Optical Surface Management System and BladderScan for Patient Setup During Radiotherapy of Postoperative Prostate Cancer.

Background: The precision of postoperative prostate cancer radiotherapy is significantly influenced by setup errors and alterations in bladder morphology. Utilizing daily cone beam computed tomography (CBCT) imaging allows for the correction of setup errors. However, this naturally leads to the question of the issue of peripheral dose and workload. Thus, a zero-dose, noninvasive technique to reproduce the bladder volume and improve patient setup accuracy was needed. Purpose: The aim of this study is to investigate if the setup method by combining Optical Surface Management System (OSMS) and BladderScan can improve the accuracy of setup and accurately reproduce the bladder volume during radiotherapy of postoperative prostate cancer and to guide CTV-PTV margins for clinic. Method: The experimental group consisted of 15 postoperative prostate cancer patients who utilized a setup method that combined OSMS and BladderScan. This group recorded 103 setup errors, verified by CBCT. The control group comprised 25 patients, among whom 114 setup errors were recorded using the conventional setup method involving skin markers; additionally, patients in this group also exhibited spontaneous urinary suppression. The errors including lateral (Lat), longitudinal (Lng), vertical directions (Vrt), Pitch, Yaw, and Roll were analyzed between the two methods. The Dice similarity coefficient (DSC) and volume differences of the bladder between CBCT and planning CT were compared as the bladder concordance indicators. Results: The errors in the experimental group at Vrt, Lat, and Lng were 0.17 ± 0.12, 0.22 ± 0.17, and 0.18 ± 0.12 cm, and the control group were 0.25 ± 0.15, 0.31 ± 0.21, 0.34 ± 0.22 cm. The rotation errors of Pitch, Roll, and Yaw in the experimental group were 0.18 ± 0.12°, 0.11 ± 0.1°, and 0.18 ± 0.13°, and in the control group, they were 0.96 ± 0.89°, 1.01 ± 0.86°, and 1.02 ± 0.84°. The DSC and volume differences were 92.52 ± 1.65% and 39.99 ± 28.75 cm3 in the patients with BladderScan, and in the control group, they were 62.98 ± 22.33%, 273.89 ± 190.62 cm3. The P < 0.01 of the above performance indicators indicates that the difference is statistically significant. Conclusion: The accuracy of the setup method by combining OSMS and BladderScan was validated by CBCT in our study. The method in our study can improve the setup accuracy during radiotherapy of postoperative prostate cancer compared to the conventional setup method.

Exploring the protective effect and mechanism of icariside II on the bladder in a rat model of radiation cystitis based on transcriptome sequencing.

PURPOSE: Radiation cystitis (RC) is a complex and common complication after radiotherapy for pelvic cancer. Icariside II (ICAII) is a flavonoid compound extracted from Epimedium, a traditional Chinese medicine, with various pharmacological activities. The aim of the present study was to investigate the cysto-protective effects of ICAII in RC rats and its possible mechanisms. MATERIALS AND METHODS: A rat model of induced radiation cystitis using pelvic X-ray irradiation was used, and bladder function was assessed by bladder volume and bladder leakage point pressure (LPP) after ICAII treatment. HE and Masson stains were used to assess the histopathological changes in the bladder. IL-6, TNF-α, IL-10, IL-4 and IL-1ß were measured by ELISA to assess the level of inflammation. The gene-level changes in ICAII-treated RC were observed by transcriptome sequencing, and then the potential targets of action and biological mechanisms were explored by PPI, GO and KEGG enrichment analysis of the differentially expressed genes. Finally, the predicted targets of action were experimentally validated using immunohistochemistry, RT-qPCR, molecular docking and CETSA. RESULTS: ICAII significantly increased bladder volume and the LPP, ameliorated pathological damage to bladder tissues, decreased the levels of IL-6, TNF-α, and IL-1ß, and increased the levels of IL-10 and IL-4 in radiation-injured rats. A total of 90 differentially expressed genes were obtained by transcriptome sequencing, and PPI analysis identified H3F3C, ISG15, SPP1, and LCN2 as possible potential targets of action. GO and KEGG analyses revealed that these differentially expressed genes were mainly enriched in the pathways metabolism of xenobiotics by cytochrome P450, arachidonic acid metabolism, Staphylococcus aureus infection and chemical carcinogenesis - reactive oxygen species. Experimental validation showed that ICAII could significantly increase the expression of H3F3C and ISG15 and inhibit the expression of SPP1 and LCN2. ICAII binds well to H3F3C, ISG15, SPP1 and LCN2, with the best binding ability to H3F3C. Furthermore, ICAII inhibited the protein degradation of H3F3C in bladder epithelial cells. CONCLUSIONS: ICAII may alleviate the bladder inflammatory response and inhibit the fibrosis process of bladder tissues through the regulation of H3F3C, ISG15, SPP1, and LCN2 targets and has a protective effect on the bladder of radioinjured rats. In particular, H3F3C may be one of the most promising therapeutic targets.

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.

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.

Background: 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. Materials and Method: 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). Results: 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. Conclusions: 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.

Automatic segmentation of high-risk clinical target volume and organs at risk in brachytherapy of cervical cancer with a convolutional neural network.

PURPOSE: This study aimed to design an autodelineation model based on convolutional neural networks for generating high-risk clinical target volumes and organs at risk in image-guided adaptive brachytherapy for cervical cancer. MATERIALS AND METHODS: A novel SERes-u-net was trained and tested using CT scans from 98 patients with locally advanced cervical cancer who underwent image-guided adaptive brachytherapy. The Dice similarity coefficient, 95th percentile Hausdorff distance, and clinical assessment were used for evaluation. RESULTS: The mean Dice similarity coefficients of our model were 80.8%, 91.9%, 85.2%, 60.4%, and 82.8% for the high-risk clinical target volumes, bladder, rectum, sigmoid, and bowel loops, respectively. The corresponding 95th percentile Hausdorff distances were 5.23mm, 4.75mm, 4.06mm, 30.0mm, and 20.5mm. The evaluation results revealed that 99.3% of the convolutional neural networks-generated high-risk clinical target volumes slices were acceptable for oncologist A and 100% for oncologist B. Most segmentations of the organs at risk were clinically acceptable, except for the 25% sigmoid, which required significant revision in the opinion of oncologist A. There was a significant difference in the clinical evaluation of convolutional neural networks-generated high-risk clinical target volumes between the two oncologists (P<0.001), whereas the score differences of the organs at risk were not significant between the two oncologists. In the consistency evaluation, a large discrepancy was observed between senior and junior clinicians. About 40% of SERes-u-net-generated contours were thought to be better by junior clinicians. CONCLUSION: The high-risk clinical target volumes and organs at risk of cervical cancer generated by the proposed convolutional neural networks model can be used clinically, potentially improving segmentation consistency and efficiency of contouring in image-guided adaptive brachytherapy workflow.

Adaptive radiotherapy for muscle invasive bladder cancer: a retrospective audit of two bladder filling protocols.

BACKGROUND: Radical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment. METHODS: Forty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols. RESULTS: Mean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p < 0.05). Significant differences in bladder volumes were observed between the planning CT and pre-treatment CBCTs for BF (p < 0.05) but not for BE (p = 0.11). Both protocols saw a significant decrease in bladder volume between first and final treatment fractions (p < 0.05). Medium plans were preferentially selected for BE whilst when using the BF protocol the small plan was chosen most frequently. With no significant change to PTV coverage between the protocols, the volume of body receiving 25.0-45.8 Gy was found to be significantly smaller for BE patients (p < 0.05). CONCLUSIONS: This work provides evidence in favour of a BE protocol compared to a BF protocol for radical radiotherapy for MIBC. The smaller treatment volumes observed in the BE protocol led to reduced OAR and total body doses and were also observed to be more consistent throughout the treatment course. These results highlight improvements in dosimetry for patients who undergo a BE protocol for MIBC.

Effect of photobiomodulation on lower urinary tract dysfunction in rat cystitis model.

OBJECTIVE: Photobiomodulation selectively controls the activity of the sensory nervous system associated with A-delta and C fibers. Hypersensitivity involving the afferent A-delta and C fibers occurs in cystitis and decreases urinary function. This study aimed to investigate the effect of photobiomodulation on urinary storage dysfunction and voiding functions in cystitis model rats. METHODS: We prepared the rat cystitis model. Under anesthesia, a cannula was connected to the bladder via a ventral incision. 0.3% acetic acid or saline was injected into the bladder. Continuous cystometry was performed, measuring bladder pressure and voiding urine volume with rats freely mobile. Laser irradiation was applied to the L6 lumbosacral intervertebral foramen using an 830 nm laser. Residual urine was extracted post-cystometry. RESULTS: In the rat cystitis model groups, there was a significant decrease in the voiding interval and volume compared to the group receiving normal saline infusion. After sham or laser irradiation, only the group with laser irradiation showed a significant increase in voiding interval (217%, p = 0.0002) and voiding volume (192%, p = 0.0012) in the parameters of storage dysfunction. The basal pressure, intravesical pressure, and residual urine volume remained unchanged in all groups before and after irradiation. CONCLUSIONS: This study indicates that photobiomodulation may improve urine storage dysfunction without exacerbating voiding function in a rat model of cystitis. Thus, photobiomodulation may be a new treatment option for the hypersensitivity and detrusor overactivity caused by cystitis.

Role of the gel spacer in safely delivering whole pelvic radiation therapy without central shielding in computed tomography-based image-guided adaptive brachytherapy for uterine cervical cancer patients.

BACKGROUND: To protect the rectum and bladder from high dose exposure, the Japanese guidelines for managing uterine cervical carcinoma recommend pelvic irradiation with central shielding (CS). Conversely, the European Society for Radiotherapy and Oncology (ESTRO) and the American Brachytherapy Society (ABS) guidelines recommend delivering ≥85 Gy to high-risk clinical target volume D90 (CTVHR D90%). In this study, we investigated whether a gel spacer can enable the safe delivery of the ESTRO/ABS-recommended doses to the target while observing dose constraints for the OARs without using CS in external beam radiation therapy (EBRT). MATERIALS AND METHODS: Twenty patients who received definitive radiation therapy without CS and were treated by brachytherapy with a gel spacer between 2017 and 2022 were retrospectively reviewed. The cumulative doses of EBRT and brachytherapy treatment outcomes and incidence of adverse events were also examined. RESULTS: The median cumulative CTVHR D90%, rectum D2cm3, and bladder D2cm3 were 86.6 Gy, 62.9 Gy, and 72.0 Gy, respectively. The 2-year local control rate was 95%. There were no CTCAE ≥Grade 3 late gastrointestinal or genitourinary adverse events. CONCLUSIONS: The use of gel spacer can enable ESTRO/ABS-recommended dose constraints even without using CS in EBRT, with favorable outcomes and low adverse event rates.

Bladder trigone sparing radiotherapy in prostate cancer treatment.

INTRODUCTION: Evidence suggests the bladder trigone to be a potential organ at risk (OAR) in predicting acute and late genitourinary (GU) side effects when treating prostate cancer with radiotherapy. METHODS: A search of MEDLINE, Cinahl, EMBASE, PubMed, the Cochrane Database of Systematic Reviews and OpenGrey was conducted and no current or underway systematic reviews or scoping reviews on the topic were identified. A systematic literature review was carried out assessing the quality of this evidence. All evidence that prospectively or retrospectively reviewed radiotherapy or modelled radiotherapy dose to the bladder trigone were included. The search was conducted on the 8th July 2021 with 32 studies included in this review. This was repeated 10th June 2023 and two additional studies were identified. Any evidence published since this date have not been included and are a limitation of this review. RESULTS: MRI imaging is recommended to assist in delineating the trigone which has been shown to have a high amount of inter-observer variability and the use of specific training may reduce this. Across all radiotherapy treatment modalities, trigone dose contributed to GU acute and late toxicity symptoms. Trigone motion is relative to prostate motion but further research is required to confirm if the prostate can be used as a reliable surrogate for trigone position. The dose tolerance given for specific trigone related toxicities is debated within the literature, and on analysis the authors of this review suggest bladder trigone dose limits: Dmean < 45.8 Gy, V61.0Gy < 40%, V59.8Gy < 25%, V42.5Gy-V41.0Gy < 91% and V47.4Gy-V43.2Gy < 91% with α/ß of 3 Gy to reduce acute and late GU toxicities. CONCLUSION: There is evidence to support further research into bladder trigone sparing radiotherapy to improve patient outcomes. IMPLICATION FOR PRACTICE: Using the bladder trigone as an organ at risk is possible and the authors are currently seeking funding for a feasibility trial to further investigate this.

Cone beam CT doses in radiotherapy patient positioning in Finland-prostate treatments.

Imaging parameters, frequencies and resulting patient organ doses in treatments of prostate cancer were assessed in Finnish radiotherapy centres. Based on a questionnaire to the clinics, Monte Carlo method was used to estimate organ doses in International Commission on Radiological Protection standard phantom for prostate, bladder, rectum and femoral head. The results show that doses from cone beam computed tomography imaging have reduced compared to earlier studies and are between 3.6 and 34.5 mGy per image for the above-mentioned organs and for normal sized patients. There still is room for further optimization of the patient exposure, as many centres use the default imaging parameters, and the length of the imaged region may not be optimal for the purpose.

Radiation exposure in pediatric videourodynamics: An evaluation of safety in comparison to voiding cystourethrogram.

INTRODUCTION: Children with spina bifida (SB) undergo a videourodynamic study (VUDS) or urodynamic study and voiding cystourethrogram (VCUG). A standardized protocol for imaging during a pediatric VUDS has not been established. Our aim is to quantify radiation exposure and establish a baseline for children with spina bifida (SB) undergoing VUDS in current practice at our institution. METHODS: This is a retrospective study from 2013 to 2020 of consecutive pediatric SB patients undergoing VUDS by a single provider. Patients were categorized into three groups based on age; group 1 (0-2 YR), group 2 (2-10 YR), group 3 (>10 YR). Radiation data was reported as mean air kerma (AK), dose area product (DAP) and exposure time (seconds). Effective dose (ED) was calculated based on radiation quantity (Air Kerma, AK) and organ sensitivity. The lifetime attributable risk (LAR) was calculated based on AK and a risk coefficient. Data points calculated for patients undergoing VUDS were then compared to age matched institutional VCUG data in the same age groups. RESULTS: 398 patients undergoing VUDS met inclusion criteria and 262 independent patients underwent VCUG. ED increased with age in both VUDS and VCUG. All VCUG groups were found to have a higher ED than VUDS. The LAR for VUDS groups 1-3 was 0.001, 0.002, and 0.006, respectively. Reported in percentages, there is a 0.1%, 0.2%, and 0.6% chance, respectively, of age groups 1, 2 and 3 developing cancer as a result of the radiation exposure from a VUDS. DISCUSSION: Our study found that ED was low across all age groups for VUDS, comparing favorably to the VCUG groups. VCUG was selected as a benchmark comparison for its diagnostic similarities and, at times, overlapping indications. Few studies have described ED with respect to VUDS or extrapolate the ED of VUDS into LAR in the pediatric population. We recognize that we have not determined the true ED of the gonads and bladder, rather we have overestimated, as the data is based on an international reference point proximal to the exposed individual. However, LAR was calculated for each age group and revealed that patients are at a negligible increased risk of developing malignancy secondary to exposure compared to the general population. CONCLUSION: Our current practice for pediatric VUDS has exhibited consistently low radiation exposure amongst all age groups. Moving forward, we have the foundation and flexibility to create an imaging protocol for pediatric VUDS, while taking more calculated steps toward incorporating ALARA, as low as reasonably achievable, principles. A protocol adhering to the ALARA principle could provide consistency across institutions and aid in multi-institutional studies.

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.

Treatment of chronic post-radiation cystitis with trans-urethral amniotic bladder therapy appears durable at 9 months: A clinical study.

PURPOSE: Chronic radiation cystitis (CRC) develops after radiation therapy and can present with symptoms like urinary frequency, urgency, pelvic pain, and nocturia. We have previously reported that amniotic bladder therapy (ABT) provides symptomatic improvement in refractory CRC patients for up to 3 months. Herein, we evaluated the durability of ABT up to 6 months. MATERIALS AND METHODS: CRC patients recalcitrant to previous treatments received ABT comprised of intra-detrusor injections of 100 mg micronized AM diluted in 10 mL 0.9% preservative-free sodium chloride. Clinical evaluation and questionnaires (Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS), Overactive Bladder (OAB) Assessment Tool, SF-12 Health Survey) were repeated at pre-op and 2, 4, 8, 12, 16, 20, 24, and 36 weeks post-injection. RESULTS: Five consecutive patients with a mean age of 64.4 ± 20.1 years with a median CRC duration of 10 years were included and followed for 6 months. After ABT, the lower urinary tract symptoms improved as early as 2 weeks and were maintained up to 20 weeks. BPIC significantly improved from 36.6 ± 1.1 at baseline to 12.6 ± 1.5 at 16 weeks and 13.8 ± 2.9 at 20 weeks. At 24 and 36 weeks, the improvement was maintained in four (80%) of the five patients (BPIC = 13.8 ± 1.0). Uroflow assessment showed voiding volume improved two-fold in four of the five patients at 24 weeks compared to baseline. CONCLUSION: Our data suggest that a significant number of CRC patients may have durable benefit after ABT. Despite this, some of them can show symptoms rebound at 24 weeks.

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.

Late Urinary Toxicity and Quality of Life With Pelvic Radiation Therapy for High-Risk Prostate Cancer: Dose-Effect Relations in the POP-RT Randomized Phase 3 Trial.

PURPOSE: The POP-RT phase 3 randomized trial showed improved biochemical failure-free survival and metastasis-free survival with whole pelvic radiation therapy versus prostate-only radiation therapy for high and very high-risk prostate cancer, albeit with worse RTOG late urinary toxicity. We report updated late urinary adverse effects and bladder dose-effect relations within this trial. METHODS AND MATERIALS: Late urinary toxicity and the cumulative severity of each symptom during the follow-up period were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Bladder dosimetry in 5-Gy increments (V5, V10, V15, V65, V68Gy) in the approved radiation therapy plans was compared with urinary symptoms and overall grade 2+ toxicity. Potential factors influencing urinary toxicity were tested using multivariable logistic regression analysis. Updated urinary quality of life (QOL) scores were compared between the trial arms. RESULTS: Complete combined data for late urinary symptoms and dosimetry was available for 193 of 224 patients. At a median follow-up of 75 months, cumulative late urinary CTCAE grade 3 toxicity was low and similar for whole pelvic radiation therapy and prostate-only radiation therapy (5.2% vs 4.1%, P = .49), and grade 2 toxicity was 31.3% versus 22.7%, respectively (P = .12). Cumulative rates of each urinary symptom were similar between both arms. Multivariable analysis with age at diagnosis, known diabetes, tumor stage, trial arm, prior transurethral resection of prostate, grade 2+ acute urinary toxicity, low bladder dose (V10Gy), and moderate bladder dose (V40Gy) did not identify any significant association with late urinary toxicity. Urinary QOL scores was similar between both the arms for all the symptoms. CONCLUSIONS: During long-term follow-up, whole pelvic radiation therapy resulted in low (∼5%) and similar grade 3 cumulative urinary toxicity as prostate-only radiation therapy. The long-term patient-reported QOL scores were similar. No causative factors affecting the late urinary toxicity were identified.

Understanding Relative Biological Effectiveness and Clinical Outcome of Prostate Cancer Therapy Using Particle Irradiation: Analysis of Tumor Control Probability With the Modified Microdosimetric Kinetic Model.

PURPOSE: Recent experimental studies and clinical trial results might indicate that-at least for some indications-continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy. METHODS AND MATERIALS: Treatment plans of 91 patients with prostate tumors (proton: 46, carbon ions: 45) applying 66 GyRBE [RBE = 1.1 for protons and LEM-I, (α/ß)x = 2.0 Gy, for carbon ions] in 20 fractions were recalculated using mMKM [(α/ß)x = 3.1 Gy]). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of androgen deprivation therapy, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared with the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans. RESULTS: mMKM predictions suggested significant biological dose deviation between the proton and carbon ion arms. Patients irradiated with protons received (3.25 ± 0.08) GyRBEmMKM/Fx, whereas patients treated with carbon ions received(2.51 ± 0.05) GyRBEmMKM/Fx. TCP predictions were (86 ± 3)% for protons and (52 ± 4)% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and improved rectum and bladder sparing compared with proton. CONCLUSIONS: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy, and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer.

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.

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.

Pattern of Expression of MicroRNA in Patients with Radiation-Induced Bladder Injury.

INTRODUCTION: Bladder cancer (BC) is sensitive to radiation treatment and a subset of patients experience radiation-induced injuries including shrinkage of bladder due to bladder fibrosis. METHODS: This study is a retrospective cohort study. Three Japanese BC patients were randomly selected. Using a microRNA (miRNA) array, comparing their samples with or without radiation-induced injuries, we have checked the clustering of miRNA expression. RESULTS: Hsa-miR-130a, hsa-miR-200c, hsa-miR-141, and hsa-miR-96 were found to be highly expressed (>50 times) in patients with fibrotic bladder shrinkage (FBS) compared to those with intact bladder (IB) function. In patients with FBS, hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 were detected to have lesser than half expression to IB patients. We have analyzed the significance of these genes in relation to overall survival of 409 BC patients retrieved from the Cancer Genome Atlas data set. All available cutoff values between the lower and upper quartiles of expression are used for the selected genes, and false discovery rate using the Benjamini-Hochberg method is computed to correct for multiple hypothesis testing. We have run combined survival analysis of the mean expression of these four miRNAs highly expressed in FBS patients. 175 patients with high expression had a longer median survival of 98.47 months than 23.73 months in 233 patients with low expression (hazard ratio [HR]: 0.53; 0.39-0.72, log-rank p value: 7.3e-0.5). Combination analysis of all 8 genes including hsa-miR-6835, hsa-miR-4675, hsa-miR-371a, and hsa-miR-6885 showed the same HR for OS. Target scanning for these miRNAs matched specific cytokines known as an early biomarker to develop radiation-induced fibrosis. CONCLUSIONS: BC patients with fibrotic radiation injury have specific miRNA expression profile targeting profibrotic cytokines and these miRNAs possibly render to favorable survival.

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.