Late Genitourinary Research Articles

Hypofractionated radiotherapy with simultaneous integrated boost for localized prostate cancer patients: effects on immune system and prediction of toxicity.

The other side of radiotherapy (RT), in addition to the cytotoxic effect, is the ability to modulate the immune system in terms of activation or suppression, also depending on the dose and fractionation delivered. This immune RT effect can be detected both locally in the irradiated tumor site and in the peripheral blood. The aim of this study was to assess the consequence of pelvic irradiation on peripheral immune cells and cytokine secretions in localized prostate cancer (PC) patients undergoing pelvic irradiation with a simultaneous moderately hypofractionated prostate/prostate bed boost by Volumetric Modulated Arc Therapy (VMAT). Furthermore, we analyzed whether there was a correlation between these peripheral immune parameters and acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Thirty-eight PC patients were treated with pelvis irradiation (dose per fraction 1.8 Gy) and simultaneous hypofractionated (median dose per fraction: 2.7 Gy) prostate/prostate bed boost. A longitudinal analysis was performed for 12 months on peripheral blood to assess changes in 9 different lymphocyte subpopulations by flow cytometry and 10 circulating cytokines by Multiplex Luminex assay and ELISA. Our analysis revealed that basal IFN-γ serum values were significantly lower in the definitive (curative intent for patients with prostate) patient group respect to the post-operative one. All the lymphocyte subsets and IFN-α, IFN-β and Il-2 peripheral concentrations displayed significant variations between the different time points considered. The immune cell population that suffers the greatest RT toxicity in the blood was B lymphocyte. We found an interesting correlation between basal TGF-β1 and late GU toxicity. In particular, TGF-β1 concentrations before RT were significantly higher in patients that experienced grade 2-3 of late GU toxicity, respect to grade 0-1. Exploring possible correlations between some clinical/biological findings and radiation planning parameters, we found no statistical significance. Our study analyzed, in the context of hypofractionated radiotherapy in prostate cancer, different parameters of the peripheral immune system. We have highlighted longitudinally the peripheral behavior of the different lymphocyte subpopulations and of a group of 10 cytokines during the first year after RT. One of the analyzed cytokines, such as TGF-β1, has proven to be promising predictive factor of severe late GU toxicity.

Evaluating a hypofractionated radiotherapy schedule for prostate cancer at an institution in South Africa

Background: Hypofractionated radiotherapy (HFRT) in the treatment of prostate cancer (PCa) has logistical and cost advantages, especially in a resource constrained setting. Studies have demonstrated equivalent efficacy with HFRT schedules using Intensity Modulated Radiation Therapy (IMRT) as treatment modality. However, higher rates of acute and late gastrointestinal (GI) and genitourinary (GU) toxicity have been reported when compared to conventionally fractionated radiotherapy (CFRT). In this study, we evaluate the efficacy and toxicity rates of a HFRT schedule using 3D conformal radiotherapy (RT) as treatment modality.Aim: With this study, we aim to describe the safety and outcomes of a definitive HFRT schedule used for localised PCa. We hypothesise that there is no difference in the biochemical relapse rate and incidence rates of normal tissue toxicities between patients receiving CFRT and HFRT schedules.Setting: This RT schedule was used at Tygerberg Academic Hospital in South Africa for the treatment of localised prostate cancer.Methods: This is a retrospective study in which the records of patients diagnosed with localised PCa were reviewed. Patients were treated with either CFRT regimen to a total of 74Gy in 37 daily fractions for 5 days a week or a HFRT regimen to a total of 65Gy in 26 daily fractions for 4 days per week.Results: In all, 116 patients were included in the study with a median follow-up of 57.2 months from the start of RT. No statistically significant differences in overall survival (OS) and biochemical relapse-free survival were found between the two schedules. A significant difference in acute GI toxicity was observed, with a higher incidence noted in the HFRT schedule. No significant differences were observed in late GI toxicity or in early and late GU toxicities.Conclusion: This study observes a hypofractionated regimen using three-dimensional conformal radiation therapy (3DCRT) with similar efficacy and RT-related toxicities to CFRT.Contribution: The HFRT schedule used in this study could be useful in hospitals with limited access to resources.

Ablative Radiation Therapy for Unfavorable Prostate Tumors (ABRUPT): Preliminary Analysis of Toxicity and Quality of Life from a Prospective Study

To assess late gastrointestinal (GI) and genitourinary (GU) side effects in patients with organ-confined unfavorable prostate cancer (PCa) treated with single-dose ablative radiation therapy (SDRT). Thirty patients enrolled in a single-arm prospective trial received 24 Gy SDRT to the whole prostate with urethra-sparing and organ motion control delivered on a Linac platform with a 10 MV flattening filter-free single partial arc. Androgen deprivation therapy was prescribed as per standard of care. Treatment-related acute and late GU and GI toxicities (Common Terminology Criteria for Adverse Events_v5 scale) and quality of life (QoL) outcomes (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-PR25/C30, International Prostate Symptom Score [IPSS]) were assessed at different time points. Minimal important difference (MID) was established as a change of >0.5 pooled standard deviations from baseline. Statistical analysis included analysis of variance and logistic regression. Median follow-up was 18 months (range, 6-31 months), with no ≥G3 late side effects observed. G2 late GI and G2 late GU toxicities occurred in 1 and 2 patients, respectively. GI toxicity of any grade correlated with maximum rectal dose (P = .021). Lower baseline QoL score (P = .025), higher baseline IPSS score (P = .049), acute GU toxicity (P = .029), and acute urinary domain MID (P = .045) predicted GU toxicity of any grade. In multivariate analysis (MVA), only baseline QoL score (odds ratio [OR], 0.95, P = .031) and acute GU toxicity (OR, 8.4, P = .041) remained significant. Significant QoL change was observed only in the urinary domain (P = .005), with a median increase from 8 to 17. Late urinary MID correlated with acute urinary MID (P = .003), acute QoL MID (P = .029), acute GU toxicity (P = .030), and lower baseline urinary score (P = .033). In MVA, only acute urinary MID predicted late urinary MID (OR, 9.7, P = .035). Our findings provide promising data on the feasibility and safety of 24 Gy whole-gland SDRT with urethra-sparing and organ motion control, in association with androgen deprivation therapy and an adequate prophylactic medication, in organ-confined unfavorable PCa. Long-term follow-up is needed to confirm these results.

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8months was mandatory for patients with intermediate or high-risk prostate cancer. From 20 institutions, 134 patients enrolled. The median follow-up was 5.16years (range, 1.43-6.47years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

High-Grade Late Urinary Toxicity Following Salvage Radiotherapy After Radical Prostatectomy: A Retrospective Cohort Study

Purpose: To find out the incidence and predictors for late high-grade genitourinary (GU) toxicity following salvage radiotherapy (SRT), we investigated the consecutive patients who were treated with SRT after radical prostatectomy.Materials and Methods: Patients who underwent SRT for biochemical recurrence after radical prostatectomy were reviewed. The incidence of GU toxicity was assessed and risk factors for grade ≥2 and ≥3 GU toxicity were evaluated. The STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guided the reporting of this study.Results: Among the total of 217 patients, 88 patients (40.5%) showed late grade ≥2 GU toxicity. The incidence of late grade ≥3 GU toxicity was 11.5%. The presence of grade ≥2 baseline GU dysfunction (hazard ratio [HR], 6.097; 95% confidence interval [CI], 3.280–11.333; p&lt;0.001) and short interval (&lt;1 year) from surgery to SRT (HR, 1.994; 95% CI, 1.182–3.365; p=0.01) were associated with late grade ≥2 GU toxicity. A short interval from surgery to SRT was an independent predictor of late grade ≥3 GU toxicity (HR, 2.975; 95% CI, 1.135–7.794; p=0.027).Conclusions: The incidence of late high-grade GU toxicity was not uncommon after SRT. Thus, care should be taken when we consider SRT in patients with baseline urinary dysfunction and a short interval from surgery to SRT, to determine an optimal treatment strategy with balancing quality of life and oncologic outcome of patients.

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.

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.

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.

Randomized Trial of Concomitant Hypofractionated Intensity Modulated Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy Boost for Localized High-Risk Prostate Cancer (pHART2-RCT)

The aim of this work is to report on the results of a phase 2 randomized trial of moderately hypofractionated (MH) versus conventionally fractionated (CF) radiation therapy to the prostate with elective nodal irradiation. This was a single-center, prospective, phase 2 randomized study. Patients with high-risk disease (cT3, prostate-specific antigen level >20 ng/mL, or Gleason score 8-10) were eligible. Patients were randomized to either MH using a simultaneous integrated boost (68 Gy in 25 fractions to prostate; 48 Gy to pelvis) or CF (46 Gy in 23 fractions with a sequential boost to the prostate of 32 Gy in 16 fractions), with long-term androgen deprivation therapy. The primary endpoint was grade ≥2 acute gastrointestinal (GI) and genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 3.0). Secondary endpoints included late GI and GU toxicity, quality of life, and oncologic outcomes. One-hundred eighty patients were enrolled; 90 were randomized to and received MH and 90 to CF. The median follow-up was 67.4 months. Seventy-five patients (41.7%) experienced a grade ≥2 acute GI and/or GU toxicity, including 34 (37.8%) in the MH and 41 (45.6%) in the CF arms, respectively (P = .29). Late grade ≥2 GI (P = .07) and GU (P = .25) toxicity was not significantly different between arms; however, late grade ≥3 GI toxicity was worse in the MH group (P = .01). There were no statistically significant quality-of-life differences between the 2 treatments. There were no statistically significant differences observed in cumulative incidence of biochemical failure (P = .71) or distant metastasis (P = .31) and overall survival (P = .46). MH to the prostate and pelvis with androgen deprivation therapy for men with high-risk localized prostate cancer was not significantly different than CF with regard to acute toxicity, quality of life, and oncologic efficacy. However, late grade ≥3 GI toxicity was more common in the MH arm.

Prostatic Urethral Length on MRI Potentially Predicts Late Genitourinary Toxicity After Prostate Cancer Radiation

The purpose of our study was to evaluate pretreatment prostate quantitative magnetic resonance imaging (MRI) measurements and clinical characteristics in predicting genitourinary (GU) toxicity after radiotherapy (RT) for prostate cancer. In this single-institutionretrospective cohort study, we evaluated patients with prostate adenocarcinoma who underwent MRI within 6 months before completing definitive RT and follow-up information in our GU toxicity database from June 2016 to February 2023. MRI measurements included quantitative urethra, prostate, and bladder measurements. GU toxicity was physician-scored using theCommon Terminology Criteria for Adverse Events (CTCAE v4.0) with acute toxicity defined as ≤180 days and late defined as >180 days. Multivariable logistic regression model was constructed for grade≥2 acute toxicity and Cox proportional hazards regression for late toxicity, adjusted for clinical factors and RT method. A total of 361 men (median age 68 years, interquartile range [IQR] 62-73) were included; 14.4% (50/347) men experienced grade≥2 acute toxicity. Brachytherapy (odds ratio [OR]:2.9, 95% confidence interval [CI]:1.5-5.8), P<0.01) was associated with increased odds of acute GU toxicity, and longer MUL (OR: 0.41[95%CI: 0.18-0.92], P=0.03) with decreased odds. Median follow-up for late toxicity was 15.0 months (IQR: 9.0-28.0) with approximately 88.7% and 72.0% patients free of toxicity at 1 and 3 years, respectively. Only longer prostatic urethral length (hazard ratio [HR]:1.6, 95%CI: 1.2-2.1, P<0.01) was associated with increased risk of late GU toxicity, notably urinary frequency/urgency symptoms (HR: 1.7 [95%CI: 1.3-2.3], P<0.01). Longer prostatic urethral length measured on prostate MRI is independently associated with higher risk of developing late grade≥2 GU toxicity after radiation therapy for prostate cancer. This pretreatment metric may be potentially valuable in risk-stratification models for quality of life following prostate RT.

Ten-Year Outcomes of Hypofractionated (45 Gy in 9 Fractions) Intensity Modulated Radiotherapy for Localized Prostate Cancer.

We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low-risk group, 17 at intermediate risk group, 5 at high-risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume, an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria, and GU and GI toxicities were cumulatively calculated. After a median follow-up of 102 months (65∼131 months), the 10-year OS was 90.0% (95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.

Toxicity Analysis of a Modified Prostate Bed CTV Based on PSMA-PET Patterns of Failure.

After radical prostatectomy (RP), about 20-50% of prostate cancer patients experience biochemical failure, and many can be cured with salvage radiotherapy (sRT). Adding androgen deprivation and pelvic lymph node (PLN) RT to sRT decreases risk of disease progression at the cost of increased toxicity. PSMA PET patterns of local failure after RP show failures outside the RTOG prostate bed CTV (RTOG_CTV) occurring postero-laterally and inferiorly, while in much of the covered bladder local failures are not seen. A modified CTV (m_CTV) encompassing all sites of observed local failures and less of the bladder would potentially reduce dose to the bladder but increase dose to rectum. Herein, we compared sRT plans using RTOG_CTV vs. m_CTV and assessed predicted genitourinary (GU) and gastrointestinal adverse events (AEs). Volumes for RTOG_CTV, m_CTV, PLN CTV, and OARs were retrospectively contoured on planning CT scans of 28 post-RP patients. Plans were generated for each RTOG_CTV and m_CTV. Doses to prostate bed PTV (CTV + 8mm expansion, 6mm posteriorly) and PLN CTV were 68 Gy and 52.7 Gy, respectively, all in in 34 fractions. Dose-volume histogram (DVH) data for bladder, rectum, and bowel of each plan were extracted. Normal Tissue Complication Probability (NTCP) curves were generated using Lyman-Kutcher-Burman model to predict risk of late G≥3 GU AEs, early GU urgency, leakage, frequency, nocturia, late GI bleed, and late G≥3 GI AEs. Data were compared using 2 sample t-test and Wilcox signed rank test. Correlation of bladder volume and differences in DVH and NTCP data between plans was assessed using Pearson coefficient. The m_CTV and RTOG_CTV had a median volume of 70.56cc (IQR 59.72-82.17cc) and 132.14cc (IQR 109.33-155.84cc), respectively. Use of m_CTVs resulted in mean absolute decrease of 20.22% and 17.94% in bladder V65 Gy and V40 Gy, respectively (p<0.01 for both), without differences in rectum V65 Gy (p = 0.44), rectum V40 Gy (p = 0.11), or bowel V45 Gy (p = 0.29). Per NTCP curves, m_CTV plans had mean absolute decrease of 24.89% in predicted late G≥3 GU AEs (p<0.01). For predicted early GU AEs, there were mean absolute decreases ranging from 4.85 to 10.21% (p<0.01 for all). Predicted late GI bleed (p = 0.98) and late G≥3 GI AEs (p = 0.99) were not significantly different between plans. When assessed as a continuous variable, smaller bladder volumes had strong correlation with more benefit from m_CTV in bladder V65 Gy (r = -0.71, p<0.01) and moderate correlation with less early GU AEs (r -0.59 to -0.56, p<0.01 for all). There was no correlation with bladder V40 Gy (p = 0.27) or late G≥3 GU AEs (p = 0.14). The m_CTV plans had significantly less dose to the bladder, no increased dose to the rectum and significantly lower predicted rates of early and late GU toxicity. Using a m_CTV encompassing observed local failures from PSMA PET could improve the therapeutic ratio for patients undergoing sRT. Further clinical validation is warranted.

Validating a Simple Urethra Surrogate Model to Facilitate Dosimetric Analysis to Predict Genitourinary Toxicity.

The urethra may be a critical structure in prostate radiotherapy planning as some studies have shown that higher urethral dose correlates with worse genitourinary (GU) toxicity. Identifying the urethra requires an MRI planning scan or foley catheter insertion at CT planning. Most surrogates have been developed and validated against the urethra identified by a foley catheter. However, the urethral position can shift with catheter placement. We, therefore, aim to validate a simple urethra surrogate model against MRI-defined urethra. The surrogate model can be used to correlate urethra dose-volume parameters (DVP) with late GU toxicity and to apply urethral constraints in those with a CT-only based workflow. Thirty-nine MRI-defined urethras from patients in the PACE-C trial were assessed to determine the average position of the urethra in the midline sagittal prostate plane along the ¼ gland, midgland, ¾ gland, apex and 3mm below apex. Using these average positions, a Python script was developed, which places a 10mm diameter circle in the 1/4 gland, midgland, ¾ gland, apex and 3mm below the apex. The observer manually contours a 10mm circle at the prostate base (prostate-bladder neck interface) to infer the urethra position and interpolates the contours. The urethra surrogate model was compared against 20 MRI-defined urethras (within the treatment PTV) in patients treated with 36.25Gy in 5 fractions as part of the PACE-B trial. To assess the surrogate's geometric performance, the Dice similarity coefficient (DSC), Hausdorff distance (HD), mean surface distance to agreement (MDTA) and the percentage of MRI-defined urethra outside the surrogate (UOS) were calculated. The surrogate model's dosimetric performance was assessed by comparing the mean D99, D98, average dose, D50, D2 and D1 using a paired t-test. The D(n) is the dose (Gy) to (n)% of the urethra. The median results were: DSC 0.36 (IQR 0.28-0.42), HD 0.88cm (IQR, 0.70-1.04), MDTA 0.24cm (IQR, 0.21-0.28), UOS 29% (IQR, 17-52%). When comparing DVP between the MRI-defined urethra and surrogate urethra, the mean D99, D98 and D95 as 38.8Gy vs 39.1Gy (p = 0.17), 39.3Gy vs 39.5Gy (p = 0.23), 40.1Gy vs 40.4Gy (p = 0.21), respectively. The mean D50, average dose, D2 and D1 was 41.8Gy vs 41.9Gy (p = 0.03), 41.7 vs 41.8Gy (p = 0.04), 42.9Gy vs 43.0Gy (p = 0.05) and 43.0Gy vs 43.1Gy (p = 0.03), respectively. While there were geometric differences between the surrogate urethra and MRI-defined urethra, there was no statistically significant difference between most urethral dose-volume parameters (D99, D98, D95, and D1). Similarly, the actual differences in urethra DVP were not clinically significant. This surrogate model could be validated in a larger cohort and then used to estimate the urethra position on CT planning scans for dosimetric analysis in those without an MRI planning scan or urinary catheter.

The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study

Acute gastrointestinal (GI) and genitourinary (GU) toxicity after prostate radiotherapy (RT) has been shown to be associated with late toxicity with 3D conformal RT. However, whether this association is present with modern approaches, such as stereotactic body radiotherapy (SBRT), remains unclear. We analyzed patients treated within the international phase III non-inferiority randomized control trial, PACE-B, to assess the association between acute and late toxicity following SBRT and conventional/moderately hypofractionated radiotherapy (CRT). We hypothesize that acute toxicity is significantly associated with equivalent late toxicity following prostate SBRT and CRT. We analyzed patients with GI and GU Common Terminology Criteria for Adverse Events (CTCAE) measurements in the acute (≤12 weeks post-RT) and late period (6-24 months post-RT). Using logistic regression, we analyze the association between G2+ acute GI and GU toxicities with equivalent late toxicities. Lasso variable selection was used to determine patient, tumor and treatment variables to include in the multivariable model. The area under the receiver operator characteristics curve (AUC) was used to evaluate the model's predictive performance. Of patients included in this analysis (n = 842), 414 were treated with SBRT and 428 with CRT. In univariable analysis (UVA), G2+ acute GU toxicity was significantly associated with developing G2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), p<0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), p<0.0001). This association remained significant in multivariable analysis (MVA). The models AUC for predicting G2+ late GU toxicity after SBRT was 0.73 (95% CI, 0.67-0.78) and 0.66 (95% CI, 0.59-0.73) following CRT. In UVA, G2+ acute GI toxicity was associated with developing G2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), p <0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), p<0.0001). This association also remained significant in MVA. The models AUC for predicting G2+ late GI toxicity after SBRT was 0.66 (0.95% CI, 0.57-0.75) and 0.64 (95% CI, 0.57-0.72) following CRT. In UVA analysis, G2+ baseline GU symptoms were also associated with developing G2+ late GU toxicity after SBRT (OR 7.59, 95% CI (2.72-21.19, p<0.0001) and CRT (OR 7.98, 95% CI (3.03-20.96), p<0.0001), and this continued to be significant in MVA. Acute toxicity remained associated with persistent late toxicity (≥2 G2+ late events) and late toxicity 12-24 months. Our study demonstrates an independent association between acute and late GU/GI toxicity in patients treated with SBRT and CRT for localized prostate cancer. Recognizing those at risk of late toxicity can provide an opportunity for early intervention to improve outcomes. G2+ acute toxicity should be considered an essential variable for predicting late GI/GU toxicity after prostate RT.

State of the art and future challenges of urethra-sparing stereotactic body radiotherapy for prostate cancer: a systematic review of literature

PurposeDoses delivered to the urethra have been associated with an increased risk to develop long-term urinary toxicity in patients undergoing stereotactic body radiotherapy (SBRT) for prostate cancer (PCa). Aim of the present systematic review is to report on the role of urethra-sparing SBRT (US-SBRT) techniques for prostate cancer, with a focus on outcome and urinary toxicity.MethodA systematic review of the literature was performed on the PubMed database on May 2023. Based on the urethra-sparing technique, 13 studies were selected for the analysis and classified in the two following categories: “urethra-steering” SBRT (restriction of hotspots to the urethra) and “urethra dose-reduction” SBRT (dose reduction to urethra below the prescribed dose).ResultsBy limiting the urethra Dmax to 90GyEQD2 (α/β = 3 Gy) with urethra-steering SBRT techniques, late genitourinary (GU) grade 2 toxicity remains mild, ranging between 12.1% and 14%. With dose-reduction strategies decreasing the urethral dose below 70 GyEQD2, the risk of late GU toxicity was further reduced (< 8% at 5 years), while maintaining biochemical relapse-free survival rates up to 93% at 5 years.ConclusionUS-SBRT techniques limiting maximum doses to urethra below a 90GyEQD2 (α/β = 3 Gy) threshold result in a low rate of acute and late grade ≥ 2 GU toxicity. A better understanding of clinical factors and anatomical substructures involved in the development of GU toxicity, as well as the development and use of adapted dose constraints, is expected to further reduce the long-term GU toxicity of prostate cancer patients treated with SBRT.

Long-term outcomes of whole-pelvis radiation therapy using volumetric modulated arc therapy for high-risk prostate cancer†.

This study investigated the outcomes of whole-pelvis radiation therapy (WPRT) using volumetric modulated arc therapy (VMAT) for high-risk prostate cancer. We retrospectively analysed 112 patients with high-risk prostate cancer who started WPRT at our hospital between August 2011 and August 2015. The prescribed dose was 78Gy in 39 fractions to the prostate and 46.8Gy in 26 fractions to the pelvic lymph node (LN) area. All patients received long-term androgen deprivation therapy. We evaluated late gastrointestinal (GI) and genitourinary (GU) toxicities using the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period for censored cases was 97 (interquartile range [IQR] = 85-108) months. The median age was 72 (IQR = 67-75) years. The high-risk and very-high-risk groups included 41 (36.6%) and 71 patients (63.4%), respectively. The median risk of LN invasion calculated by the Roach formula was 36.9 (IQR = 26.6-56.3) %. The 8-year overall survival, biochemical failure-free survival, disease-free survival and distant metastasis-free survival rates were 88.4, 91.9, 83.8 and 98.0%, respectively. Only one patient experienced common iliac LN recurrence, which was outside the pelvic irradiation area. All patients with recurrent disease were categorized into the very-high-risk group. The 8-year cumulative rates of ≥Grade 2 late GI and GU toxicities were 12.8 and 11.8%, respectively. No patients experienced Grade 4 or higher toxicities. WPRT using VMAT for high-risk prostate cancer was well tolerated and effective.

Hypofractionated Post-Prostatectomy Radiotherapy in 16 Fractions: A Single-Institution Outcome.

The optimal hypofractionated schedule of post-prostatectomy radiotherapy remains to be established. We evaluated treatment outcomes and toxicity of moderately hypofractionated post-prostatectomy radiotherapy in 16 daily fractions delivered with intensity-modulated radiotherapy. The treatment schedule selection was motivated by limited technology resources and was radiobiologically dose-escalated. One hundred consecutive M0 patients with post-prostatectomy radiotherapy were evaluated. Radiotherapy indication was adjuvant (ART) in 19%, early-salvage (eSRT) in 46% and salvage (SRT) in 35%. The dose prescription for prostate bed planning target volume was 52.8 Gy in 16 fractions of 3.3 Gy. The Common Terminology Criteria v. 4 for Adverse Events scale was used for toxicity grading. The median follow-up was 61 months. Five-year biochemical recurrence-free survival (bRFS) was 78.6%, distant metastases-free survival (DMFS) was 95.7% and overall survival was 98.8%. Treatment indication (ART or eSRT vs. SRT) was the only significant factor for bRFS (HR 0.15, 95% CI 0.05-0.47, p = 0.001) and DMFS (HR 0.16, 95% CI 0.03-0.90; p = 0.038). Acute gastrointestinal (GI) toxicity grade 2 was recorded in 24%, grade 3 in 2%, acute genitourinary (GU) toxicity grade 2 in 10% of patients, and no grade 3. A cumulative rate of late GI toxicity grade ≥ 2 was observed in 9% and late GU toxicity grade ≥ 2 in 16% of patients. The observed results confirmed efficacy and showed a higher than anticipated rate of early GI, late GI, and GU toxicity of post-prostatectomy radiobiologically dose-escalated hypofractionated radiotherapy in 16 daily fractions.

Assessing the toxicity after moderately hypofractionated prostate and whole pelvis radiotherapy compared to conventional fractionation.

To evaluate acute and late gastrointestinal (GI) and genitourinary (GU) toxicities after moderately hypofractionated (HF) or conventionally fractionated (CF) primary whole-pelvis radiotherapy (WPRT). Primary prostate-cancer patients treated between 2009 and 2021 with either 60 Gy at 3 Gy/fraction to the prostate and 46 Gy at 2.3 Gy/fraction to the whole pelvis (HF), or 78 Gy at 2 Gy/fraction to the prostate and 50/50.4 Gy at 1.8-2 Gy/fraction to the whole pelvis (CF). Acute and late GI and GU toxicities were retrospectively assessed. 106patients received HF and 157 received CF, with amedian follow-up of 12and 57months. Acute GI toxicity rates in the HF and CF groups were, respectively, grade2: 46.7% vs. 37.6%, and grade3: 0% vs. 1.3%, with no significant difference (p = 0.71). Acute GU toxicity rates were, respectively, grade2: 20.0% vs. 31.8%, and grade3: 2.9% vs. 0%, (p = 0.04). We compared prevalence of late GI and GU toxicities between groups after 3,12, and 24months and did not find any significant differences (respectively, p = 0.59, 0.22, and 0.71 for GI toxicity; p = 0.39, 0.58, and 0.90 for GU toxicity). Moderate HF WPRT was well tolerated during the first 2years. Randomized trials are needed to confirm these findings.

Ten-year outcomes of hypofractionated (45 Gy in 9 fractions) intensity-modulated radiotherapy for localized prostate cancer.

e17100 Background: We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. Methods: From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low risk group, 17 at intermediate risk group, 5 at high risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume , an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival(PFS) and overall survival(OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria , and GU and GI toxicities were cumulatively calculated. Results: After a median follow-up of 102 months (65~131 months), the 10-year OS was 90.0%(95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. Conclusions: The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.