Late GU Research Articles

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center

BackgroundProton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. MethodsWe reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). ResultsMedian follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72–79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4–96.0 %) and 93.2 % (95 % CI 91.3–95.7 %), respectively (log-rank p = 0.22). ConclusionsProton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Conditional Risk and Predictive Factors Associated With Late Toxicity in Patients With Prostate Cancer Treated With External Beam Radiation Therapy Alone in the Randomized Trial RTOG 0126

The objective of this study was to characterize the conditional risk of developing grade 2+ urinary or gastrointestinal (GI) toxicity for patients treated with external beam radiation therapy in Radiation Therapy Oncology Group 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and at later points of follow-up. One thousand five hundred thirty-two patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1499 were eligible and included in data analysis with a median follow-up of 8.4 years (range, 0.02-13 years). Patients were treated with either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy according to institutional practice without the addition of androgen deprivation and randomized to receive either standard-dose radiation therapy of 70.2 Gy or dose-escalated radiation therapy of 79.2 Gy of radiation therapy to the prostate only with standard fractionation. Univariate and multivariate analyses were performed to determine whether initial factors were predictive of late toxicity at the time of treatment and at later time points. As patients proceed further from completion of radiation therapy without the development of toxicity, the subsequent risk of both grade 2+ genitourinary (GU) and GI toxicity decreases with time. At the time of enrollment, the risk of developing grade 2+ toxicity over the next 5 years was 9.57% and 17.89%, respectively. After 5 years of toxicity-free survival, the risk of developing grade 2+ GU or GI toxicity in the subsequent 5 years was 3.02% and 1.54%, respectively. Baseline treatment and patient-related factors predicted late toxicity both at trial enrollment and after 2 years of toxicity-free survivorship. Baseline urinary dysfunction and dose-escalated radiation therapy were associated with increased late GU toxicity. Acute GI toxicity and dose-escalated radiation therapy were associated with increased risk of late GI toxicity. Treatment with intensity-modulated radiation therapy was associated with reduced risk of either toxicity. The conditional risk of grade 2+ toxicities decreases as patients proceed further from treatment, with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

PROSTOX, a signature of late GU toxicity after SBRT radiotherapy in MIRAGE, a prospective trial.

PROSTOX, a signature of late GU toxicity after SBRT radiotherapy in MIRAGE, a prospective trial.

Simultaneous Focal Boost With Stereotactic Radiation Therapy for Localized Intermediate- to High-Risk Prostate Cancer: Primary Outcomes of the SPARC Phase 2 Trial

Purpose: Dose escalated radiotherapy is associated with better biochemical control at the expense of toxicity. Stereotactic body radiotherapy (SBRT) with dose escalation to the dominant intraprostatic lesion (DIL) provides a logical approach to improve outcomes in high-risk disease whilst limiting toxicity. This study evaluated the toxicity and quality of life (QOL) with CyberKnife-based SBRT and simultaneous integrated boost in localised prostate cancer. Methods and Materials: Eligible participants included newly diagnosed, biopsy-proven unfavourable intermediate to high risk localised prostate cancer (at least one of the following: Gleason ≥ 4+3, MRI defined T3a N0, PSA ≥ 20) with up to two MRI-identified DILs. Participants received 36.25Gy in 5 fractions on alternative days with a simultaneous boost to DIL up to 47.5Gy as allowed by organs at risk constraints delivered by CyberKnife. All participants received androgen deprivation therapy. The primary outcome measure was acute grade 2 + genitourinary toxicity. Acute and late genitourinary and gastrointestinal toxicity using RTOG scoring, biochemical parameters, IPSS, IIEF5, EQ5D QOL outcomes were assessed. Results: Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 30 months. The median D95 dose to DIL was 47.43Gy. Cumulative acute grade 2 + genitourinary and gastrointestinal toxicity was 25% and 30%, respectively. One patient developed acute grade 3 genitourinary toxicity (5%). There is no late grade 3 genitourinary or gastrointestinal toxicity to date. IPSS score and urinary QOL scores recovered to baseline by 6months. Patient-reported outcomes showed no significant change in EQ-5D QOL scores at 12 weeks and 1 year. There are no cases of biochemical relapse reported to date. Conclusions: CyberKnife SBRT delivered dose of 36.25Gy to the prostate with a simultaneous integrated boost up to 47.5Gy is well tolerated. Acute and late GU and GI toxicity rates are comparable to other contemporary SBRT trials and series with focal boost.

Five Fractions versus Seven Fractions SBRT for Intermediate- and High-Risk Prostate Cancer: A Propensity Score Matched Pair Analysis.

To compare two stereotactic body radiotherapy (SBRT) regimens in patients with intermediate- or high-risk prostate cancer with regards toxicity and efficacy. We retrospectively collected data from 198 patients treated with SBRT for prostate cancer at two different institutions. Patients received either 35-36.25 Gy in five fractions (group A) using Cyberknife robotic platform or 42.7 Gy in seven fractions (group B) using a C-arm LINAC (image-guided). Propensity score matching was done (2:1 nearest neighbor matching without replacement), resulting in 120 patients (80 patients for group A, 40 patients for group B). Toxicity, PSA nadir, biochemical failure and disease-free survival (DFS) were analyzed. Median follow up of all patients was 13 months (range 1-91 months). Overall, 23.3% of patients had ≥G2 acute GU toxicity (21.1% group A versus 30% group B (p = 0.222)) and 6.6% of patients ≥G2 GI toxicity (2.5% versus 15% (p = 0.010)). There was one acute G3 GU toxicity in arm A and one acute G4 rectal bleeding in group B (anticoagulated patient). Regarding late toxicity, 14.1% of patients had ≥G2 late GU toxicity (17.4% versus 6.6% (p = 0.159)) and 5.0% of patients had ≥G2 late GI toxicity (1.4% versus 13.3% (p = 0.013)). There was one G3 late GU toxicity in arm B and two G3 late GI toxicities, one in each arm. Relative median PSA reduction was 92.4% (-53.9-99.9%) from baseline PSA (93.7% (-53.9-99.9%) in group A versus 87.7% (39.8-99.9%) in group B (p = 0.043). In total, 4.2% of patients had biochemical relapse, 5.0% in group A and 2.5% in group B (p = 0.518). One-year DFS in the overall cohort was 97.3%, 98.8% in group A and 94.3% in group B (p = 0.318). Both SBRT regimens have acceptable acute and late toxicity and good efficacy. There are significantly more GI toxicities in the seven-fraction regimen. Longer follow-up is warranted for better comparison of long-term efficacy.

Toxicity profile and Patient-Reported outcomes following salvage Stereotactic Ablative Radiation Therapy to the prostate Bed: The POPART multicentric prospective study

BackgroundWhile SBRT to the prostate has become a valuable option as a radical treatment, limited data support its use in the postoperative setting. Here, we report the updated results of the multicentric Post-Prostatectomy Ablative Radiation Therapy (POPART) trial, investigating possible predictors of toxicities and patient-reported outcomes. MethodsPatients with PSA levels between 0.1–2.0 ng/mL after radical prostatectomy received Linac-based SBRT to the prostate bed in five fractions every other day for a total dose of 32.5 Gy (EQD21.5 = 74.3 Gy). Late toxicity was assessed using CTCAE v.5 scale, while EPIC-CP, ICIQ-SF, IIEF 5 questionnaires and PSA levels measured quality of life and biochemical control. Pre- and post-treatment scores were compared using a paired t-test, with MID established at > 0.5 pooled SD from the baseline. A logistic regression analysis was performed to evaluate potential associations between specific patient/tumor/treatment factors and outcome deterioration. ResultsFrom April 2021 to April 2023 a total of 50 pts were enrolled and treated. Median follow-up was 12.2 (3–27) months. No late ≥ G2 GI or GU toxicity was registered. Late G1 urinary and rectal toxicities occurred in 46 % and 4 % of patients, respectively. Among 47 patients completing all EPIC-CP domains, four (9 %) showed worsened QoL, and eleven (26 %) developed erectile dysfunction correlating with PTV D2% (P = 0.032). At Multivariate analysis bladder wall D10cc independently correlated with late G1 GU toxicity (P = 0.034). Median post-treatment PSA nadir was 0.04 ng/mL (0.00 – 0.84). At the last follow-up, six patients presented with biochemical failure, including two nodal relapses. ConclusionsOur findings show that post-prostatectomy SBRT did not result in increased toxicity nor a significant decline in QoL measures, thus showing that it can be safely extended to the postoperative setting. Long-term follow-up and randomized comparisons with different RT schedules are needed to validate this approach.

Prospective results for 5-year survival and toxicity of moderately hypofractionated radiotherapy with simultaneous integrated boost (SIB) in (very) high-risk prostate cancer

PurposeHigh-risk (HR) prostate cancer patients usually receive high-dose radiotherapy (RT) using a two-phase sequential technique, but data on a simultaneous integrated boost (SIB) technique are lacking. We prospectively evaluated the long-term results of urinary (GU) and digestive (GI) toxicity and survival data for high-dose RT using a SIB technique in HR and very high-risk (VHR) prostate cancer. MethodsPatients were treated using an SIB technique in 34 fractions, at a dose of 54.4 Gy to the pelvis and seminal vesicles and 74.8 Gy to the prostate, combined with 36 months of androgen-depriving therapy in a prospective multicenter study. Acute and late GU and GI toxicity data were collected. Overall survival (OS), biochemical-relapse-free survival (bRFS), loco-regional-relapse-free survival (LRRFS), metastasis-free-survival (MFS) and disease-free-survival (DFS) were assessed. ResultsWe recruited 114 patients. After a median follow-up of 62 months, very few patients experienced acute (M0-M3) (G3-4 GU = 3.7 %; G3-4 GI = 0.9 %) or late (M6-M60) severe toxicity (G3-4 GU = 5.6 %; G3-4 GI = 2.8 %). The occurrence of acute G2 + GU or GI toxicity was significantly related to the consequential late G2 + toxicity (p < 0.01 for both GU and GI). Medians of OS, bRFS, LRRFS, MFS and DFS were not reached. At 60 months, OS, bRFS, LRRFS, MFS and DFS were 88.2 % [82.1; 94.7], 86.0 % [79.4 %;93.2 %], 95.8 % [91.8 %;99.9 %], 87.2 % [80.9 %;94.0 %] and 84.1 % [77.2 %;91.6 %] respectively. ConclusionSIB RT at a dose of 54.4 Gy to the pelvis and 74.8 Gy to the prostate is feasible, leading to satisfying tumor control and reasonable toxicity in HR and VHR prostate cancer.

Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer.

High dose-rate (HDR) brachytherapy as monotherapy is an effective treatment for patients with low- and intermediate-risk prostate cancer and is increasingly being offered as a 2-fraction protocol. There is a lack of consensus on the optimal dosimetric planning parameters to use, or whether there is any benefit summating dosimetric parameters from more than one implant. Our goal is to determine planning parameters associated with disease control, toxicity and health-related quality of life (HRQOL). Data were collected on 83 patients with low- and intermediate-risk prostate cancer who received 2 fractions of 13.5 Gy HDR brachytherapy without androgen-deprivation therapy as part of a randomized phase II clinical trial. An in-house deformable, registration algorithm was used to co-register and dose-summate the plans from both implants for each patient. Acute and late GU and GI toxicities were measured using CTCAE 4.0 and HRQOL was measured in urinary, bowel, sexual and hormonal domains using the EPIC scores. Treatment efficacy was assessed through PSA measurement and imaging with or without biopsy where indicated. Covariates included baseline clinical factors, disease characteristics and treatment dosimetric parameters. Cox proportional hazards was performed to evaluate covariates impact on treatment toxicity and efficacy, and logistic regression analysis evaluated covariates impact on HRQOL. Among the 83 patients, median prostate volume was 46.7cm3. Median summated planning target volume receiving 100% prescription dose (PTV V100%) was 97.4%, median PTV V150% 42.4% and median PTV V200% 15.5%. Median highest dose to the 1cm3 rectum (D1cc) was 66.9% of the prescription dose and median rectum V80% was 0.008cm3. Median urethral D1cc was 99.0% of the prescription dose, median urethral Dmax 121.7% and median urethral D10% 116.2%. Grade ≥2 GI toxicity was uncommon (3.7% acute and 8.5% late), but grade ≥2 GU toxicity was reported in 73.2% (acute) and 46.3% (late) patients. Rectum D1cc and V80% were found to be significantly associated with grade 2 or higher acute GI toxicity, while use of a-blocker at baseline was associated with grade ≥2 acute GU toxicity. Similarly, use of a-blocker was associated with late grade ≥2 GU toxicity, but with no dosimetric associations. No other variables were associated with treatment-related toxicities. Only rectum D1cc was significantly associated with changes in bowel EPIC scores. Estimated 5-year biochemical disease-free survival was 93.9% and 5-year cumulative incidence of local failure was 3.8%. HDR monotherapy with 27 Gy delivered in 2 fractions in treatment of prostate cancer is well tolerated with high rates of disease control and minimal toxicity. Dose summation between 2 fractions of HDR brachytherapy is feasible, with rectal dose predicting acute GI toxicity. The lack of association between dose metrics and urinary toxicity raises the potential for further dose escalation.

Focal Boosted IMRT Treatment of Prostate Cancer to 84 Gy in 28 Fractions: Preliminary Clinical Outcomes and Dosimetry

The FLAME trial reported that focal boosting of prostate tumor to 95 Gy in 35 fractions improves biochemical control. However, this treatment is not commonly used in the United States. We investigated a focally boosted treatment of 84 Gy in 28 fractions (EQD2 108 Gy, BED 252 Gy). Between 2019-2022, men with unfavorable intermediate risk (uIR) and high risk (HR) prostate cancer were enrolled on a prospective registry and received a novel IMRT regimen. The dose levels were 84 Gy to the gross tumor volume (GTV) as defined on mpMRI (T2W and ADC) with no added margin, 70 Gy to the prostate and proximal seminal vesicles, and optional 50.4 Gy to elective pelvic lymph nodes (all 28 fractions). Patients received fiducial markers and hydrogel spacer. The treatment planning goal was to cover 95% of the GTV at 84 Gy, and also meet the target and normal tissue dosimetry criteria of the hypofractionated treatment arm of NRG-GU005. VMAT was used for treatment delivery. ADT was given at the discretion of the treating physician. A total of 20 men were included in the study, 2 (10%) uIR and 18 (90%) HR. 9 (45%) tumors were GS 7, 7 (35%) were GS 8, and 4 (20%) were GS 9. There were 13 (65%) stage cT1, 4 (20%) cT2 and 3 (15%) cT3. One (5%) patient received short term ADT, 18 (95%) long term ADT, and 1 (5%) refused ADT. 18 (90%) men received elective nodal radiation. The mean baseline PSA was 25.1 (range 4.2-73.4). The median baseline IPSS score was 11.1 (IQR 4.5-12), and 4 patients had severe baseline urinary symptoms (IPSS ≥20). The mean baseline prostate volume was 57.4 cc (range 26.8-198.3). The mean volume of the 84 Gy boost target was 7.1 cc (range 2.3-15.0) and the mean proportion of the prostate boosted was 14.8% (range 2% - 47%). There were 10 (50%) men with 1 boost target, 6 (30%) with two, 3 (15%) with three, and 1 (5%) had 4 boost targets. Targets were located in peripheral zone (85%), transition zone (30%), and central zone (5%). Patients met all per-protocol normal tissue criteria of NRG-GU005, except for bladder D0.03cc. The mean±SD (Gy) rectum D15%, D25%, and D30% were 51±5, 45±5, 42±4. The mean±SD (Gy) bladder D0.03cc, D30%, D50% were 79±4, 50±8, 38±10. At a median follow up time of 21.3 months (range 7.1-38.2), no patients have developed biochemical progression, local recurrence, distant progression, or death from prostate cancer. One patient died at 18 months from metastatic colorectal cancer, unrelated to prostate cancer treatment. Acute grade 1-2 GU toxicity occurred in 13 (65%) patients, and acute grade 1-2 GI toxicity occurred in 4 (20%) patients. No patients developed grade 3+ acute or late GU or GI toxicity. Two patients required temporary foley catheter for obstruction during RT, and both had IPSS >20 at baseline. The patient who refused ADT had a PSA bounce of magnitude 2.2 ng/mL at 14 months, PSA values declined without additional treatment. A novel 28-fraction focal boosted IMRT treatment is feasible and has an acceptable early toxicity profile. Oncologic results are promising but require longer follow up.

Conditional Risk and Predictive Factors Associated with Late Toxicity for Prostate Cancer Patients Treated with External Beam Radiotherapy Alone on Randomized Trial RTOG 0126

Patients with localized prostate cancer (PCA) treated with RT alone have excellent outcomes, making quality of life and minimization of toxicities of great concern. The risk of developing toxicity may evolve with time from treatment which is of interest to patients seen in follow up. The primary objective of this study is to determine the conditional risk of grade 2+ GI or GU toxicity for patients treated with RT. A secondary objective is to determine risk factors associated with the development of late toxicities. We performed a post-hoc analysis of RTOG 0126, which enrolled patients with intermediate risk PCa who were randomized to receive standard dose RT of 70.2 Gy in 39 fractions vs dose escalated dose RT (DE-RT) of 79.2 Gy in 44 fractions. Cumulative incidence was used to calculate risk of grade 2+ GU and grade 2+ GI toxicity at initial time points, as well as for patients who survived 2 years and 5 years without respective grade 2+ toxicity. Risk factors of age, race, urinary incontinence, baseline urinary frequency, acute GU toxicity, treatment arm, RT method (3DCRT vs IMRT), and OAR contouring protocol violation were analyzed using univariate and multivariate Cox proportional hazards modeling for late GU toxicity. Risk factors of age, race, RT method, acute GI toxicity, DE-RT, RT method, and OAR contouring protocol violation were analyzed for late GI toxicity. One thousand four hundred ninety-nine patients with a median follow up of 8.4 years (range 0.02-13 years) were included for analysis. The conditional cumulative 5-year risk of late grade 2+ GI toxicity at enrollment, 2-, and 5-years of grade 2+GI toxicity free survivorship was 14.7%, 6.2%, and 1.8% respectively. The cumulative 5-year risk of late grade 2+ GU toxicity at enrollment, 2-, and 5-years of late grade 2+ GU toxicity free survivorship was 7.9%, 4.7%, and 2.7% respectively. Initially DE-RT (HR 1.401, 95% CI 1.099-1.787; p = 0.0066), acute GI toxicity (HR 1.962, 95% CI 1.271-2.616; P<0.0001), and black race (HR 0.630, 95% CI 0.4-0.993; p<0.0463) were predictive of late GI toxicity. After two years of 2+ GI toxicity free survivorship, only acute GI toxicity (HR 2.015, 95% CI 1.238-3.279, p<0.0048) remained predictive of late GI toxicity on MVA. DE-RT (HR 1.616, 95% CI 1.187-2.2, p<0.0023), IMRT (HR 0.559, 95% CI 0.389-0.804, p = 0.0017), and urinary frequency at baseline (HR 1.377, 95% CI 1-1.895 p<0.0498) were predictive of late GU toxicity at enrollment. This data suggests that as patients proceed further from completion of EBRT, the conditional risk of late toxicity decreases. The majority of grade 2+ GI and GU toxicities occur in the first two years of treatment and patients who have not had a grade 2+ GU or GI toxicity within the first five years are likely to remain toxicity free. Factors such as presence of baseline urinary dysfunction, presence of acute toxicities, DE-RT, and radiation modality predict for late toxicity. These findings are of relevance for clinicians and patients in the post treatment setting.

Outcomes of dose-escalated IMRT and ADT in Octogenarians with prostate cancer.

We evaluated long-term outcomes for octogenarians with localised prostate cancer treated using dose-escalated image-guided intensity-modulated radiation therapy (IMRT) at our institution. The charts of octogenarians treated for localised prostate cancer were retrospectively reviewed. Overall survival (OS), prostate cancer-specific survival (PCaSS), toxicity rates and changes from baseline were collected. The median follow-up was 97 months. Of 107 eligible patients, 27.1% had intermediate-risk and 72.9% had high-risk localised prostate cancer. Median dose was 78Gy, and 97.2% received ADT. OS was 91.4% and 67.2% at 5 and 10 years. PCaSS was 98.0% and 88.7% at 5 and 10 years. In all, 39 (36.4%) of patients died, with the cause of death known in 30: in 26.7% of these patients, prostate cancer was the cause of death. Grade ≥ 2 late GI and GU toxicity was 0.9% and 24.3% respectively. In all, 11.2% and 22.4% of patients reported worsening of GI or GU function from baseline, and 13.1% and 21.5% reported improvement in GI and GU function compared to baseline. Selected octogenarian patients with localised prostate cancer appear to benefit from radiation therapy and ADT. Despite excellent long-term PCaSS, 26.7% of patients died of prostate cancer. Rates of GI and GU toxicity were acceptable, and deterioration of urinary and bowel function compared to baseline was just as common as improvement in function from baseline.

Comparison of chronic gastrointestinal and genitourinary toxicities between brachytherapy and external beam radiotherapy for patients with prostate cancer: A systematic review and meta-analysis.

125I BT is an effective radiotherapy for prostate cancer. However, comparison data of GI and GU toxicities between BT, BT + EBRT, and EBRT-alone patient groups is limited. To define the GI and GU toxicities in prostate cancer to prevent adverse events after treatment. We searched published studies in PubMed, Cochrane, and Embase databases up to December 31, 2022. The endpoints were the RRs of GI and GU toxicities. Pooled data were assessed using a random-effects model. Fifteen eligible studies were included into this analysis. LDR-BT had significantly lower RRs than LDR-BT + EBRT for acute GI (2.13; 95% CI, 1.22-3.69; P= 0.007) and late GI toxicities (3.96; 95% CI, 1.23-12.70; P= 0.02). Moreover, EBRT had significantly higher RRs than LDR-BT for acute GU (2.32; 95% CI, 1.29-4.15; P= 0.005) and late GU toxicities (2.38; 95% CI, 1.27-4.44; P= 0.007). HDR-BT had significantly higher RRs for acute GU toxicities than LDR-BT alone (0.30; 95% CI, 0.23-0.40; P< 0.00001). The results implied that BT with and without EBRT can result in both GI and GU toxicities in patients with prostate cancer, with LDR-BT leading to a poorer urinary function than EBRT.

Salvage Stereotactic Reirradiation for Local Recurrence in the Prostatic Bed After Prostatectomy: A Retrospective Multicenter Study

BackgroundManagement of local recurrence of prostate cancer (PCa) in the prostatic bed after radical prostatectomy (RP) and radiotherapy remains challenging. ObjectiveTo assess the efficacy and safety of salvage stereotactic body radiotherapy (SBRT) reirradiation in this setting and evaluate prognostic factors. Design, setting, and participantsWe conducted a large multicenter retrospective series that included 117 patients who were treated with salvage SBRT for local recurrence in the prostatic bed after RP and radiotherapy in 11 centers across three countries. Outcome measurements and statistical analysisProgression-free survival (PFS; biochemical, clinical, or both) was estimated using the Kaplan-Meier method. Biochemical recurrence was defined as prostate-specific antigen nadir +0.2 ng/ml, confirmed by a second increasing measure. The cumulative incidence of late toxicities was estimated using the Kalbfleisch-Prentice method by considering recurrence or death as a competing event. Results and limitationsThe median follow-up was 19.5 mo. The median SBRT dose was 35 Gy. The median PFS was 23.5 mo (95% confidence interval [95% CI], 17.6–33.2). In the multivariable models, the volume of the recurrence and its contact with the urethrovesical anastomosis were significantly associated with PFS (hazard ratio [HR]/10 cm3 = 1.46; 95% CI, 1.08–1.96; p = 0.01 and HR = 3.35; 95% CI, 1.38–8.16; p = 0.008, respectively). The 3-yr cumulative incidence of grade ≥2 late GU or GI toxicity was 18% (95% CI, 10–26). In the multivariable analysis, a recurrence in contact with the urethrovesical anastomosis and D2% of the bladder were significantly associated with late toxicities of any grade (HR = 3.65; 95% CI, 1.61–8.24; p = 0.002 and HR/10 Gy = 1.88; 95% CI, 1.12–3.16; p = 0.02, respectively). ConclusionsSalvage SBRT for local recurrence in the prostate bed may offer encouraging control and acceptable toxicity. Therefore, further prospective studies are warranted. Patient summaryWe found that salvage stereotactic body radiotherapy after surgery and radiotherapy allows for encouraging control and acceptable toxicity in locally relapsed prostate cancer.

Application of a genetic signature of late GU toxicity in SCIMITAR, a Post-op SBRT trial.

Predictors of genitourinary toxicity after post-prostatectomy radiotherapy remain elusive. A previously defined germline DNA signature (PROSTOX) has shown predictive ability for late grade≥2 GU toxicity after intact prostate stereotactic body radiotherapy. We explore whether PROSTOX would predict toxicity among patients receiving post-prostatectomy SBRT on a phase II clinical trial.

Radiation technique and outcomes following moderately hypofractionated treatment of low risk prostate cancer: a secondary analysis of RTOG 0415.

While moderately hypofractionated radiotherapy (MHRT) for prostate cancer (PC) is commonly delivered by intensity modulated radiation therapy, IMRT has not been prospectively compared to three-dimensional conformal radiotherapy (3D-CRT) in this context. We conducted a secondary analysis of the phase III RTOG 0415 trial comparing survival and toxicity outcomes for low-risk PC following MHRT with IMRT versus 3D-CRT. RTOG 0415 was a phase III, non-inferiority trial randomizing low-risk PC patients to either MHRT or conventionally fractionated radiation with stratification by RT technique. A secondary analysis for differences in overall survival (OS), biochemical recurrence free survival (BRFS), or toxicity by EPIC scores and Common Terminology Criteria for Adverse Events (CTCAE) was performed. 1079 patients received the allocated intervention with a median follow up of 5.8 years. 79.1% of patients were treated with IMRT and radiation technique was balanced between arms. Across all patients, RT technique was not associated with significant differences in BRFS, OS, or rates of acute and late toxicities. For patients completing MHRT, there was a difference in the late GU toxicity distribution between 3D-CRT and IMRT but no difference in late grade 2 or greater GU or GI toxicity. Stratifying patients by RT technique and fractionation, no significant differences were observed in the minimal clinically important difference (MCID) in EPIC urinary and bowel scores following RT. RT technique did not impact clinical outcomes following MHRT for low-risk PC. Despite different late GU toxicity distributions in patients treated with MHRT by IMRT or 3D-CRT, there was no difference in late Grade 2 or greater GU or GI toxicity or patient reported toxicity. Increases in late GU and GI toxicity following MHRT compared to CFRT, as demonstrated in the initial publication of RTOG 0415, do not appear related to a 3D-CRT treatment technique.

5-Year result of single-institute cohort study in single-fraction HDR monotherapy for localised prostate cancer.

362 Background: The aim if this single institute UK-based study was to look at 3-year and 5-year bRFS and toxicity profiles. Methods: It is a prospective data study with a total number of 174 patients who were treated with single-fraction HDR monotherapy between July 2014 and February 2017. Biochemical recurrence is defined using Phoenix criteria. Results: The median age was 67.5 years with the median presenting PSA of 8. Majority of patients were lower risk group with 55% for combined low and favourable intermediate risks. 81 patients had Gleason score 6(3+3) and 77 patients had GS 7(3+4). Total hormone duration was 8 months and median duration of hormone prior to HDR monotherapy was 4 months. Overall bRFS at 3 years was 96% and 5 years was 88%. 5-year bRFS as per risk stratification was 100% in low risk, 92% in favourable intermediate risk, 83% in unfavourable intermediate risk and 79% in high-risk groups. This study had better 5-year overall bRFS compared to published data in single fraction HDR monotherapy (88% vs 73.5%, p value 0.001) (Morton et al., 2020). Despite inferior 5-year overall bRFS in compared to 2-fractionated HDR monotherapy (88% vs 95%) (p value 0.001), no difference in 5-year bRFS noted in low and favourable intermediate risk groups (100% vs 100% and 92% vs 93% respectively) (Morton et al., 2020). Two-thirds (71%) of biochemically recurred patients found to have local recurrence disease. The median time of biochemical recurrence was 47 months. Higher risk groups had higher 5-year biochemical recurrence risk. Acute and late toxicity profiles were minimum with acute G2 GU toxicity (2%) and GI toxicity (1%); late G2 GU toxicity (2%) and GI toxicity (0%) with no G3, G4 GU or GI toxicities. Conclusions: This prospective study had shown better overall 5-year bRFS especially in low and favourable intermediate risk groups with minimal toxicities. Therefore, single-fraction HDR monotherapy could be considered for elderly or patients with significant co-morbidities who are more suitable for single treatment rather than 2 fractions in these risk groups. Further randomised multicentre studies in these risk groups are suggested.

Effects of gold fiducial marker implantation on tumor control and toxicity in external beam radiotherapy of prostate cancer.

Evidence regarding the effects of fiducials in image-guided radiotherapy (IGRT) for tumor control and acute and late toxicity is sparse. Patients with primary low- and intermediate-risk prostate cancer, 40 with and 21 without gold fiducial markers (GFM), and treated between 2010 and 2015 were retrospectively included. The decision for or against GFM implantation took anaesthetic evaluation and patient choice into account. IGRT was performed using electronic portal imaging devices. The prescribed dose was 78 Gy, with 2 Gy per fraction. Biochemical no evidence of disease (bNED) failure was defined using the Phoenix criteria. Acute and late gastrointestinal (GI) and genitourinary toxicity (GU) were assessed using the Radiation Therapy Oncology Group criteria. Most patients did not receive GFM due to contraindications for anaesthesia or personal choice (60% and 25%). Regarding tumor control, no significant differences were found regarding bNED and overall and disease-specific survival (p = 0.61, p = 0.56, and p > 0.9999, respectively). No significant differences in acute and late GI (p = 0.16 and 0.64) and GU toxicity (p = 0.58 and 0.80) were observed. We were unable to detect significant benefits in bNED or in early or late GI and GU side effects after GFM implantation.

GSOR5 Presentation Time: 9:20 AM: Balloon Intravaginal Packing Reduces Rectal Dose and Toxicity in Brachytherapy for Cervical Cancer

<h3>Purpose</h3> To compare differences in normal tissue toxicity between conventional gauze vs. balloon intravaginal packing in women receiving brachytherapy for cervical cancer. <h3>Materials and Methods</h3> We retrospectively identified women with 2009 FIGO stage IB1-IVB cervical cancer who received definitive EBRT with cisplatin and T&O or T&R brachytherapy between 2010-2016 at our institution. The primary endpoints were rates of grade ≥2 vaginal, GU, and GI toxicity. Dose metrics were compared via the Mann-Whitney U test. Toxicity rates were estimated via the Kaplan-Meier method and compared via log-rank test, and factors associated with toxicity were identified with Cox regression analysis. <h3>Results</h3> 96 patients received brachytherapy with a median follow-up of 39 months. 32 patients received intravaginal gauze packing, while 64 patients received intravaginal balloon packing. Two balloon leakages occurred and were replaced with gauze packing for that fraction. Gauze packing was associated with significantly higher rectal D2cc vs. balloon packing (median 66 Gy gauze vs. 55 Gy balloon, p<0.01), but not with vaginal or bladder D2cc. As shown in the figure, on Kaplan-Meier analysis, gauze packing was also associated with higher rates of grade ≥2 vaginal toxicity vs. balloon packing (3-year rate 30.1% vs. 20.0%, p<0.05), GU (32.2% vs. 11.3%, p<0.05), and GI (42.3% vs. 18.4%, p<0.05) toxicity. Grade ≥3 vaginal (3-year rate 11.9% vs. 5.5%, p<0.05) and GI (21.0% vs. 4.8%, p<0.05) toxicity was also higher with gauze vs. balloon packing. On multivariate Cox regression analysis, gauze packing remained significantly associated with grade ≥2 vaginal toxicity (HR 5.15, 95% CI 1.41-18.85, p<0.05), but not with GU or GI toxicity. <h3>Conclusions</h3> Compared to conventional gauze packing, intravaginal packing balloons were associated with reduced rectal D2cc and late GI toxicity. Decreased rates of late vaginal and GU toxicity were also observed, though corresponding D2cc metrics were not significantly reduced.

Ten-Year Follow-Up on 160 Patients Treated with Hypofractionated Prostate Salvage Radiation Therapy

<h3>Purpose/Objective(s)</h3> Patients with biochemical failure after prostatectomy are commonly treated with standard fractionation radiotherapy requiring 6.5-8 weeks of treatment. GU003 recently reported favorable short-term efficacy and acceptable toxicity using hypofractionated salvage radiotherapy after prostatectomy. However, follow-up for the study is short and questions remain regarding whether late toxicities will remain acceptable. Here, we report on long term outcomes of patients treated with a similar regimen. <h3>Materials/Methods</h3> We evaluated a consecutive cohort of patients treated from 2003-2013 with salvage RT to 65-70 Gy in 25-28 fractions using image-guided IMRT. Freedom from biochemical recurrence (FFBR), prostate cancer specific survival (PCSS), and overall survival (OS) were assessed using Kaplan-Meier analysis. Factors associated with biochemical failure were assessed using Cox regression analysis (surgical margins, Gleason score ≥8, PSA nadir, time to detectable PSA, PSA doubling time, and presalvage PSA). Late GU toxicities were scored based on a modified LENT/RTOG grading system. <h3>Results</h3> A total of 160 patients were identified with a median follow-up of 155 months. Twenty-six patients (16.3%) received androgen deprivation therapy following surgery or concurrently with radiation and 20 patients (12.5%) had lymph nodes electively treated. FFBR was 63% at 5 years and 56% at 10 years; PCSS was 99% at 5 years and 93% at 10 years; OS was 97% at 5 years and 85% at 10 years. Factors associated with increased biochemical recurrence included negative surgical margin status and higher pre-salvage PSA (p =0.025, 0.050). Total incidence grade ≥3 late toxicities was 21.9% (n=35, 33 GU, 1 GI, 1 lymphovascular) which were observed a median of 101 months after the end of radiation. There were four late grade 4 toxicities and three observed deaths potentially associated with radiation (urothelial cancer, urosepsis related to a suprapubic catheter, and pelvic sarcoma). <h3>Conclusion</h3> Prostate cancer has a long natural history as do many late RT toxicities. This cohort of patients with >10 years follow-up treated with hypofractionated salvage RT shows long-term control comparable to that seen in other salvage RT series with long-term follow-up. Although we do not have a comparator group treated with standard fractionation, these data illustrate the importance of long-term follow-up when considering toxicity from salvage RT.

The Use of HA as Rectal Spacer in Prostate Cancer Patients Undergoing Hypofractionated RT: An Australian Experience

<h3>Purpose/Objective(s)</h3> To report the feasibility, post-operative complications and recto-prostatic separation achieved with hyaluronic acid (HA) inserted into the perirectal fat before definitive prostate radiotherapy (RT). <h3>Materials/Methods</h3> Fifty-seven patients with clinical stage T1-3 prostate cancer underwent transrectal ultrasound guided transperineal insertion of fiducial markers and HA into the perirectal space before volumetric arc RT between 7/2020 to 7/2021. Post insertion computerized tomography (CT) and magnetic resonance imaging (MRI) scans were obtained for treatment planning. HA feasibility, safety and recto-prostatic separation were assessed. The prescribed dose to the planning target volume (PTV) ranged from 60-62Gy in 20 fractions. <h3>Results</h3> The mean age was 74.7 years. The median PSA was 8.1 [Interquartile range (IQR)6.2-10.0]. The majority of patients had ISUP 2 adenocarcinoma (60%). The rest had ISUP 1 (11%) and ISUP 3 (30%). The disease risk was staged as early in 11%, favorable intermediate in 30%, unfavorable intermediate in 58% and high in 2%. Androgen deprivation therapy was delivered in 63%. HA insertion was completed with a 100% success rate. This was rated as ‘easy' to ‘very easy' 100% of the time. There were no device related complications, rectal perforation, serious bleeding, infections or allergic reactions. The mean prostate size was 43cc (IQR 30-55cc). Recto-prostatic separation at the base (measured 5mm below the prostate base), mid gland and apex (measured 5mm above the prostate apex) were 12mm (0.2), 11mm (0.2) and 0.9mm (0.1) respectively. The HA was also symmetrically placed in breadth at the mid gland in all patients. The mean rectal volume receiving 53Gy (rV53) was 3.2% (IQR 1.3-5.5) for patients receiving 60-62Gy. The median follow up was 13.5 months (IQR 9.5-17.5). The risk of any acute GU toxicity was 81%. The majority had grade 1 GU toxicity at 67% with urinary frequency, urgency and obstruction being the commonest reported side effects. The risk of any grade 2 GU toxicity was 14% with urinary obstruction (13%) and urgency (7%). The risk of any acute GI toxicity was 2%. Only 1 patient developed grade 1 GI toxicity with diarrhea. The risk of any late GU toxicity was 43%. The majority had grade 1 GU toxicity at 32% with urinary frequency, urgency and obstruction. The risk of any grade 2 GU toxicity was 11% with urinary obstruction (5%), urgency (5%) and incontinence (2%). The risk of any late GI toxicity was 2%. Only 1 patient had grade 1 GI toxicity with diarrhea. <h3>Conclusion</h3> HA was successfully inserted in all patients and was well tolerated. Recto-prostatic separation was symmetrical in length from the base to the apex and in breadth at the midgland. The risk of developing any acute GI toxicity was minimal at 2% with the use of HA. In addition, the risk of late GI toxicity was 2%, albeit with short follow up.