Urinary Toxicity Research Articles

Urothelial toxicity of esketamine in the treatment of depression

RationaleKetamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis.ObjectivesThis study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity.MethodsWe included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25–0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate.ResultsThe participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001).ConclusionsThis study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.

Predictors of urinary toxicity with MRI-assisted radiosurgery for low-dose-rate prostate brachytherapy

PurposeMRI-assisted radiosurgery (MARS) is a modern technique for prostate brachytherapy that provides superior soft tissue contrast. The purpose of this analysis was to evaluate treatment planning factors associated with urinary toxicity, particularly damage to the membranous urethra (MUL) and external urethral sphincter (EUS), after MARS. Material and MethodsWe retrospectively reviewed 227 patients treated with MARS. Comparisons were made between several factors including preimplantation length of the MUL and EUS dosimetric characteristics after implantation with longitudinal changes in American Urological Association (AUA) urinary symptom score. ResultsRates of grade 3 urinary incontinence and obstructive urinary symptoms were 4% and 2%. A piecewise mixed univariate model revealed that MUL and V200, V150, V125, and D5 to the EUS were all associated with increased rates of urinary toxicity over time. On univariate logistic regression, MUL >14.2 mm (odds ratio [OR] 2.03 per cm3, 95% confidence interval [CI] 1.10–3.77, p = 0.025), V125 to the EUS (OR 3.21 cm3, 95% CI 1.18–8.71, p = 0.022), and use of the I-125 isotope (OR 3.45, 95% CI 1.55–7.70, p = 0.001) were associated with subacute urinary toxicity (i.e., that occurring at 4–8 months). Optimal dose-constraint limits to the EUS were determined to be V200 < 0.04 cm3 (p = 0.002), V150 < 0.12 cm3 (p = 0.041), V125 < 0.45 cm3 (p = 0.033), D30 < 160 Gy (p = 0.004), and D5 < 218 Gy (p = 0.016). ConclusionsMARS brachytherapy provides detailed anatomic information for treatment planning, implantation, and quality assurance. Overall rates of urinary toxicity are low; however, several dosimetric variables associated with the EUS were found to correlate with urinary toxicity.

Rectal and Urethro-Vesical Subregions for Toxicity Prediction After Prostate Cancer Radiation Therapy: Validation of Voxel-Based Models in an Independent Population

Recent voxel-based studies have shown that the dose to specific rectal and urethro-vesical subregions is predictive of toxicities after prostate cancer intensity modulated radiation therapy. The objective of this study was to validate the discriminatory power of these subregions with respect to the whole organs in a large independent population. The validation cohort consisted of 450 patients from the TROG03.04-RADAR trial treated with 3-dimensional conformal radiation therapy at 66 to 74 Gy. Previous voxel-based analyses identified an inferoanterior rectal subregion as predictive of rectal bleeding and 5 subregions in the urethra and the posterior and superior part of the bladder as predictive of urinary incontinence, dysuria, retention, and hematuria. In the validation cohort, these subregions were segmented in each patient's anatomy. Dose-volume histograms (DVHs) of the whole organs and the 6 subregions were compared bin-wise between patients with and without toxicities. The discriminatory power of DVHs for grade ≥2 toxicity endpoints was assessed using the area under the receiver operating characteristic curve (AUC). Subregion DVHs were significantly different between patients with and without toxicities for late rectal bleeding (V44-V74), acute urinary incontinence (V68-V72), late dysuria (V56-V68), and late retention (V14-V64). The dose to the rectal subregion and the whole rectum were equally predictive of rectal bleeding (V68; AUC = 0.61). The doses to 3 out of the 5 urethro-vesical subregions were found to be more predictive than the dose to the whole bladder: in the urethra for acute incontinence (V71 AUC = 0.69 vs V71 AUC = 0.66), in the posterior part of the bladder for late dysuria (V65 AUC = 0.66 vs V68 AUC = 0.59), and late retention (V39 AUC = 0.74 vs no significant AUC). Three subregions located in the urethra and the bladder were successfully validated as more predictive of urinary toxicity than the whole bladder for urinary incontinence, retention, and dysuria. Sparing the posterior part of the bladder in particular in treatment planning may reduce the risk of late urinary retention.

Stereotactic Body Radiation Therapy (SBRT) for Prostate Cancer in Men With a High Baseline International Prostate Symptom Score (IPSS ≥ 15).

Background: Patients with a high pretreatment IPSS may have higher rates of late urinary morbidity after radiation therapy for prostate cancer (1). Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation, which may be radiobiologically favorable to the conventional low-dose external beam fractions. The urinary toxicity associated with SBRT, however, remains unclear in patients with a high IPSS (1). We report our experience using SBRT for localized prostate cancer in patients with pretreatment IPSS ≥ 15.Methods: Localized prostate cancer patients with a pre-treatment IPSS ≥ 15 treated with SBRT at Georgetown University Hospital from 2009 to 2016 were included in this retrospective review of prospectively collected data. These patients were treated to 35–36.25 Gy in five fractions delivered via CyberKnife (Accuray Inc., Sunnyvale, CA). Urinary toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). Urinary quality of life was assessed using validated questionnaires (IPSS and EPIC-26).Results: 53 patients at a median age of 71 years (range 57–89 years) received SBRT with a minimum follow up of 3 years. The median prostate size was 37 cm3 (range 12–100 cm3) and 30.2% patients received ADT. The 3-years incidence rate of Grade 3 urinary toxicity was 7.5% with median time to toxicity of 2.9 years. There were no Grade 4 or 5 toxicities. A mean baseline IPSS score of 19.8 significantly decreased to 12.9 at 3 months post-SBRT (p = 0.002) and remained stable at 36 months (13.7). A mean baseline EPIC-26 obstructive/irritative score of 64.1 significantly improved to 80.2 at 3 months (p = 0.002). This improvement was maintained to 36 months. There was no significant change from the mean baseline EPIC-26 urinary incontinence score at any point during follow up.Conclusions: SBRT for clinically localized prostate cancer was well-tolerated in men with baseline IPSS ≥ 15 (1). Grade 3 toxicities occurred but resolved with time. Our data suggest that poor baseline urinary function does not worsen following SBRT and may even improve. High baseline IPSS score should not be considered a contraindication to SBRT.

Hyaluronic acid spacer in focal prostate reirradiation: A single centre experience

PurposeThe optimal management of locally recurrent prostate cancer after curative radiotherapy is still unknown. In this study, we evaluated the preliminary results of reirradiation using stereotactic body radiotherapy for locally recurrent prostate cancer after initial definitive local radiotherapy. Materials and methodsBetween April 2016 and February 2019, 11 patients with recurrent disease at the previously irradiated prostate were treated. Local recurrence was detected by radiological with or without functional imaging modalities including prostate multiparametric/pelvic MRI or positron-emission tomography–computerised tomography with (68Ga)-labelled prostate-specific membrane antigen performed after rising prostate specific antigen serum level during follow-up. All patients received stereotactic body radiotherapy to the recurrent nodule to a total dose of 30Gy in five fractions. Hyaluronic acid spacer was injected between prostate and rectum in seven patients to decrease the rectal dose. Acute toxicity was evaluated by using Common Terminology Criteria for Adverse Events version 4.0, and late toxicity was evaluated by using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. ResultsAt the diagnosis, the median age was 64 years, and the mean prostate specific antigen serum concentration was 17.7ng/mL. The median interval time between local recurrence and initial definitive radiotherapy was 63 months. Mean prostate specific antigen concentration nadir value during follow-up was 0.43ng/mL. With a median follow up of 19 months, three patients developed either local or distant relapse. One patient had grade 3 acute rectal toxicity, and one patient had grade 2 late urinary toxicity. We did not observe any acute or late toxicity due to hyaluronic acid spacer injection. ConclusionReirradiation after local recurrence following initial definitive radiotherapy together with hyaluronic acid spacer use seems to be effective and safe.

External Validation of a Predictive Model of Urethral Strictures for Prostate Patients Treated With HDR Brachytherapy Boost.

Purpose: For prostate cancer treatment, comparable or superior biochemical control was reported when using External-Beam-Radiotherapy (EBRT) with High-Dose-Rate-Brachytherapy (HDRB)-boost, compared to dose-escalation with EBRT alone. The conformal doses produced by HDRB could allow further beneficial prostate dose-escalation, but increase in dose is limited by normal tissue toxicity. Previous works showed correlation between urethral dose and incidence of urinary toxicity, but there is a lack of established guidelines on the dose constraints to this organ. This work aimed at fitting a Normal-Tissue-Complication-Probability model to urethral stricture data collected at one institution and validating it with an external cohort, looking at neo-adjuvant androgen deprivation as dose-modifying factor.Materials and Methods: Clinical and dosimetric data of 258 patients, with a toxicity rate of 12.8%, treated at a single institution with a variety of prescription doses, were collected to fit the Lyman–Kutcher–Burman (LKB) model using the maximum likelihood method. Due to the different fractionations, doses were converted into 2 Gy-equivalent doses (α/β = 5 Gy), and urethral stricture was used as an end-point. For validation, an external cohort of 187 patients treated as part of the TROG (Trans Tasman Radiation Oncology Group) 03.04 RADAR trial with a toxicity rate of 8.7%, was used. The goodness of fit was assessed using calibration plots. The effect of neo-adjuvant androgen deprivation (AD) was analyzed separating patients who had received it prior to treatment from those who did not receive it.Results: The obtained LKB parameters were TD50 = 116.7 Gy and m = 0.23; n was fixed to 0.3, based on numerical optimization of the likelihood. The calibration plot showed a good agreement between the observed toxicity and the probability predicted by the model, confirmed by bootstrapping. For the external validation, the calibration plot showed that the observed toxicity obtained with the RADAR patients was well-represented by the fitted LKB model parameters. When patients were stratified by the use of AD TD50 decreased when AD was not present.Conclusions: Lyman–Kutcher–Burman model parameters were fitted to the risk of urethral stricture and externally validated with an independent cohort, to provide guidance on urethral tolerance doses for patients treated with a HDRB boost. For patients that did not receive AD, model fitting provided a lower TD50 suggesting a protective effect on urethra toxicity.

Low-Dose-Rate Brachytherapy Combined With Ultrahypofractionated Radiation Therapy for Clinically Localized, Intermediate-Risk Prostate Cancer: Results From a Prospective Trial

To report early toxicity and tumor control outcomes of Pd-103 brachytherapy with ultrahypofractionated stereotactic radiation therapy (RT) for intermediate-risk prostate cancer. This prospective trial included 40 patients with intermediate-risk prostate cancer who underwent low-dose-rate (Pd-103) brachytherapy (prescription dose, 100 Gy), followed 1 month later with ultrahypofractionated stereotactic RT (25 Gy in 5 fractions) to the prostate and seminal vesicles. The primary endpoint was the rate of grade 2+ genitourinary toxicity at 12 months using Common Terminology Criteria for Adverse Events v 4.0. Secondary endpoints included patient-reported quality-of-life metrics (International Prostate Scoring System [IPSS], International Index of Erectile Function, and Expanded Prostate Cancer Index Composite-bowel). Biochemical failure was defined as prostate-specific antigen nadir +2 ng/mL. Posttreatment biopsies were performed at between 24 and 36 months; median follow-up was 36 months. The rate of grade 2 urinary toxicity at 12 months was 25% with no grade 3 urinary toxicity noted. Mean IPSS at baseline and 12 and 24 months was 5, 10, and 6.2, respectively. Mean change in IPSS from baseline at 12 months was +5.5 (interquartile range, 1-9.75) and +1.05 (interquartile range, -3 to 3.25) at 24 months. Grade 2 bowel toxicity was 5% at 12 months with no grade 3 bowel toxicity noted. Mean Expanded Prostate Cancer Index Composite-bowel domain scores at baseline and 12 months were 92.8 and 90.3, respectively. Of patients who were potent (International Index of Erectile Function ≥21) at baseline, 75% remained potent at 12 months. Of 40 patients, 28 underwent posttreatment prostate biopsy (PPB), which was negative (n = 20) or demonstrated severe treatment effect (n = 8). No patient had a positive PPB or developed biochemical failure during the follow-up period. One patient without a PPB developed osseous metastases at 18 months posttreatment in the absence of biochemical failure. Low-dose-rate brachytherapy in combination with ultrahypofractionated stereotactic RT was safe and effective for intermediate-risk prostate cancer in early results of this trial.

Dosimetric correlations with urinary quality of life in patients receiving post-prostatectomy radiation therapy

Acute urinary toxicity is well-documented in individuals receiving post-prostatectomy radiation. However, dosimetric correlations between bladder dose and acute urinary symptoms in the post-prostatectomy setting have not been well-studied. We examined the relationship between bladder dosimetry and acute changes in individual urinary symptoms among men receiving post-prostatectomy radiation therapy. Patient-reported urinary symptoms were prospectively collected for 90 consecutive prostate cancer patients receiving post-prostatectomy radiation using the validated quality of life instrument Prostate Cancer Symptom Indices. Data were collected prior to treatment and weekly during treatment. Individual symptom scores were examined and a change in severity of an individual symptom (from baseline) of ≥ 2 points was considered clinically significant. DVHs were generated for all the patients. Receiver operating characteristic curves were generated to evaluate the ability of different dose-volume metrics to identify patients who developed individual urinary symptoms during radiation treatment from those who did not. Logistic regression was used to examine the relationship between dose-volume parameters and worsening of individual urinary symptoms. Worsening of individual urinary symptoms during radiation treatment was reported by 7% (urinary flow) to 29% (urgency) of patients. The relative bladder volume receiving moderate doses of radiation was associated with urgency (AUC 0.67 for V30 Gy). Dose-volume parameters were not significantly associated with flow, frequency, nocturia, or dysuria. There is an acute worsening of urinary symptoms among men receiving modern post-prostatectomy radiation. Worsening of urgency is associated with bladder dosimetry while flow, frequency, nocturia, and dysuria are not. This data can be used during treatment planning to reduce acute urinary toxicity during post-prostatectomy radiation.

Implementation of image-guided brachytherapy as part of non-surgical treatment in inoperable endometrial cancer patients

ObjectiveThis study assessed outcomes of inoperable endometrial cancer (IEC) patients treated with definitive external beam radiation therapy (EBRT) followed by a 3D image-guided brachytherapy boost. MethodsAll consecutive patients treated with EBRT followed by 3D image-guided brachytherapy for IEC were retrospectively included. EBRT delivered a dose of 45Gy. Then, patients had an uterovaginal brachytherapy guided by 3D imaging. Clinical target volume (CTVBT) included the whole uterus and the initial disease extent. Gross tumour volume (GTVres) included the residual disease at time of brachytherapy. ResultsTwenty-seven patients were identified. Causes of inoperability were comorbidities (37%) or tumour loco regional extent (63%). Including EBRT and brachytherapy, the median D90 (minimal dose delivered to 90% of the volume) was 60.7 GyEQD2 (IQR = 56.4–64.2) for the CTVBT, and was 73.6 GyEQD2 (IQR = 64.1–83.7) for the GTVres. The median overall treatment time was 50 days (IQR = 46–54). The mean follow-up was 36.5 months (SD = 30.2). The cumulative incidence of local, pelvic and distant failures was 19% (n = 5), 7% (n = 2) and 26% (n = 7), respectively. Five-year overall survival was 63% (95% CI = 43–91). Late urinary and gastro intestinal toxicities ≥ grade 2 were reported in four (15%) and two patients (7%) respectively. No vaginal toxicity ≥ grade 2 was reported. ConclusionsEBRT followed by intracavitary brachytherapy seems to be an effective option for IEC. The implementation of 3D concepts at time of brachytherapy may contribute to high local control probability and low toxicity profile. Large scale retrospective or prospective data are needed to confirm these early data.

Preliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer

BackgroundCarbon-ion radiotherapy (CIRT) for prostate cancer was initiated at Kanagawa Cancer Center in 2015. The present study analyzed the preliminary clinical outcomes of CIRT for prostate cancer.MethodsThe clinical outcomes of 253 patients with prostate cancer who were treated with CIRT delivered using the spot scanning method between December 2015 and December 2017 were retrospectively analyzed. The irradiation dose was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. Biochemical relapse was defined using the Phoenix definition. Toxicities were assessed according to CTCAE version 4.0. Results: The median patient age was 70 (47–86) years. The median follow-up duration was 35.3 (4.1–52.9) months. According to the D’Amico classification system, 8, 88, and 157 patients were classified as having low, intermediate, and high risks, respectively. Androgen deprivation therapy was administered in 244 patients. The biochemical relapse-free rate in the low-, intermediate-, and high-risk groups at 3 years was 87.5, 88.0, and 97.5%, respectively (P = 0.036). Grade 2 acute urinary toxicity was observed in 12 (4.7%) patients. Grade 2 acute rectal toxicity was not observed. Grade 2 late urinary toxicity and grade 2 late rectal toxicity were observed in 17 (6.7%) and 3 patients (1.2%), respectively. Previous transurethral resection of the prostate was significantly associated with late grade 2 toxicity in univariate analysis. The predictive factor for late rectal toxicity was not detected.ConclusionThe present study demonstrated that CIRT using the spot scanning method for prostate cancer produces favorable outcomes.

Transitioning from conformal radiotherapy to intensity-modulated radiotherapy after radical prostatectomy: Clinical benefit, oncologic outcomes and incidence of gastrointestinal and urinary toxicities.

The purpose of this study was to review genitourinary (GU) and gastrointestinal (GI) toxicity associated with high-dose radiotherapy (RT) delivered with 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT) following radical prostatectomy (RP). RP is a therapeutic option for the management of prostate cancer (PrCa). When assessing postoperative RT techniques for PrCa, the published literature focuses on patients treated with 2-dimensional conventional methods without reflecting the implementation of 3D-CRT, IMRT, or VMAT. A total of 83 patients were included in this analysis; 30 patients received 3D-CRT, and 53 patients received IMRT/VMAT. Acute and late symptoms of the GU and lower GI tract were retrospectively graded according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer radiation toxicity grading systems. The relapse failure-free rate and overall survival were also evaluated. The rate of acute GU toxicity was 9.4% vs. 13.3% for the IMRT/VMAT and 3D-CRT groups (p = 0.583). The 5-year actuarial rates of late GI toxicity for IMRT/VMAT and 3D-CRT treatments were 1.9% and 6.7%, respectively. The rate of late GU toxicity for the IMRT/VMAT and 3D-CRT treatment groups was 7.5% and 16.6%, respectively (p = 0.199). We found no association between acute or late toxicity and the RT technique in univariate and multivariate analyses. Postprostatectomy IMRT/VMAT and 3D-CRT achieved similar morbidity and cancer control outcomes. The clinical benefit of highly conformal techniques in this setting is unclear although formal analysis is needed.

Impact of real-time, dose-escalated permanent seed implant brachytherapy in intermediate-risk prostate cancer.

To retrospectively evaluate biochemical control and toxicity in patients who underwent 125I seed brachytherapy (BT) for intermediate-risk prostate cancer (PCa). Between January 2004-December 2014, 395 patients with intermediate-risk PCa underwent 125I BT. Of these, 117 underwent preoperative planning (PP; 145 Gy) and 278 real-time intraoperative preplanning (IoP; 160 Gy). All patients were followed for ≥ 6 months (> 5 years in 48% of patients and > 7 years in 13%). Median follow-up was 59 months. Biochemical relapse-free survival (BRFS) rates at 5 and 8 years were, respectively, 91.7% and 82.1%. By treatment group, the corresponding BRFS rates were 93.5% and 90% for IoP and 89% and 76.8% for PP. The maximum dose to the urethra remained unchanged (217 Gy) despite the dose escalation (from 145 to 160 Gy), without any significant increase in treatment-related toxicity (p = 0.13). Overall toxicity outcomes in the series were excellent, with only 3 cases (0.76%) of grade 3 genitourinary toxicity. The real-time intraoperative planning technique at 160 Gy yields better biochemical controls than the preoperative planning technique at 145 Gy. Dose escalation did not increase urinary toxicity. The excellent results obtained with the IoP BT technique support its use as the first treatment option in this patient population.

Urinary Morbidity in Men Treated With Stereotactic Body Radiation Therapy (SBRT) for Localized Prostate Cancer Following Transurethral Resection of the Prostate (TURP).

Background: Clinical data suggest that stereotactic body radiation therapy (SBRT) provides similar clinical outcomes as other radiation modalities for prostate cancer. However, data reporting on the safety of SBRT after TURP is limited. Herein, we report our experience using SBRT to deliver hypofractionated radiotherapy in patients with a history of TURP including physician-reported toxicities and patient-reported quality of life.Methods: Forty-seven patients treated with SBRT from 2007 to 2016 at Georgetown University Hospital for localized prostate carcinoma with a history of prior TURP were included in this retrospective analysis. Treatment was delivered using the CyberKnife® (Accuray Incorporated, Sunnyvale, CA) with doses of 35 Gy or 36.25 Gy in 5 fractions without prostatic urethral sparing. Toxicities were recorded and scored using the CTCAE v.4. Cystoscopy findings were retrospectively reviewed. Urinary quality of life data was assessed using the International Prostate Symptom Scoring (IPSS) and Expanded Prostate Cancer Index Composite 26 (EPIC-26). A Wilcoxon signed-rank sum test was used to determine if there was a statistically significant increase or decrease in IPSS or EPIC scores between timepoints. Minimally important differences were calculated by obtaining half the standard deviation at time of start of treatment.Results: Forty-seven patients at a median age of 72 years (range 63–84) received SBRT. The mean follow-up was 4.7 years (range 2–10 years). Late Grade 2 and grade 3 urinary toxicity occurred in 23 (48.9%) and 3 (6.4%) men, respectively. There were no Grade 4 or 5 toxicities. Approximately 51% of patients experienced hematuria following treatment. Mean time to hematuria was 10.5 months. Twenty-five cystoscopies were performed during follow-up and the most common finding was hyperemia, varices of the bladder neck/TURP defect, and/or necrotic tissue in the TURP defect. Baseline urinary QOL composite scores were low, but they did not clinically significantly decline in the first 2 years following treatment.Conclusions: In patients with prior TURP, prostate SBRT was well-tolerated. GU toxicity rates were comparable to similar patients treated with conventionally fractionated radiation therapy. Urinary quality of life was poor at baseline, but did not worsen clinically over time. Stricter dosimetric criteria could potentially improve the rate of high-grade late toxicity, but may increase the risk of peri-urethral recurrence.

Оценка взаимодействия фактора роста нервов и тучных клеток при интерстициальном цистите/синдроме болезненного мочевого пузыря в эксперименте

to evaluate the level of nerve growth factor (NGF) in the blood and urine and mast cell infiltration of the bladder wall in a model of interstitial cystitis/bladder pain syndrome (IC/BPS) and to analyze their relationships. IC/BPS modeling was performed on 38 female rabbits, which were divided into 4 groups. In the group 1, IC/BPS was simulated by an instillation of 70% alcohol into the bladder, while in group 2 and 3 animals own urine and normal saline were injected into the bladder wall. The group 4 consisted of intact animals. The NGF level was determined by ELISA. To determine the concentration of mast cell in tissues, each cross-section was divided into 10 sections. The severity of mast cell infiltration was evaluated in each area using the following scale: 0 - no mast cells; 1 - less than 20 cells; 2 - 20-45 cells; 3 - more than 45 cells. The points of all 10 areas were added up, divided by 30 (the maximum possible score) and multiplied by 100. An increase in the NGF level in the blood and urine was seen in different models of IC/BPS, but it was significantly more pronounced in the group 2 (toxic model). Mast cells were determined only in the group 1 (0.25+/-0.707) and 2 (14,200+/-5,796). In animals with the urinary toxicity model, mast cell activity was significantly higher in comparison with those in the model with an instillation of 70% alcohol (p<0.001). The level of NGF in blood and urine correlated in different directions. Mast cell proliferation and activation was determined in case of impairment of the bladder wall integrity by the injection of urine. Our animal model of IC/BPS, which was created by instillation of 70% alcohol into the bladder and the injection of urine into the bladder wall, showed an increase in the level of NGF in urine and blood and the concentration of mast cells. These findings, as well as relationship between these values indicate the development of neuroimmune inflammation in this pathological condition. Considering the involvement of many factors in the pathogenesis of this syndrome, further researches are required.

Multi-atlas-based auto-segmentation for prostatic urethra using novel prediction of deformable image registration accuracy.

Accurate identification of the prostatic urethra and bladder can help determine dosing and evaluate urinary toxicity during intensity-modulated radiation therapy (IMRT) planning in patients with localized prostate cancer. However, it is challenging to locate the prostatic urethra in planning computed tomography (pCT). In the present study, we developed a multiatlas-based auto-segmentation method for prostatic urethra identification using deformable image registration accuracy prediction with machine learning (ML) and assessed its feasibility. We examined 120 patients with prostate cancer treated with IMRT. All patients underwent temporary urinary catheter placement for identification and contouring of the prostatic urethra in pCT images (ground truth). Our method comprises the following three steps: (a) select four atlas datasets from the atlas datasets using the deformable image registration (DIR) accuracy prediction model, (b) deform them by structure-based DIR, (3) and propagate urethra contour using displacement vector field calculated by the DIR. In (a), for identifying suitable datasets, we used the trained support vector machine regression (SVR) model and five feature descriptors (e.g., prostate volume) to increase DIR accuracy. This method was trained/validated using 100 patients and performance was evaluated within an independent test set of 20 patients. Fivefold cross-validation was used to optimize the hype parameters of the DIR accuracy prediction model. We assessed the accuracy of our method by comparing it with those of two others: Acostas method-based patient selection (previous study method, by Acosta et al.), and the Waterman's method (defines the prostatic urethra based on the center of the prostate, by Waterman et al.). We used the centerlines distance (CLD) between the ground truth and the predicted prostatic urethra as the evaluation index. The CLD in the entire prostatic urethra was 2.09±0.89mm (our proposed method), 2.77±0.99mm (Acosta et al., P=0.022), and 3.47±1.19mm (Waterman et al., P<0.001); our proposed method showed the highest accuracy. In segmented CLD, CLD in the top 1/3 segment was highly improved from that of Waterman et.al. and was slightly improved from that of Acosta et.al., with results of 2.49±1.78mm (our proposed method), 2.95±1.75mm (Acosta et al., P=0.42), and 5.76±3.09mm (Waterman et al., P<0.001). We developed a DIR accuracy prediction model-based multiatlas-based auto-segmentation method for prostatic urethra identification. Our method identified prostatic urethra with mean error of 2.09mm, likely due to combined effects of SVR model employment in patient selection, modified atlas dataset characteristics and DIR algorithm. Our method has potential utility in prostate cancer IMRT and can replace use of temporary indwelling urinary catheters.

Dosimetric predictors of patient-reported toxicity after prostate stereotactic body radiotherapy: Analysis of full range of the dose–volume histogram using ensemble machine learning

Background and purposeThis study aims to evaluate the associations between dosimetric parameters and patient-reported outcomes, and to identify latent dosimetric parameters that most correlate with acute and subacute patient-reported urinary and rectal toxicity after prostate stereotactic body radiotherapy (SBRT) using machine learning methods. Materials and methodsEighty-six patients who underwent prostate SBRT (40 Gy in 5 fractions) were included. Patient-reported health-related quality of life (HRQOL) outcomes were derived from bowel and bladder symptom scores on the Expanded Prostate Cancer Index Composite (EPIC-26) at 3 and 12 months post-SBRT. We utilized ensemble machine learning (ML) to interrogate the entire dose–volume histogram (DVH) to evaluate relationships between dose–volume parameters and HRQOL changes. The latent predictive dosimetric parameters that were most associated with HRQOL changes in urinary and rectal function were thus identified. An external cohort of 26 prostate SBRT patients was acquired to further test the predictive models. ResultsBladder dose–volume metrics strongly predicted patient-reported urinary irritative and incontinence symptoms (area under the curves [AUCs] of 0.79 and 0.87, respectively) at 12 months. Maximum bladder dose, bladder V102.5%, bladder volume, and conformity indices (V50/VPTV and V100/VPTV) were most predictive of HRQOL changes in both urinary domains. No strong rectal toxicity dosimetric association was identified (AUC = 0.64). ConclusionWe demonstrated the application of advanced ML methods to identify a set of dosimetric variables that most highly correlated with patient-reported urinary HRQOL. DVH quantities identified with these methods may be used to achieve outcome-driven planning objectives to further reduce patient-reported toxicity with prostate SBRT.

Two-year outcomes of moderately hypofractionated 70 Gy in 28 fractions, intensity-modulated radiotherapy and volumetric modulated arc therapy for localised prostate cancer

AbstractIntroduction:Standard external beam radiotherapy is a treatment option for patients with localised prostate cancer and is used in patients with low-, intermediate- and high-risk disease with androgen deprivation according to the risk of the disease. In the last few years, hypofractionated radiotherapy has been demonstrated to be as safe as standard radiotherapy if given over a shorter time than standard radiotherapy with larger doses per fraction. External radiotherapy for localised prostate cancer typically delivers 37–42 fractions of 1·8–2·0 Gy per fraction given 5 days per week over 7·5–8·5 weeks. Hypofractionated radiotherapy delivers 20–28 fractions of 2·5–2·6 Gy per fraction given 5 days per week over 4–5·6 weeks.Methods:A retrospective analysis of assessment of 30 patients was undertaken from 2016 to 2018. The aim of this study was to evaluate the 2-year outcomes of 30 patients with prostate cancer treated with hypofractionated radiotherapy 70 Gy in 28 fractions.Results:Biochemical failure with hypofractionated radiotherapy was found in a total of 20% of patients. In the classification by risk groups, there were no biochemical failures in low-risk patients; in the low intermediate course, 3·3% of patients; in the high intermediate group, 3·3% patients; and in the high-risk group, the largest documented biochemical failure was in 13·3% of patients. For acute urinary toxicity, grade I was 56·6%; grade II, 6·6%. For acute rectal toxicity, grade I was 46·6%; grade II, 3·3%.Conclusion:This is one of the first studies of hypofractionated radiotherapy in prostate cancer in Latin America, and the results of this study demonstrated that the outcomes were similar to the standard regimen in all risk groups.

Local dose analysis to predict acute and late urinary toxicities after prostate cancer radiotherapy: Assessment of cohort and method effects

PurposeTo perform bladder dose-surface map (DSM) analysis for (1) identifying symptom-related sub-surfaces (Ssurf) and evaluating their prediction capability of urinary toxicity, (2) comparing DSM with dose-volume map (DVM) (method effect), and (3) assessing the reproducibility of DSM (cohort effect). Methods and materialsUrinary toxicities were prospectively analyzed for 254 prostate cancer patients treated with IMRT/IGRT at 78/80 Gy. DSMs were generated by unfolding bladder surfaces in a 2D plane. Pixel-by-pixel analysis was performed to identify symptom-related Ssurf. Likewise, voxel-by-voxel DVM analysis was performed to identify sub-volumes (Svol). The prediction capability of Ssurf and Svol DVHs was assessed by logistic/Cox regression using the area under the ROC curve (AUC). The Ssurf localization and prediction capability were compared to (1) the Svol obtained by DVM analysis in the same cohort and (2) the Ssurf obtained from other DSM studies. ResultsThree Ssurf were identified in the bladder: posterior for acute retention (AUC = 0.64), posterior–superior for late retention (AUC = 0.68), and inferior–anterior–lateral for late dysuria (AUC = 0.73). Five Svol were identified: one in the urethra for acute incontinence and four in the posterior bladder part for acute and late retention, late dysuria, and hematuria. The overlap between Ssurf and Svol was moderate for acute retention, good for late retention, and bad for late dysuria, and AUCs ranged from 0.62 to 0.81. The prediction capabilities of Ssurf and Svol models were not significantly different. Among five symptoms comparable between cohorts, common Ssurf was found only for late dysuria, with a good spatial agreement. ConclusionSpatial agreement between methods is relatively good although DVM identified more sub-regions. Reproducibility of identified Ssurf between cohorts is low.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

Combined Long-Term Androgen Deprivation and Pelvic Radiotherapy in the Post-operative Management of Pathologically Defined High-Risk Prostate Cancer Patients: Results of the Prospective Phase II McGill 0913 Study.

Purpose: Following radical prostatectomy, prostate bed radiotherapy (PBRT) has been combined with either long-term androgen deprivation therapy (LT-ADT) or short-term ADT with pelvic lymph node radiotherapy (PLNRT) to provide an oncological benefit in randomized trials. McGill 0913 was designed to characterize the efficacy of combining PBRT, PLNRT, and LT-ADT. It is the first study to do so prospectively.Methods: In a single arm phase II trial conduced from 2010 to 2016, 46 post-prostatectomy prostate cancer patients at a high-risk for relapse (pathological Gleason 8+ or T3) were assessed for treatment with combined LT-ADT (24 months), PBRT, and PLNRT. Patients received PLNRT and PBRT (44 Gy in 22 fractions) followed by a PBRT boost (22 Gy in 11 fractions). The primary endpoint was progression-free survival (PFS). Toxicity and quality of life (QoL) were evaluated using CTCAE V3.0 and EQ-5D-3L questionnaires, respectively.Results: Among the 43 patients were treated as per protocol, median PSA was 0.30 μg/L. On surgical pathology, 51% had positive margins, 40% had Gleason 8+ disease, 42% had seminal vesicle involvement, and 19% had lymph node involvement. At a median follow-up of 5.2 years, there were no deaths or clinical progression. At 5 years, PFS was 78.0% (95% Confidence Interval 63.7–95.5%). Not including erectile dysfunction, patients experienced: 14% grade 2 endocrine toxicity while on ADT, one incident of long-term gynecomastia, 5% grade 2 acute urinary toxicity, 5% grade 2 late Urinary toxicity, and 24% long-term hypogonadism. No comparison between the average or minimum self-reported QoL at baseline, during ADT, nor after ADT demonstrated a statistically significant difference.Conclusions: Combining PBRT, PLNRT, and LT-ADT had an acceptable PFS in patients with significant post-operative risk factors for recurrence. While therapy was well-tolerated, long-term hypogonadism was a substantial risk. Further investigations are needed to determine if this combination is beneficial.Trial registration: NCT01255891.