotherapy is a primary treatment modality for organ-confined prostate cancer and early-stage endometrial cancer. While effective in improving survival rates and reducing recurrence, it is associated with a range of side effects that can impact patient quality of life. Objective: The study aimed to assess the incidence, management, and resolution of acute and chronic side effects of pelvic radiotherapy in prostate and endometrial cancer patients, focusing on bowel and bladder functions. Methods: This single-center, observational study included 50 patients diagnosed with prostate or endometrial cancer who underwent pelvic radiotherapy with a dose of 66-70 Gy using a four-field technique on a linear accelerator. Patients were assessed for bladder and bowel dysfunction, with follow-up at 6, 12, and 18 months post-treatment. Statistical analysis involved univariate weighted distribution of response frequencies and paired t-tests for ordinal scale scores, using SPSS version 25 for data analysis. Results: Of the participants, 22% experienced dysuria, 64% reported bladder outlet obstruction, and 20% had constipation. Acute bowel symptoms like diarrhea occurred in 32%, and chronic proctitis developed in 22% of patients. Urinary symptoms appeared by the third week and generally resolved within weeks; however, bowel symptoms persisted longer but returned to baseline by 18 months post-treatment. Approximately 70% of patients reported good tolerance to radiotherapy. Conclusion: Pelvic radiotherapy is effective in treating prostate and endometrial cancers but requires management of transient side effects to improve patient outcomes. Advanced radiotherapy techniques such as IMRT and 3D CRT have shown potential in reducing these side effects, emphasizing the need for continuous technological advancements and patient-centered care in radiotherapy.

2574: Comparison of androgen deprivation therapy drugs in attenuating the RT-induced bladder toxicity

2574: Comparison of androgen deprivation therapy drugs in attenuating the RT-induced bladder toxicity

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

Comparative Study between Two Fractions of 9Gy & Three Fractions of 7Gy High Dose Rate Brachytherapy Following Concurrent Chemo Radiotherapy in Patients with Locally Advanced Carcinoma of Uterine Cervix

Introduction: Traditionally, a judicious combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is the widely accepted primary modality of treatment for locally advanced carcinoma of the cervix. Although the recommendation ofAmerican Brachytherapy Society is <7.5 Gyfor individual fraction and four to eight should be the range of fractions; however, literature showed high dose rate (HDR) brachytherapy of two fractions of 9Gyresults in acceptable toxicity without compromising the local control. Methods: This was a Prospective Quasi-Experimental study, conducted in Department of Radiation Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka from July 2018 to June 2019. Patients with Clinically diagnosed and histopathologically proven squamous cell carcinoma of uterine cervix in locally advanced stage (FIGO stage IIB to IVA) were selected. Total 60 patients were enrolled according to selection criteria and allocated in to group. Both arm was received 50Gy EBRT in 25 fractions with concurrent inj.Cisplatin 40 mg/m2 weekly. Then Arm A was given HDR Brachytherapy 9Gy in each fraction for 2 fractions and Arm B was given HDR Brachytherapy 7Gy in each fraction for 3 fractions. Then treatment responses, locoregional control of disease and acute toxicities were compared between groups. Result:Follow up at 6 months after completion of treatment, complete remission was 90% and 86% respectively for arm A and arm B. The overall complete response was 88%. The common toxicities associated with treatment were bladder and rectal toxicities, skin reaction, small bowel toxicity and haematologic complications which were managed well. During follow up after 6 months, 3 patients in arm A and 2 patients in arm B developed grade II bladder toxicities and only 2 patients in arm A developed rectal grade II toxicities, but there was no rectal toxicity in arm B. Conclusions: Present study showed that a total dose of 18 Gy ICRT in two fractions of 9 Gy over 2 weeks is equally effective in short term local control with acceptable toxicities in comparison with a total dose of 21 Gy in three fractions of 7 Gy ICRT. J Bangladesh Coll Phys Surg 2024; 42: 49-56

Rectal toxicity of 3-dimensional conformal radiation therapy following hydrogel spacer (Space OAR) injection for men with prostate cancer.

To evaluate whether hydrogel spacer injection, which increases the distance between the prostate and rectum, prior to local radiation therapy for prostate cancer reduces rectal and bladder toxicity. With institutional review board approval (05-004), we retrospectively reviewed rectal and bladder toxicity after local radiation therapy in patients with prostate cancer who were followed up for more than 1 year. We included 156 patients who had received local radiation therapy. Their ages ranged from 63 to 86 years, with an average of 75 years. Most patients were treated only on the prostate and seminal vesicles. All prostate sites were irradiated as follows: whole pelvis with prostate in 10 patients, whole pelvis with prostate and metastatic sites in six, and prostate and metastatic sites in eight. Radiation therapy (70-74 Gy) was performed for the prostate. Irradiation of 45-46.8 Gy was applied to whole pelvic and para-aortic lymph nodes, with 54-60 Gy applied to bone metastatic sites. In one case, stereotactic body radiation therapy (36 Gy) was performed for a sacral bone metastatic site. The hydrogel spacer was injected in 39 patients. Rectal toxicity was reported in 21 patients without (17.9%) and 3 patients with (7.7%) the hydrogel spacer. Bladder toxicity was reported in five patients without and only one patient with the hydrogel spacer. Hydrogel spacer injection prior to local radiation therapy for prostate cancer reduces rectal radiation exposure, lowers the risk of rectal complications, and may be a promising method for boosting the irradiation dose in the future.

Clinical and dosimetric correlation in terms of treatment response, bladder and rectal toxicities in cervical cancer patients treated with cobalt 60 high dose rate brachytherapy.

High dose rate (HDR) image-guided brachytherapy with Cobalt-60 isotope is a relatively recent approach. The aim of the study is to evaluate the clinical and dosimetric parameters in terms of tumour response, bladder, and rectal toxicity in patients undergoing Co-60 HDR brachytherapy. All patients were initially treated with chemoradiation (CT-RT) at our center or other referral centers with external beam radiation therapy (EBRT) for a dose of 45 Gy-60 Gy at 1.8-2Gy/fraction (including nodal boost) with concomitant chemotherapy with either cisplatin or carboplatin. Patients were then scheduled for brachytherapy within 1 week after completion of CT-RT and are assessed by local examination. Depending on local examination parameters at the time of brachytherapy they were eligible either for intracavitary brachytherapy (ICBT) or interstitial brachytherapy (ISBT). The complete response (CR) observed in stage I, II, III, IVA were 60%, 79.4%, 86% and 76.2% respectively. Complete response was seen in patients with mean EQD2 of 78.67 Gy10, 83.33 Gy10, 84.23 Gy10, 85.63 Gy10 in stages I, II, III, IVA respectively. 79.2% of cisplatin-treated patients and 87.5% of carboplatin-treated patients had a complete response indicating that patients treated with either chemotherapy had similar response rates. According to results obtained from the study we conclude by saying that higher rates of complete response to treatment in cervical cancer is seen in patients with shorter overall treatment time (OTT), shorter interval between end of definitive CT-RT and beginning of brachytherapy and squamous cell histology. The study also noted the trend of increasing mean EQD2 to tumor with increasing stage for achieving complete response. Higher acute bladder and rectal toxicity is seen in patients who received EQD2 of ¿70-90Gy3 and ¿70Gy3 respectively. The study findings suggest that the clinical outcomes and the toxicities are clinically comparable with other radioisotope based HDR brachytherapy treatment.

An overview of pharmacological effects of Crocus sativous and its constituents.

Crocus sativus L. was used for the treatment of a wide range of disorders in traditional medicine. Due to the extensive protective and treatment properties of C. sativus and its constituents in various diseases, the purpose of this review is to collect a summary of its effects, on experimental studies, both in vitro and in vivo. Databases such as PubMed, Science Direct, and Scopus were explored until January 2023 by employing suitable keywords. Several investigations have indicated that the therapeutic properties of C. sativus may be due to its anti-oxidant and anti-inflammatory effects on the nervous, cardiovascular, immune, and respiratory systems. Further research has shown that its petals also have anticonvulsant properties. Pharmacological studies have shown that crocetin and safranal have anti-oxidant properties and through inhibiting the release of free radicals lead to the prevention of disorders such as tumor cell proliferation, atherosclerosis, hepatotoxicity, bladder toxicity, and ethanol induced hippocampal disorders. Numerous studies have been performed on the effect of C. sativus and its constituents in laboratory animal models under in vitro and in vivo conditions on various disorders. This is necessary but not enough and more clinical trials are needed to investigate unknown aspects of the therapeutic properties of C. sativus and its main constituents in different disorders.

Twice-daily HDR brachytherapy: a one-week apart protocol for treating cervix uteri in a resource-limited setting

Abstract Background: High dose rate (HDR) intracavitary brachytherapy (ICBT) plays a crucial role in cervix cancer treatment, with variations in fractionation schedules across different radiation societies. This study aims to assess the effectiveness and tolerability of a 7 Gy per fraction twice daily schedule over two successive weeks versus an 8 Gy per fraction once weekly schedule over three successive weeks. Patients and Methods: From 2020 to 2022, 87 patients with uterine cervix cancer (Stages II and III) underwent concomitant external beam radiotherapy (EBRT) and chemotherapy, followed by HDR-ICBT. Patients were randomised into two arms: Arm A (8 Gy per fraction once weekly for 3 fractions) and Arm B (7 Gy per fraction twice daily once a week for 4 fractions). Local control is defined as any patient free from local progression (CR + PR + SD) in the first year after ending brachytherapy (BTH). Results: The median follow-up was 16·5 months. Local control at 1 year was 78·7% in Arm A and 89·2% in Arm B (p = 0·24). No clinically significant differences in rectal and bladder toxicities were observed between the two arms (p = 0·40). Conclusion: There were limited treatment machines and other BTH challenges in Egypt, and the HDR BTH schedule of 7 Gy per fraction twice daily over 2 successive weeks presents an acceptable alternative to the current national standard of 8 Gy per fraction once weekly over 3 weeks. Both schedules demonstrate comparable local control, late toxicity and progression-free survival. Notably, the 7 Gy per fraction twice daily per week for 4 fractions offers the advantage of a reduced total treatment time.

Evaluation of the Mechanisms Involved in the Development of Bladder Toxicity following Exposure to Occupational Bladder Cancer Causative Chemicals Using DNA Adductome Analysis.

Occupational exposure to aromatic amines (AAs) is an important risk factor for urinary bladder cancer. This study aimed to evaluate the toxicity of AAs and analyze the carcinogenic mechanisms in rat bladder by comprehensive analysis of DNA adducts (DNA adductome). DNA was extracted from the bladder epithelia of rats treated with AAs, including acetoacet-o-toluidine (AAOT) and o-toluidine (OTD), and adductome analysis was performed. Principal component analysis-discriminant analysis revealed that OTD and AAOT observed in urinary bladder hyperplasia could be clearly separated from the controls and other AAs. After confirming the intensity of each adduct, four adducts were screened as having characteristics of the OTD/AAOT treatment. Comparing with the in-house DNA adduct database, three of four candidates were identified as oxidative DNA adducts, including 8-OH-dG, based on mass fragmentation together with high-resolution accurate mass (HRAM) spectrometry data. Therefore, findings suggested that oxidative stress may be involved in the toxicity of rat bladder epithelium exposed to AAs. Consequently, the administration of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase, in six-week-old rats fed with 0.6% OTD in their diet resulted in simple hyperplastic lesions in the bladder that were suppressed by apocynin. The labeling indices of Ki67, γ-H2AX, and 8-OHdG were significantly decreased in an apocynin concentration-dependent manner. These findings indicate that oxidative stress may have contributed to the development of urinary cancer induced by OTD.

A new predictive parameter for dose-volume metrics in intensity-modulated radiation therapy planning for prostate cancer: Initial phantom study.

Organ-at-risk (OAR) sparing is often assessed using an overlap volume-based parameter, defined as the ratio of the volume of OAR that overlaps the planning target volume (PTV) to the whole OAR volume. However, this conventional overlap-based predictive parameter (COPP) does not consider the volume relationship between the PTV and OAR. We propose a new overlap-based predictive parameter that consider the PTV volume. The effectiveness of proposed overlap-based predictive parameter (POPP) is evaluated compared with COPP. We defined as POPP=(overlap volume between OAR and PTV/OAR volume) × (PTV volume/OAR volume). We generated intensity modulated radiation therapy (IMRT) based on step and shoot technique, and volumetric modulated arc therapy (VMAT) plans with the Auto-Planning module of Pinnacle3 treatment planning system (v14.0, Philips Medical Systems, Fitchburg, WI) using the American Association of Physicists in Medicine Task Group (TG119) prostate phantom. The relationship between the position and size of the prostate phantom was systematically modified to simulate various geometric arrangements. The correlation between overlap-based predictive parameters (COPP and POPP) and dose-volume metrics (mean dose, V70Gy, V60Gy, and V37.5Gy for rectum and bladder) was investigated using linear regression analysis. Our results indicated POPP was better than COPP in predicting intermediate-dose metrics. The bladder results showed a trend similar to that of the rectum. The correlation coefficient of POPP was significantly greater than that of COPP in<62Gy (82% of the prescribed dose) region for IMRT and in<55Gy (73% of the prescribed dose) region for VMAT regarding the rectum (p<0.05). POPP is superior to COPP for creating predictive models at an intermediate-dose level. Because rectal bleeding and bladder toxicity can be associated with intermediate-doses as well as high-doses, it is important to predict dose-volume metrics for various dose levels. POPP is a useful parameter for predicting dose-volume metrics and assisting the generation of treatment plans.

Multimodality radiomics prediction of radiotherapy-induced the early proctitis and cystitis in rectal cancer patients: a machine learning study

Purpose. This study aims to predict radiotherapy-induced rectal and bladder toxicity using computed tomography (CT) and magnetic resonance imaging (MRI) radiomics features in combination with clinical and dosimetric features in rectal cancer patients. Methods. A total of sixty-three patients with locally advanced rectal cancer who underwent three-dimensional conformal radiation therapy (3D-CRT) were included in this study. Radiomics features were extracted from the rectum and bladder walls in pretreatment CT and MR-T2W-weighted images. Feature selection was performed using various methods, including Least Absolute Shrinkage and Selection Operator (Lasso), Minimum Redundancy Maximum Relevance (MRMR), Chi-square (Chi2), Analysis of Variance (ANOVA), Recursive Feature Elimination (RFE), and SelectPercentile. Predictive modeling was carried out using machine learning algorithms, such as K-nearest neighbor (KNN), Support Vector Machine (SVM), Logistic Regression (LR), Decision Tree (DT), Random Forest (RF), Naive Bayes (NB), Gradient Boosting (XGB), and Linear Discriminant Analysis (LDA). The impact of the Laplacian of Gaussian (LoG) filter was investigated with sigma values ranging from 0.5 to 2. Model performance was evaluated in terms of the area under the receiver operating characteristic curve (AUC), accuracy, precision, sensitivity, and specificity. Results. A total of 479 radiomics features were extracted, and 59 features were selected. The pre-MRI T2W model exhibited the highest predictive performance with an AUC: 91.0/96.57%, accuracy: 90.38/96.92%, precision: 90.0/97.14%, sensitivity: 93.33/96.50%, and specificity: 88.09/97.14%. These results were achieved with both original image and LoG filter (sigma = 0.5–1.5) based on LDA/DT-RF classifiers for proctitis and cystitis, respectively. Furthermore, for the CT data, AUC: 90.71/96.0%, accuracy: 90.0/96.92%, precision: 88.14/97.14%, sensitivity: 93.0/96.0%, and specificity: 88.09/97.14% were acquired. The highest values were achieved using XGB/DT-XGB classifiers for proctitis and cystitis with LoG filter (sigma = 2)/LoG filter (sigma = 0.5–2), respectively. MRMR/RFE-Chi2 feature selection methods demonstrated the best performance for proctitis and cystitis in the pre-MRI T2W model. MRMR/MRMR-Lasso yielded the highest model performance for CT. Conclusion. Radiomics features extracted from pretreatment CT and MR images can effectively predict radiation-induced proctitis and cystitis. The study found that LDA, DT, RF, and XGB classifiers, combined with MRMR, RFE, Chi2, and Lasso feature selection algorithms, along with the LoG filter, offer strong predictive performance. With the inclusion of a larger training dataset, these models can be valuable tools for personalized radiotherapy decision-making.

Cuminum cyminum Ameliorates Urotoxic Effects of Cyclophosphamide by Modulating Antioxidant, Inflammatory Cytokines, and Urinary Bladder Overactivity: In vivo and in Silico Investigations.

Interstitial Cystitis (IC) is a chronic inflammatory disease that lacks effective treatment. The present study aimed to investigate the potential of aqueous ethanol extract of Cuminum cyminum (AEECC) on oxidative stress, inflammation and overactivity of urinary bladder induced by cyclophosphamide (CYP). Female Sprague-Dawley rats received intraperitoneal administration of cyclophosphamide (150 mg/kg, i. p. 1st , 4th , and 7th days). To investigate the urothelial damage, the bladder weight, nociception behavior, and Evans blue dye extravasation method was used. The antioxidants CAT, GPX and NO were measured. ELISA determined the IL-6 and TNF-α levels. The spasmolytic effect of AEECC was investigated on isolated bladder strips and its mechanisms were determined. The enhanced nociception behavior, bladder weight, vascular permeability, edema, hemorrhage, nitric oxide, IL-6 and TNF-α levels by CYP administration were significantly reduced by AEECC (250 and 500 mg/kg). A significant increase in serum antioxidant system such as CAT and GPx was also observed in AEECC-treated rats. The AEECC (3 mg/ml) significantly reduced urinary bladder tone in the strips pre-contracted with carbachol in both control and CYP-treated rats. This relaxation was demolished by atropine, nifedipine, glibenclamide, and indomethacin but not with propranolol. The plant extract showed the presence of antioxidant and anti-inflammatory phytochemicals. These results suggest that Cuminum cyminum offers uroprotective activity and can ameliorate CYP-induced bladder toxicity by modulating antioxidant parameters, pro-inflammatory cytokine levels and bladder smooth muscle overactivity. The in silico binding interactions of antioxidant 2I3Y and anti-inflammatory protein 1TNF with various ligands from Cuminum cyminum seeds revealed potential bioactive compounds with promising antioxidant and anti-inflammatory properties, providing valuable insights for drug development and nutraceutical research.

Rectum and Bladder Toxicity in Postoperative Prostate Bed Irradiation: Dose-Volume Parameters Analysis.

Although prostate cancer treatment is increasingly effective, its toxicities pose a major concern. The aim of our study was to assess the rate of adverse events (AEs) and the prognostic value of dose-volume histogram (DVH) parameters for the occurrence of treatment toxicity in patients treated with post-prostatectomy prostate bed radiotherapy (RT). The AEs were scored according to the CTCAE v.5.0. The rectum and bladder were contoured according to the RTOG Guidelines. The DVH parameters were assessed using data exported from the ECLIPSE treatment-planning system. Genitourinary (GU) and gastrointestinal (GI) toxicity were analysed using consecutive dose thresholds for the percentage of an organ at risk (OAR) receiving a given dose and the QUANTEC dose constraints. A total of 213 patients were included in the final analysis. Acute grade 2 or higher (≥G2) GU AEs occurred in 18.7% and late in 21.3% of patients. Acute ≥G2 GI toxicity occurred in 11.7% and late ≥G2 in 11.2% of the patients. Five patients experienced grade 4 AEs. The most common adverse effects were diarrhoea, proctitis, cystitis, and dysuria. The most significant predictors of acute ≥G2 GI toxicity were rectum V47 and V46 (p < 0.001 and p < 0.001) and rectum wall V46 (p = 0.001), whereas the most significant predictors of late ≥G2 GI AEs were rectum wall V47 and V48 (p = 0.019 and p = 0.021). None of the bladder or bladder wall parameters was significantly associated with the risk of acute toxicity. The minimum doses to bladder wall (p = 0.004) and bladder (p = 0.005) were the most significant predictors of late ≥G2 GU toxicity. Postoperative radiotherapy is associated with a clinically relevant risk of AEs, which is associated with DVH parameters, and remains even in patients who fulfil commonly accepted dose constraints. Considering the lack of survival benefit of postoperative adjuvant RT, our results support delaying treatment through an early salvage approach to avoid or defer toxicity.

Real World Multi-Institutional Outcomes of Bladder Carbogen and Nicotinamide (BCON) in Muscle-Invasive Bladder Cancer (MIBC).

Bladder carbogen and nicotinamide (BCON), combined with radiotherapy, is a standard of care in the bladder-preserving treatment of muscle-invasive bladder cancer (MIBC). UK national guidelines recommend neoadjuvant chemotherapy (NAC) before bladder preservation. However, patients did not receive NAC in the definitive phase III BCON trial. This study assessed tolerability and real-world outcomes of BCON alone or with NAC (NAC-BCON). With institutional approval, demographics and clinical information were obtained for a retrospective cohort study of BCON patients (2017-2021) across 3 UK centers. Clinician-reported toxicity was assessed using RTOG grading during radiotherapy, 6 weeks and 12 months after. Cross-sectional imaging and cystoscopy determined local control, metastasis-free survival (MFS), and cancer-specific survival (CSS). Subgroup differences were compared using T and χ2 tests. Survival was analyzed by Kaplan-Meier, log-rank, and multivariate Cox proportional hazard regression. Statistical analysis was conducted using R version 4.2.1 (R Core Team (2022)). A total of 317 patients were treated with BCON; 75 (24%) received NAC-BCON. Median follow-up was 29 months (4-63m). Patient characteristics are shown in Table 1. NAC-BCON patients were younger (median 72 vs 78 years, p<0.05), with better PS (p<0.05) and ACE-27 (p<0.05), with no statistical difference in T-staging and histopathology. 298 (94%) completed BCON, whilst 59/75 (79%) completed ≥3 cycles of NAC. There was no significant increased grade 3 acute or late bowel or bladder toxicity with NAC. 3-month cystoscopy post radiotherapy demonstrated complete response in 282/317 (89%). 121 (38%) developed metastases, and 112 (35%) died of MIBC. 5-year BCON MFS was 62% and 49% for NAC-BCON (HR 0.69, 95% CI 0.98- 2.51, p = 0.064); 5-year BCON CSS was 55% and 52% for NAC-BCON (HR 0.83, 95% CI 0.79-1.83, p = 0.39). This remained after adjusting for clinical factors in a multivariate Cox model for both MFS (p = 0.22) and CSS (p = 0.37). Our real-world data compares favorably to published BCON 5-year relapse-free survival (41%) and OS (49%). NAC-BCON has no increased toxicity with comparable treatment completion rates to BCON alone. No significant improvement in survival outcomes was seen with NAC, possibly due to small numbers and patient selection in a non-randomized cohort. Further analysis is planned with additional center input.

Single Institute Experience with MRI-Guided Adaptive Brachytherapy for Locally Advanced Cervix Cancer: Long Term Outcomes and Toxicity Analysis

We report over 10 years' experience of MRI-guided adaptive brachytherapy (MRIGABT) in locally advanced cervix cancer (LACC). A total of 162 patients with LACC FIGO stage IB-IVB were treated at our institute between 2010 and 2020. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m², 5 cycles, 1 day per cycle, 45-50.4 Gy external beam radiotherapy (EBRT) in 1·8-2 Gy fractions, followed by MRIGABT. Target volume definition and dose reporting for MRIGABT was according to GEC-ESTRO recommendations. MRIGABT dose prescription was according to our institutional practice. Overall survival (OS) and disease-free survival (DFS) were the primary endpoints. Kaplan-Meier estimates were calculated for OS and DFS at 2, 5 and 10-years. Organ-specific late toxicity grade ≥3 (≥G3) (CTCAEv5.0) was reported, alongside rates of bowel fistula, stricture, and perforation. Using logistic regression, we explored the relationship between EQD2 D2cc bladder and ≥G3 genitourinary (GU) toxicity. We compared patient proportions developing ≥ G3 GU toxicity in those who received EQD2 ≥85 Gy versus <85 Gy. We examined the following predictors of ≥G3 gastrointestinal (GI) toxicity: EQD2 dose (≥65 Gy versus <65 Gy), pre-existing bowel conditions, nodal boost, and extended field EBRT. Median follow up was 4.7 years (IQR 3.3-7.1 years). Median EBRT dose was 50.4 Gy (IQR 50.4-50.4 Gy); 91% received chemotherapy. Median high-risk clinical target volume (HRCTV) was 23.6 cm3 (IQR 16.6-31.3 cm3). Median doses were as follows; D90 HRCTV 88.9 Gy EQD210 (IQR 84.1-91.3 Gy), median D2cc bladder 81.6 (IQR 76.9-85.7 Gy), rectum 62.2 (IQR 57.9-65.3 Gy), sigmoid 67.4 (IQR 60.8-71.1 Gy), and bowel 55 (IQR 49.9-63.2 Gy), (all EQD23). The 2, 5 and-10-year OS were 98%, 80% and 75%. The 2, 5 and 10-year DFS were 98%, 75% and 60%. Late toxicity ≥G3 was 9% GU, 6% GI and 3% vaginal. There was a significant relationship between EQD2 and ≥G3 GU toxicity (OR: 1.11, 95% CI: 1.01-1.25; P = 0.04). When comparing those who received EQD2≥ 85Gy versus <85Gy, higher doses were associated with a greater proportion of ≥G3 GU toxicity (13% vs 6%). No significant predictors of ≥ G3 GI toxicity were observed. We observed excellent LC and OS. A significant relationship was found between EQD2 >85 Gy and bladder toxicity, although ≥G3 toxicity was low. We did not identify predictors of bowel toxicity. New predictors of bowel toxicity are required. Mean EBRT dose, D1.0 cc rectum, sigmoid and bowel are being investigated further.

Multiple Sessions vs. Single Session Image-Based Intracavitary Brachytherapy for Locally Advanced Cervical Cancer: A Randomized Control Trial

The objectives of this study are: 1) To compare the acute toxicity caused in the treatment of locally advanced cervical cancer (LACC) treated with weekly multiple applications vs. a single application for image-guided intracavitary High Dose Rate (HDR) brachytherapy (BT) after External Beam Radiation Therapy (EBRT) 2) To compare the loco-regional control of cancer at six months in the two arms MATERIALS/METHODS: In a prospective study, 40 patients with biopsy-proven LACC with FIGO-2018 stage IIB-IIIC1 disease, underwent EBRT to the pelvis at a dose of 50.4 Gy/ 28 fractions over 5.5 weeks with weekly concurrent cisplatin. After completion of EBRT, they were randomized into two arms with 20 patients each. In the Control arm (Arm-A), BT sessions were given with weekly 3 applications whereas, in the experimental arm (Arm-B), all the sessions were given with a single application at 6-12 hours intervals with aim of the high-risk clinical target volume receiving >80 Gy EQD2 and 2 cm3 of the bladder and rectum/sigmoid receiving <85 Gy and <75 Gy, respectively. The OAR contouring was done on CT RESULTS: All 40 patients were treated as per protocol. The mean duration of treatment including EBRT and BT was 73.15 days [95% CI 68.63-77.66] in Arm A and 55.85 days [95% CI 52.11-59.58] in Arm B which was significant. After 6 months, 37 patients came for follow-up, all 19 patients in Arm A had Grade 1 or Grade 2 rectal toxicity. In Arm B as well all 18 patients had Grade 1 or Grade 2 rectal toxicity. Bladder toxicity was Grade 1 or Grade 2 in 18 patients and Grade 3 severity in 1 patient among Arm A. Among 18 patients of Arm B, bladder toxicity of Grade 1 or Grade 2 was seen in 16 patients, and 2 patients had grade 3 toxicity. 2 patients in Arm A and 3 in Arm B complained of Grade 1 urinary incontinence. Moreover, Abdominal pain at 6 months was of Grade 1 in around 6 patients in Arm A but 14 patients had abdominal pain in Arm B which was of Grade 1 in 8, 4 had grade 2 and 2 patients had grade 3 severity abdominal pain. In the monthly analysis of acute toxicity, none of the patients showed Grade 3 or 4 toxicity at the 1st, 2nd, or 3rd month of completion of treatment. When comparing local control in both arms at 6 months, 2 patients had treatment failure in the Experimental Arm compared to only 1 patient in the Control Arm CONCLUSION: Single Application Multiple Fraction Intracavitary Brachytherapy post concurrent CTRT is a safe option for the treatment of locally advanced cervical cancer. When compared to the weekly application arm, single-application ICRT showed a comparable acute toxicity profile and comparable local control rates as well. Some patients in Single Application Arm showed abdominal pain which needs to be investigated with further trials. The overall treatment time in the single application arm is significantly lower than the standard weekly application arm.

ARTIA-Bladder: Daily Online Adaptive Short-Course Radiation Therapy (RT) and Concurrent Chemotherapy for Muscle-Invasive Bladder Cancer (MIBC): A Prospective Trial of an Individualized Approach for Reducing Bowel and Bladder Toxicity

Concurrent chemo-radiotherapy is commonly prescribed for muscle-invasive bladder cancer (MIBC). Post hoc analysis of two large, randomized trials found that hypofractionation improves loco-regional control (LRC) vs. standard fractionation in this population. A challenge in traditional image-guided radiotherapy of the bladder is that daily changes in bladder position and size requires large margins to ensure target coverage. This makes it difficult to spare uninvolved bladder from high-dose treatment, increases the risk of bowel toxicity, and results in historical rates of acute G3+ toxicity exceeding 20-30%. Daily online adaptive RT (ART) may enable reduced, personalized margins that maintain target coverage while reducing dose to OARs. This prospective clinical trial will test whether: 1) participants undergoing ART for MIBC have a lower rate of acute G3+ GI/GU toxicity compared with the 31% historical control rate (Stage III BC2001 trial), and 2) 2-year LRC with ART will be non-inferior to historical controls (75%). This multi-national trial will enroll 165 adult subjects with stage cT2-T4aN0M0 urothelial MIBC. Subjects will have undergone an attempt at maximal transurethral resection of bladder tumor. Patients with clinically involved nodes or G2+ GI or G3+ GU symptoms/conditions at baseline are ineligible. Concurrent with chemotherapy, participants will receive (at the discretion of the investigator) either 55 Gy in 20 fx to whole-bladder or 46 Gy in 20 fx to whole-bladder plus simultaneous in-field boost of 55 Gy in 20 fx to tumor bed. A personalized ITV will be derived for each subject based on bladder expansion, as assessed on two CT simulations separated by 30 min. Daily ART will be attempted for all subjects. The primary endpoint is acute G3+ GI/GU toxicity. Secondary endpoints are LRC; quality of life (EORTC QLQ-BLM30, EPIC 26 bowel and urinary); global function (EQ-5D-5L ); 2-year disease-free, bladder intact event-free, and overall survival; 2-year bladder cancer-specific mortality; NTCP model of acute GI toxicity for hypofractionated bladder RT; workflow feasibility of ART; improved target coverage ± reduced dose to critical OARs vs. non-ART dosimetry; acute G3+ GI/GU toxicity rate in subjects with ≥75% of their treatments as ART; and acute G3+ GI/GU toxicity in the cohort treated with partial bladder boost. Exploratory translational and correlative endpoints will also be examined. This trial opened to enrollment on Feb 2, 2023; the study duration is expected to be 4-5 years. This prospective clinical trial will provide robust clinical data to inform healthcare providers' decisions on the use of daily online ART and hypofractionation as a bladder preservation strategy for this population.

Mucosal damage and γ-H2AX formation in the rat urinary bladder induced by aromatic amines with structures similar to o-toluidine and o-anisidine.

Although aromatic amines are widely used as raw materials for dyes, some, such as o-toluidine and o-anisidine, have shown concerning results regarding carcinogenicity in the urinary bladder. We have recently developed a short-term detection method for bladder carcinogens using immunohistochemistry for γ-H2AX, a DNA damage marker. Here, using this method, we evaluated aromatic amines with structures similar to o-toluidine and o-anisidine for bladder mucosal damage and potential carcinogenicity. In total, 17 aromatic amines were orally administered to male F344 rats for 28days, and histopathological examination and γ-H2AX immunostaining of the urinary bladder were performed. Histopathological analysis revealed that seven aromatic amines, including 4-chloro-o-toluidine (4-CT), o-aminoazotoluene, 2-aminobenzyl alcohol (ABA), o-acetotoluidine (o-AT), 3,3'-dimethoxybenzidine, 4-aminoazobenzene (AAB), and 4,4'-methylenedianiline (MDA), induced various bladder lesions, such as hemorrhage, necrosis, and urothelial hyperplasia. The morphological characteristics of mucosal damage induced by these substances were divided into two major types: those resembling o-toluidine and those resembling o-anisidine. Six of these aromatic amines, excluding MDA, also caused significant increases in γ-H2AX formation in the bladder urothelium. Interestingly, 4-CT did not cause mucosal damage or γ-H2AX formation at the lower dose applied in previous carcinogenicity studies. These results showed for the first time that o-AT and ABA, metabolites of o-toluidine, as well as AAB caused damage to the bladder mucosa and suggested that they may be bladder carcinogens. In addition, 4-CT, which was thought to be a noncarcinogen, was found to exhibit bladder toxicity upon exposure to high doses, indicating that this compound may contribute to bladder carcinogenesis.