Genitourinary Toxicity Research Articles

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy

NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

ONE SHOT - single shot radiotherapy for localized prostate cancer: 18-month results of a single arm, multicenter phase I/II trial

PurposeTo assess in a prospective, multicenter, single-arm phase I/II study the early safety and efficacy profile of single fraction urethra-sparing stereotactic body radiotherapy (SBRT) for men with localized prostate cancer. Material and methodsPatients with low- and intermediate-risk localized prostate cancer without significant tumor in the transitional zone were recruited. A single-fraction of 19 Gy was delivered to the prostate, with 17 Gy dose-reduction to the urethra. Intrafraction motion was monitored using intraprostatic electromagnetic transponders with intra-fraction correction of displacements exceeding 3 mm. Genitourinary (GU), gastrointestinal (GI), and sexual toxicity during the first 18 months were evaluated using the CTCAE v4.0 grading scale. Quality of life was assessed using the International Prostate Symptom Score, the Expanded Prostate Cancer Index composite 26 score, and the International Index of Erectile Function score. ResultsAmong the 45 patients recruited in 5 centers between 2017 and 2022, 43 received the single fraction without protocol deviations, and 34 had a minimal follow-up of 18 months. The worst GU toxicity was observed at day-5 after SBRT (42.5 % and 20 % with grade 1 and 2, respectively), returning to baseline at week-12 and month-6 (<3% with grade 2), with a 12 % grade 2 flare at month 18. Gl toxicity was mild in the acute phase, with no grade ≥ 2 events (12 % grade 1 at month 6). Grade-3 proctitis was observed in one patient at month 12, with < 3 % grade 2 toxicity at month 18. Mean GU and GI bother scores showed a decline at day 5, a complete recovery at month 6, and a flare between month 12 and 18. Mean PSA dropped from 6.2 ng/ml to 1.2 ng/ml at month 18 and 0.7 ng/ml at month 24. After a median follow-up time of 26 months, 3 biochemical failures (7 %) were observed at month 17, 21 and 30. ConclusionsIn this multicenter phase I/II trial, we demonstrated that a 19 Gy single-fraction urethra-sparing SBRT is feasible and associated with an acceptable toxicity rate, mostly returning to the baseline at week-12 and with a symptoms flare between months 12 and 18. Longer follow-up is needed to assess the potential long-term adverse effects and the disease control efficacy.

Magnetic resonance guided adaptive post prostatectomy radiotherapy: Accumulated dose comparison of different workflows.

The aim of this study was to assess the use of magnetic resonance guided adaptive radiotherapy (MRgART) in the post-prostatectomy setting; comparing dose accumulation for our initial seven patients treated with fully adaptive workflow on the Unity MR-Linac (MRL) and with non-adaptive plans generated offline. Additionally, we analyzed toxicity in patients receiving treatment. Seven patients were treated with MRgART. The prescription was 70-72Gy in 35-36 fractions. Patients were treated with an adapt to shape (ATS) technique. For each clinically delivered plan, a non-adaptive plan based upon the reference plan was generated and compared to the associated clinically delivered plan. A total of 468 plans were analyzed. Concordance Index of target and Organs at Risk (OARs) for each fraction with reference contours was analyzed. Acute toxicity was then assessed at six-months following completion of treatment with Common Terminology for Adverse Events (CTCAE) Toxicity Criteria. A total of 246 fractions were clinically delivered to seven patients; 234 fractions were delivered via MRgART and 12 fractions delivered via a traditional linear accelerator due to machine issues. Pre-treatment reference plans met CTV and OAR criteria. PTV coverage satisfaction was higher in the clinically delivered adaptive plans than non-adaptive comparison plans; 42.93% versus 7.27% respectively. Six-month CTCAE genitourinary and gastrointestinal toxicity was absent in most patients, and mild-to-moderate in a minority of patients (Grade 1 GU toxicity in one patient and Grade 2 GI toxicity in one patient). Daily MRgART treatment consistently met planning criteria. Target volume variability in prostate bed treatment can be mitigated by using MRgART and deliver satisfactory coverage of CTV whilst minimizing dose to adjacent OARs and reducing toxicity.

Evaluation of the safety and efficacy of high-dose rate brachytherapy for radiorecurrent prostate cancer: asystematic review and meta-analysis.

High-dose-rate brachytherapy (HDR-BT) plays an important role in the treatment of locally recurrent prostate cancer after definitive treatment. The objective of this study is to summarize the efficacy and toxicity of HDR-BT in these patients. We performed asystematic review of PubMed and EMBASE from inception to July 2023. The primary endpoint was relapse-free survival (RFS) in different subgroups, and the secondary endpoint was gastrointestinal (GI) and genitourinary (GU) toxicity. Asemi-automated tool (WebPlotDigitizer) and anew Shiny application combined with Rsoftware (R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/ ) helped to reconstruct survival curves. Twenty-six studies met the inclusion criteria for quantitative analysis, including 1447 patients. Atotal of 761 patients from 13studies were included in survival reconstruction, and the median RFS time was 61.2 months (57.6-72.0months). The estimated 2‑, 3‑, and 5‑year rates were 75.9% (95% confidence interval [CI] 72.8 ~ 79.2%), 66.7% (95% CI 63.0 ~ 70.5%), and 52.3% (95% CI 47.5 ~ 57.4%), respectively. Whole-gland irradiation with multiple fractions (≥ 2F) resulted in better RFS compared with focal gland irradiation with fewer fractions (1F mostly; hazard ratio [HR]: 0.60, 95% CI 0.47-0.77, p < 0.0001). According to the different median time from primary treatment to salvage therapy (TRS) and median age at recurrence, short median TRS (56-67.2 months vs. 70-120 months; HR 0.52, 95% CI 0.68-0.40; p < 0.0001) and younger median age (60-70years vs. 71-75years; HR 0.58, 95% CI 0.46-0.74; p < 0.0001) were positive factors for RFS. The cumulative incidences estimated for grade ≥ 3 acute and late GU toxicities were 1% (95% CI 0 ~ 1%) and 5% (95% CI 4 ~ 7%), respectively. Three patients (3/992) experienced grade ≥ 3 late GI toxicity, and no cases of grade ≥ 3 acute GI toxicity were reported. HDR-BT has ahigh safety profile and good RFS benefit for salvage treatment of radiorecurrent prostate cancer. In terms of RFS, whole-gland irradiation with multiple fractions seems to be better than focal gland irradiation with fewer fractions, while short TRS and younger age are good prognostic factors. In view of the low level of evidence in the included studies and the large heterogeneity of each study, these conclusions still need to be confirmed by randomized controlled trials.

Image-guided moderately hypofractionated radiotherapy for localized prostate cancer: a multicentric retrospective study (IPOPROMISE)

BackgroundModerate hypofractionated radiotherapy is a treatment option for the cure of localized prostate cancer (PCa) patients based on the results of randomized prospective trials, but there is a clinical concern about the relatively short length of follow-up, and real-world results on outcome and toxicity based on cutting-edge techniques are lacking. The objective of this study is to present the long-term results of a large multicentric series.Materials and methodsWe retrospectively evaluated 1325 PCa patients treated with daily volumetric image-guided hypofractionated radiotherapy between 2007 and 2020 in 16 Centers. For survival endpoints, we used Kaplan–Meier survival curves and fitted univariate and multivariable Cox’s proportional hazards regression models to study the association between the clinical variables and each survival type.ResultsAt the end of the follow-up, 11 patients died from PCa. The 15-year values of cancer-specific survival (CSS) and biochemical relapse-free survival (b-RFS) were 98.5% (95%CI 97.3–99.6%) and 85.5% (95%CI 81.9–89.4%), respectively. The multivariate analysis showed that baseline PSA, Gleason score, and the use of androgen deprivation therapy were significant variables for all the outcomes. Acute gastrointestinal (GI) and genitourinary (GU) toxicities of grade ≥ 2 were 7.0% and 16.98%, respectively. The 15-year late grade ≥ 2 GI and GU toxicities were 5% (95%CI 4–6%) and 6% (95%CI 4–8%), respectively.ConclusionReal-world long-term results of this multicentric study on cutting-edge techniques for the cure of localized PCa demonstrated an excellent biochemical-free survival rate of 85.5% at 15 years, and very low rates of ≥ G3 late GU and GI toxicity (1.6% and 0.9% respectively), strengthening the results of the available published trials.

Revolutionizing localized prostate cancer treatment: Stereotactic radiotherapy "Moroccan experience".

Prostate cancer is the most common urological cancer, and its incidence is increasing. Radical prostatectomy and radiotherapy are theprimary treatments for localized forms. Stereotactic Body RadioTherapy (SBRT), a new and innovative therapy, has been validated for some cancer localizations but not yet for localized prostate cancer. Our study aims to report the efficacy and tolerance results of SBRT for localized prostate cancer. This is a retrospective study of 27 patients with localized prostate cancer (CaP) who were treated with SBRT in our department from 2017 to 2021 using transponders for tumor tracking. The dose was 36.25 Gy delivered in five fractions of 7.25 Gy. The delineation and doses of organs at risk were determined based on the recommendations of the SFRO and the TG101 report of medical physics. All patients were treated using a latest-generation linear accelerator (True Beam STXÒ). Acute toxicities were observed in 33.3% of cases, with 22.2% grade 1 or 2 genitourinary (GU) and no grade 3 while 11.1% gastrointestinal (GI) toxicities were reported as grade 1-2 (7.4%) and one case grade 3 (3.7%). Late grade 1 or 2 GU toxicity was observed in 14.84% of cases, with no reports of late GI toxicity. After a 26-month follow-up period, the biochemical failure-free survival rate was 92.6%. The results of our study are consistent with the existing literature and support the safety and effectiveness of SBRT as a treatment option for localized prostate cancer (CaP). In the United States, both ASTRO and the NCCN recognize SBRT as a valid treatment option for localized CaP. Ongoing phase III trials are being conducted to further substantiate these long-term results and to establish SBRT as the future standard of care for localized CaP.

Nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiotherapy: a systematic review and meta-analysis.

To conduct a meta-analysis to provide the latest evidence of nonsurgical local salvage options in the first-line radiotherapy (RT) failure setting for localized prostate cancer patients. Recurrence of localized prostate cancer after primary RT remains a clinical challenge. There is no consensus on optimal nonsurgical local salvage therapies, which mainly consist of cryotherapy (CRYO), high-intensity focused ultrasound (HIFU), high/low-dose-rate brachytherapy (HDR/LDR), and stereotactic body radiotherapy (SBRT). Our study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The authors systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov up to September 2023 to identify potentially relevant studies. The risk of bias was assessed using the European Association of Urology (EAU) items. Biochemical recurrence-free survival (bRFS) and genitourinary/gastrointestinal toxicities were the outcomes of interest. Pooled rates with 95% CIs were evaluated. A total of 99 studies comprising 8440 patients were included. The pooled rate of 1-year biochemical control (BC) was highest for LDR (0.88, 95% CI: 0.72-0.95) and lowest for SBRT (0.68, 95% CI: 0.49-0.83). The pooled rate of 5-year BC was highest for CRYO (0.52, 95% CI: 0.33-0.69) and lowest for HDR (0.23, 95% CI: 0.08-0.51). HIFU presented the worst outcome of grade ≥3 genitourinary toxicities (GU3), with a rate of 0.22 (95% CI: 0.12-0.3). Conversely, CRYO (0.09, 95% CI: 0.04-0.14), HDR (0.05, 95% CI: 0.02-0.07), LDR (0.10, 95% CI: 0.06-0.14), and SBRT (0.06, 95% CI: 0.03-0.09) presented low rates of GU3. All subgroups induced a quite low incidence of grade ≥3 gastrointestinal toxicities (GI3). Nonsurgical salvage therapies are promising modalities for prostate cancer in the local radiorecurrence setting. Based on the preliminary evidence from this study, CRYO and SBRT might present a relatively steady efficacy of BC with acceptable treatment-related toxicities.

High-risk prostate cancer treated with a stereotactic body radiation therapy boost following pelvic nodal irradiation.

Modern literature has demonstrated improvements in long-term biochemical outcomes with the use of prophylactic pelvic nodal irradiation followed by a brachytherapy boost in the management of high-risk prostate cancer. However, this comes at the cost of increased treatment-related toxicity. In this study, we explore the outcomes of the largest cohort to date, which uses a stereotactic body radiation therapy (SBRT) boost following pelvic nodal radiation for exclusively high-risk prostate cancer. A large institutional database was interrogated to identify all patients with high-risk clinical node-negative prostate cancer treated with conventionally fractionated radiotherapy to the pelvis followed by a robotic SBRT boost to the prostate and seminal vesicles. The boost was uniformly delivered over three fractions. Toxicity was measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Oncologic outcomes were assessed using the Kaplan-Meier method. Cox proportional hazard models were created to evaluate associations between pretreatment characteristics and clinical outcomes. A total of 440 patients with a median age of 71 years were treated, the majority of whom were diagnosed with a grade group 4 or 5 disease. Pelvic nodal irradiation was delivered at a total dose of 4,500 cGy in 25 fractions, followed by a three-fraction SBRT boost. With an early median follow-up of 2.5 years, the crude incidence of grade 2+ genitourinary (GU) and gastrointestinal (GI) toxicity was 13% and 11%, respectively. Multivariate analysis revealed grade 2+ GU toxicity was associated with older age and a higher American Joint Committee on Cancer (AJCC) stage. Multivariate analysis revealed overall survival was associated with patient age and posttreatment prostate-specific antigen (PSA) nadir. Utilization of an SBRT boost following pelvic nodal irradiation in the treatment of high-risk prostate cancer is oncologically effective with early follow-up and yields minimal high-grade toxicity. We demonstrate a 5-year freedom from biochemical recurrence (FFBCR) of over 83% with correspondingly limited grade 3+ GU and GI toxicity measured at 3.6% and 1.6%, respectively. Long-term follow-up is required to evaluate oncologic outcomes and late toxicity.

Retrospective study on the toxicity induced by stereotactic body radiotherapy: overview of the reunion experience on prostate cancer in elderly patients.

Prostate cancer is the fourth most commonly diagnosed cancer among men worldwide. Various tools are used to manage disease such as conventional radiotherapy. However, it has been demonstrated that large prostate volumes were often associated with higher rates of genitourinary and gastrointestinal toxicities. Currently, the improvements in radiotherapy technology have led to the development of stereotactic body radiotherapy, which delivers higher and much more accurate radiation doses. In order to complete literature data about short-term outcome and short-term toxic effects of stereotactic body radiotherapy, we aimed to share our experience about gastrointestinal and genitourinary toxicities associated with stereotactic body radiotherapy in prostate cancer in patients over 70 years old. We retrospectively reviewed the medical records of elderly patients with prostate cancer treated between 2021 and 2022. The elderly patients were treated with a non-coplanar robotic stereotactic body radiotherapy platform using real-time tracking of implanted fiducials. The prostate, with or without part of the seminal vesicles, was treated with a total dose of 36.25 Gy delivered in five fractions, each fraction being administered every other day. We analyzed a total of 80 elderly patients, comprising 38 low-, 37 intermediate- and 5 high-risk patients. The median follow-up duration was 12 months. We did not observe biochemical/clinical recurrence, distant metastasis, or death. Grade 2 acute genitourinary toxicity was observed in 9 patients (11.25%) and Grade 2 acute gastrointestinal toxicity in 4 patients (5.0%). We did not observe any grade 3 or more acute or late toxicities. Over the follow-up period, we noted a low frequency of gastrointestinal and genitourinary toxicities induced by stereotactic body radiotherapy in the context of prostate cancer in elderly patients. Therefore, stereotactic body radiotherapy seems to represent a promising treatment option for elderly patients, with acceptable acute toxicity.

Clinical Outcomes of Prostate SBRT Using Non-adaptive MR-Guided Radiotherapy.

Stereotactic body radiotherapy (SBRT) is widely used for localized prostate cancer and implementation of MR-guided radiotherapy has the advantage of tighter margins and improved sparing of organs at risk. Here we evaluate outcomes and time required to treat using non-adaptive MR-guided SBRT (MRgSBRT) for localized prostate cancer at our institution. From 9/2019 to 11/2021 we conducted a retrospective review of 80 consecutive patients who were treated with MRgSBRT to the prostate. Patients included low (LR) (5%), favorable intermediate (FIR) (40%), unfavorable intermediate (UIR) (49%), and high risk (HR) (6%). Short-term androgen deprivation therapy was used in 32% of patients. Target volumes included prostate gland and proximal seminal vesicles with an isotropic 3mm margin. Treatment was prescribed to 36.25 Gy in 5 fractions every other day with urethral sparing. Hydrogel spacer was used in 18% of patients. Time on the linac was recorded as beam on time (BOT) plus total treatment time (TTT) including gating. Analyzed outcomes included PSA response and patient reported outcomes scored by the American Urological Association (AUA) questionnaire and toxicity per CTCAE v5. General linear regression model was used to analyze factors affecting PSA and AUA in longitudinal follow up, and chi-square test was used to assess factors affecting toxicity. Median follow up was 19.3months (3.8 - 36.6). Median BOT was 4.6min (2.6 - 7.2) with a median TTT of 11 min (7.6 - 15.8). Pre-treatment vs post-RT median PSA was 6.36 (2.20 - 19.6) vs 0.85 (0.19 - 3.6), respectively (P < 0.001). PSA decrease differed significantly when patients were stratified by risk category, favoring LR/FIR vs UIF/HR group (P = 0.019). Four (5%) patients experienced a biochemical failure (BCF), with a median time to BCF of 20.4months (7.9 - 34.5). Median biochemical failure free survival (BCFFS) was not reached, with 2-yr and 4-yr BCFFS of 97.1% and 72.1%, respectively. Patients with LR/FIR disease had 100% 2-yr and 4-yr BCFFS, whereas patients with UIF/HR had 95% and 41% 2-yr and 4-yr BCFFS (P = 0.05). Mean pre-treatment AUA was 7.3 (1 - 25) vs 11.3 (1 - 26) at first follow-up; however, AUA normalized to baseline over time. Urethral Dmax ≥35Gy trended to lower AUA score at all follow-ups (P = 0.07). Forty-one (51%) patients reported grade 1-2 genitourinary toxicities at the 1 month follow up. Grade 3 toxicity (proctitis) was noted in 1 patient. There was no decrease in any grade rectal toxicity with use of hydrogel spacer (3 vs 6, P = 0.2). No grade ≥4 toxicities was observed. MRgSBRT has the potential for treatment adaptation but this comes at the cost of increased resource utilization. Our experience with non-adaptive MRgSBRT of the prostate highlights its short treatment times as well as efficacy with good PSA control and low toxicity profile.

A comparative study between two different dose fractionation schedules of cobalt-60-based HDR intracavitary brachytherapy in carcinoma cervix stages IIB-IIIC1.

High dose rate (HDR) intracavitary brachytherapy (ICBT) is an integral element in the treatment of carcinoma uterine cervix. The main objective of brachytherapy in carcinoma cervix is to deliver a lethal dose to tumor cells without inducing unacceptable damage to the surrounding normal tissue. Because the absorbed dose falls off rapidly, higher doses can be safely delivered to the targeted tissue over a short time. The quest for optimum dose and fractionation schedule in HDR ICBT is still ongoing, and there is no uniform consensus. This study aimed to assess the acute dose-related toxicities of HDR brachytherapy schedule of 7 Gy x 3 fractions over 6 Gy x 4 fractions in the treatment of cervical cancer. The aim of this study was to study the acute treatment-related gastrointestinal (GI) and genitourinary (GU) toxicities between two HDR brachytherapy regimens. This is a prospective institutional study carried out from May 2018 to September 2018. In this time period, 66 patients of cervical cancers fulfilling our inclusion criteria were treated with concurrent chemoradiation (CCRT) following brachytherapy. During treatment, patients were randomized to arm A-7 Gy per fraction for three fractions and arm B-6 Gy per fraction for four fractions. Acute GI and GU toxicities were assessed using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. All patients were kept for follow-up for 3 months in this study. There is no statistically significant difference between the two arms for acute GI and GU toxicities, and the results were comparable. Considering the increased hospital burden of locally advanced cervical cancer patients in the Indian context, the HDR brachytherapy schedule of 7 Gy per fraction is preferable to 6 Gy per fraction for a lesser fractionation schedule.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac: Estimated delivered dose and early toxicity results.

Magnetic resonance (MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation (UHF-WPRT) is a novel approach to radiotherapy for patients with high-risk (HR) and very high-risk (VHR) prostate cancer (PCa). However, the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time. We aimed to estimate the delivered dose, study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac. Ten patients with clinical stage T3a-4N0-1M0-1c PCa, who consecutively received UHF-WPRT, were enrolled prospectively. The contours of the target and organ-at-risks on the position verification-MR (PV-MR), beam-on 3D-MR(Bn-MR), and post-MR (after radiotherapy delivery) were derived from the pre-MR data by deformable image registration. The physician then manually adjusted them, and dose recalculation was performed accordingly. GraphPad Prism 9 (GraphPad Prism Software Inc.) was utilized for conducting statistical analyses. In total, we collected 188 MR scans (50 pre-MR, 50 PV-MR, 44 Bn-MR, and 44 post-MR scans). With median 59 min, the mean prostate clinical target volume (CTV)-V100% was 98.59% ± 2.74%, and the mean pelvic CTVp-V100% relative percentages of all scans was 99.60% ± 1.18%. The median V29 Gy change in the rectal wall was -2% (-18% to 20%). With a median follow-up of 9 months, no patient had acute Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or more severe genitourinary (GU) or gastrointestinal (GI) toxicities (0%). UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape (ATS) workflow was technically feasible for patients with HR and VHR PCa, presenting only mild GU and GI toxicities. The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis. Chinese Clinical Trial Registry ChiCTR2000033382.

Safety of high-dose-rate brachytherapy in patients with prostate cancer and inflammatory bowel disease: A case series.

Inflammatory bowel disease (IBD) is a relative contraindication to external beam radiation therapy (EBRT) for prostate cancer patients due to fear of increased risk of gastrointestinal (GI) toxicity. High-dose-rate (HDR) brachytherapy, capable of minimizing radiation dose to surrounding tissues, is a feasible alternative. Given limited data, this study examined the safety profile of HDR brachytherapy in this setting. We conducted a retrospective review of patients with localized prostate cancer and IBD treated with HDR brachytherapy at the University of California San Francisco (UCSF), between 2010 and 2022. Eligibility criteria included biopsy-proven prostate cancer, no distant metastases, absence of prior pelvic radiotherapy, IBD diagnosis, and at least one follow-up visit post-treatment. Eleven patients were included, with a median follow-up of 28.7 months. The median dose administered was 2700 cGy (range, 1500-3150 cGy) over 2 fractions (range, 1-3 fractions). Two patients also received EBRT. Rectal spacers (SpaceOAR) were applied in seven patients. All patients experienced acute genitourinary (GU) toxicity, ten of which were grade 1 and one was grade 2. Eight patients experienced late grade 1 GU toxicity, and three patients had late grade 2 GU toxicity. GI toxicities were similarly low-grade, with six grade 1 acute toxicity, no grade 2 or higher acute toxicity, six grade 1 late toxicity, and one late grade 2 GI toxicity. No grade 3 or higher acute or late GI or GU toxicities were reported. HDR brachytherapy appears to be a safe and tolerable treatment modality for patients with prostate cancer and IBD, with minimal acute and late GI and GU toxicity. These findings warrant multi-institutional validation due to small sample size.

Veza između nivoa citokina u serumu i razvoja akutne radijacione toksičnosti kod pacijenata sa karcinomom prostate

Radiotherapy plays a significant role in the multidisciplinary approach to treating prostate cancer patients. However, some of these patients may develop severe adverse effects after receiving radiotherapy that negatively affect their quality of life. Radiotoxicity may manifest in the lower gastrointestinal (GI) tract by damaging the rectum or bowel, or genitourinary (GU) tract, causing symptoms due to urethral, bladder or prostate damage. The probability of complications in normal tissue increases as the delivered radiation dose increases. However, there are patients with satisfactory dosimetric parameters who develop radiation toxicity and vice versa. Prediction models that take into account additional parameters to identify patients most susceptible to developing toxicity may serve as essential factors toward personalized radiotherapy. The main objectives are morbidity reduction and life-quality improvement. Changes in the cytokine levels could also be connected with the occurrence of acute gastrointestinal and genitourinary toxicity. Literature data indicate the association of numerous cytokines with the appearance of GI and GU toxicity. There is proof that TGF-b1 stimulates fibroblasts to generate extracellular matrix. According to the literature, IL-6 is regarded as one of the most important immune markers for predicting the radiotherapy-induced toxicity of normal tissues. Increased IL-6 concentrations in the serum during radiotherapy are significantly linked to a higher degree of acute genitourinary toxicity. The goal of this work is to summarize the results of contemporary research in which the connection between the occurrence of acute radiation toxicity and changes in the cytokines levels in the serum during radiotherapy were examined, considering the great future potential of the use of toxicity prediction factors in clinical practice. It can be concluded that radiation therapy, the development of an inflammatory process, and the occurrence of radiation toxicity are all related. However, further research with the aim of adequate stratification of patients for the development of an individualized approach to radiotherapy is required.

Low-dose-rate brachytherapy and long-term treatment outcomes in patients younger than 60 years of age.

Low-dose-rate (LDR) brachytherapy in young men remains controversial amongst urologists due to their concerns regarding long-term biochemical control and treatment-related toxicities. The purpose of this study was to evaluate the treatment outcomes of men under 60 years of age who underwent LDR brachytherapy with iodine-125 (125I) for clinically localized low- to intermediate-risk prostate cancer. All consecutive patients with clinically localized prostate cancer treated at our institution from 2003 to 2016 with 125I monotherapy were included in the study. Prescription dose was 145.0 Gy modified peripheral loading (MPD). All patients were assessed for biochemical progression-free survival using Phoenix definition (nadir +2 ng/ml), clinical progression-free survival, overall survival (OS), and any associated treatment toxicity. A total of 161 patients were included, with a median follow-up of 6.8 years (range, 3-14.54 years). Median age at implant was 57 years (range, 53-59 years). Mean prostate specific antigen (PSA) level at diagnosis was 4.43 ng/ml (SD = 2.29). Majority of men had low-risk prostate cancer (70.2%). Biochemical progression-free survival at 8 years was 94% for the entire cohort. Median PSA at 4 years was 0.169 (IQR, 0.096-0.360), with 45% of patients having a PSA greater than 0.2. OS was 96.9%, with 5 deaths reported but only one was secondary to prostate cancer. Late grade > 2 genitourinary toxicities were reported in 18 patients (11.2%). Three patients (1.9%) developed secondary cancers, all considered unrelated to their LDR brachytherapy. With excellent long-term treatment outcomes and minimal associated toxicities, our results showed that LDR brachytherapy can be an effective treatment of choice in younger men.

Hypofractionated versus standard chemoradiotherapy in the definitive treatment of uterine cervix cancer: interim results of a randomized controlled clinical trial

PurposeConcurrent chemoradiation has been the mainstay of treatment for cervix cancer. We aimed to evaluate the non-inferiority of hypofractionated chemoradiation.MethodsThis study was designed as a phase 2, 1:1 randomized, investigator-blinded, controlled, non-inferiority trial and we report the interim results after 50% accrual. Cervical cancer patients with FIGO stages IIA–IIIC were recruited from April 2021 to September 2022. The intervention consisted of 40 Gy of 3D-conformal radiation therapy (RT) in 15 fractions over 3 weeks. In the control group, patients received standard chemoradiation of 45 Gy in 25 fractions over 5 weeks. Both groups received concurrent weekly cisplatin (40 mg/m2). Intravaginal brachytherapy of 28 Gy in 4 weekly fractions was delivered starting 1 week after the end of chemoradiation. The primary outcome was complete clinical response(CCR) at 3 months. Secondary outcomes included acute gastrointestinal (GI), genitourinary(GU), skin, and hematologic toxicities. A p value less than 0.05 was considered significant for analyses.Results59 patients were randomized; 30 in the control group and 29 in the intervention group. 20/30 (66.7%) of the patients in the control group and 19/29 (65.5%) in the intervention group achieved a CCR (absolute difference of 0.011, 95% CI − 0.23 to 0.25, p value: 0.13). There was a significantly higher rate of acute grade ≥ 3 GI toxicity in the intervention group (27.6%) compared with the control group (6.7%) (p value 0.032).ConclusionsDespite an absolute difference of 1.1% in the 3-month CCR, our interim analysis failed to show the non-inferiority of the hypofractionated chemoradiation. Due to the higher GI toxicities, we will continue this trial using intensity-modulated radiation therapy.Registration number and dateClinicalTrials.gov: NCT04831437, 2021.4.1.

Timing of High-Dose-Rate Brachytherapy With External Beam Radiation Therapy in Patients With Intermediate- and High-Risk Localized Prostate Cancer and Its Effects on Toxicity and Quality of Life: A Randomized Controlled Trial (THEPCA)

BackgroundHDR brachytherapy(HDR-BT) and external beam radiotherapy(EBRT) are effective treatments for prostate cancer(PC) but cause genitourinary(GU) and gastrointestinal(GI) toxicities. There is no consensus on the timing of HDR-BT in relation to EBRT and the effect of sequencing on patients. ObjectiveThe primary objective was to assess differences, if any, in the incidence of Grade 3 or higher GU toxicities from treatment. We also aimed to explore the incidence of G1-4 GI toxicities, quality of life and patient satisfaction. Suppression of PSA and signals for survival differences were also analysed. MethodologyA single-centre randomised trial in intermediate and high-risk localised PC patients to receive HDR-BT before (Arm A) or after (Arm B) EBRT. Toxicities were graded using CTCAE. IIEF and FACT-P were used to assess erectile dysfunction and QOL at 0, 3, 9 and 12 months. Results50 patients were recruited to each arm, with 48 and 46 patients completing treatment and follow up in each arm. 81.5% had high-risk disease. There were no G3 or G4 GU or GI toxicities. G1 urinary frequency was the most common adverse event experienced in both arms, peaking in incidence 3 months after commencing treatment (45.7 and 42.2% in Arm A and B, respectively). Up to 11 % of patients reported G1 urinary frequency at 12 months. Other G1 GU toxicities experienced by >10% of patients were urinary tract obstruction, tract pain and urgency. These symptoms also peaked in incidence at 3 months. G2 GU toxicities were uncommon and experienced in a maximum of 2 patients within each arm at any time point.Over 30% of patients had G1 flatulence at baseline and this remained the most frequently occurring G1 GI toxicity throughout the study, peaking at 12months (21.4% and 25.6% in Arm A and Arm B, respectively). Other GI toxicities experienced by more than 10% of patients were GI pain, proctitis and rectal mucositis, most of which demonstrated a peak incidence at 3 or 9 months. G2 GI toxicities were uncommon, except G2 flatulence.No significant difference was found in CTCAE, IPSS, IIEF, FACT-P and QOL scores between the arms.Median PSA follow-up was 5 years. 7 patients had treatment failure in each arm. DFRS was 93.3% and 90.7% at 5 years in Arm A and B respectively, with median failure time of 60 and 48 months in Arm A and B respectively. There were no statistically significant difference between arms. ConclusionsThe sequencing of HDR-BT and EBRT did not impact the incidence of G3 or G4 toxicities and no significant differences were seen in other patient reported outcomes. Treatment was well tolerated with maintained QOL scores. Treatment failure was low in both arms in a high-risk cohort, however a larger study with longer follow up is underway to establish whether the difference in median time to failure between the two arms is a signal of superiority.

Quantifying Intrafraction Motion and the Impact of Gating for Magnetic Resonance Imaging-Guided Stereotactic Radiation therapy for Prostate Cancer: Analysis of the Magnetic Resonance Imaging Arm From the MIRAGE Phase 3 Randomized Trial

Real-time intrafraction tracking/gating is an integral component of magnetic resonance imaging-guided radiation therapy (MRgRT) and may have contributed to the acute toxicity reduction during prostate stereotactic body radiation therapy observed on the MRgRT-arm of the MIRAGE (MAGNETIC RESONANCE IMAGING-GUIDED Stereotactic Body Radiotherapy for Prostate Cancer) randomized trial (NCT04384770). Herein we characterized intrafraction prostate motion and assessed gating effectiveness. Seventy-nine patients were treated on an MR-LINAC. Real-time cine imaging was acquired at 4Hz in a sagittal plane. If >10% of the prostate area moved outside of a 3-mm gating boundary, an automatic beam hold was initiated. An in-house tool was developed to retrospectively extract gating signal for all patients and identify the tracked prostate in each cine frame for a subgroup of 40 patients. The fraction of time the prostate was within the gating window was defined as the gating duty cycle (GDC). A total of 391 treatments from 79 patients were analyzed. Median GDC was 0.974 (IQR, 0.916-0.983). Fifty (63.2%) and 24 (30.4%) patients had at least 1 fraction with GDC ≤0.9 and GDC ≤0.8, respectively. Incidence of low GDC fractions among patients appeared stochastic. Patients with minimum GDC <0.8 trended toward more frequent grade 2 genitourinary toxicity compared with those with minimum GDC >0.8 (38% vs 18%, P = .065). Prostate intrafraction motion was mostly along the bladder-rectum axis and predominantly in the superior-anterior direction. Motion in the inferior-posterior direction was associated with significantly higher rate of acute grade 2 genitourinary toxicity (66.7% vs 13.9%, P = .001). Gating limited mean prostate motion during treatment delivery in fractions with a GDC <0.9 (<0.8) to 2.9 mm (2.9 mm) versus 4.1 mm (4.7 mm) for ungated motion. Fractions with large intrafraction motion were associated with increased toxicity and their occurrence among patients appears stochastic. Real-time tracking/gating effectively mitigated this motion and is likely a major contributing factor of acute toxicity reduction associated with MRgRT.

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Dose-volume relationships of planned versus estimated delivered radiation doses to pelvic organs at risk and side effects in patients treated with salvage radiotherapy for recurrent prostate cancer

PurposeTo investigate estimated delivered dose distributions using weekly cone-beam computed tomography (CBCT) scans for pelvic organs at risk (OARs) in salvage radiotherapy (SRT) after radical prostatectomy. Furthermore, to compare them with the originally planned dose distributions and analyse associations with gastrointestinal (GI) and genitourinary (GU) side effects. MethodsThis study is part of a phase II trial involving SRT for recurrent prostate cancer. Treatment was personalised based on PSA response during SRT, classifying patients as PSA responders or non-responders. Estimated radiation dose distributions were obtained using deformable image registration from weekly CBCT scans. GI and GU toxicities were assessed using the RTOG toxicity scale, while patient-reported symptoms were monitored through self-assessment questionnaires. ResultsThe study included 100 patients, with similar treatment-related side effects observed in both responders and non-responders. Differences in dose-volume metrics between the planned and estimated delivered doses for the examined OARs were mostly modest, although generally statistically significant. We identified statistically significant associations between QUANTEC-recommended dose-volume constraints and acute bowel toxicity, as well as late urinary patient-reported symptoms, for both the estimated delivered and planned dose distributions. ConclusionWe found small but statistically significant differences between estimated delivered and planned doses to OARs. These differences showed trends toward improved associations for estimated delivered dose distributions with side effects. Enhanced registration methods and imaging techniques could potentially further enhance the assessment of truly delivered doses and yield more reliable dose-volume constraints for future therapies.