PURPOSE:To evaluate the safety of moderately hypofractionated radiotherapy to the prostate and pelvic elective nodal irradiation (ENI) with intraprostatic and nodal boost in patients with high-risk prostate cancer. METHODS:In this prospective phase 2 single-arm study, patients with high-risk or node-positive prostate cancer received external beam radiotherapy to the prostate and ENI with moderate hypofractionation (60 Gy in 20 fractions to the prostate; 48 Gy ENI) with ADT. Simultaneous integrated boosts were allowed to 68 Gy to intraprostatic gross disease (MRI-defined) and 55 Gy to radiographically-involved nodes. The primary endpoint was acute gastrointestinal (GI) side effects (CTCAE v5.0) at 3 months following radiotherapy, with an a priori hypothesis that acute grade ≥ 2 GI side effects would not exceed 35%. Secondary endpoints included acute genitourinary (GU) side effects and quality of life (QoL) (EPIC-26 and IPSS). RESULTS:100 patients were enrolled; 97 completed treatment. Median age was 73, 49% had grade group 4-5 disease, median PSA was 22.2 ng/mL, 21% were cN1. 23 (24%) and 18 (19%) of patients received intraprostatic and nodal boosts, respectively. The rate of acute grade ≥ 2 GI side effects was 15.5% (one-sided 95% upper confidence bound22.8%). On univariable analysis, higher rectal and bowel D1cc and intraprostatic boost were significantly associated with increased acute GI side effects. The rate of grade ≥ 2 acute GU side effects was 26.8% (95% CI 18.3-36.8%). There was no statistically significant detriment to mean GI or GU QoL at 3 months post-treatment. CONCLUSIONS:Moderately hypofractionated radiotherapy to the prostate and ENI with boosts to gross disease was associated with lower-than-expected side effects and no statistically significant detriment to patient-reported mean GI or GU QoL at 3 months post-treatment.

Introduction Salvage radiotherapy (sRT) is an effective curative option for patients with biochemical recurrence following radical prostatectomy (RP). However, a subset of patients will develop local recurrence (LR) following treatment. Predictive factors and patterns of LR after sRT remain poorly defined. This study evaluates clinicopathological predictors of LR and characterizes failures anatomically relative to prior sRT fields. Methods Patients who received RP followed by sRT and subsequently underwent 18F-PSMA PET/CT for biochemical recurrence were identified from a prospective imaging registry. Logistic regression and Fine–Gray competing risks analyses were used to evaluate clinical, pathological, and treatment-related predictors of LR. Anatomical mapping localized LR relative to prior radiotherapy fields. Results Among 370 eligible patients, 68 (18.4%) had LR after sRT, including 34 (9.2%) with isolated LR. Median PSA at time of imaging was 0.77 ng/mL (IQR: 0.40-2.10 ng/mL) overall, and 0.83 ng/mL (IQR: 0.41-3.33 ng/mL) for patients with LR. On UVA, Gleason grade groups 1-3 and pN0 status were significantly associated with LR (p < 0.05). No variables remained significant on multivariable analysis. Fine–Gray analysis identified younger age and longer PSA doubling time as additional predictors of LR. Of all patients with LR, 35 had sRT plans available for spatial analysis, encompassing 39 discrete lesions. When mapped to the treatment-planned CTV, 29 lesions (74.4%) were in-field, 8 (20.5%) marginal, and 2 (5.1%) out-of-field. Marginal and out-of-field lesions commonly involved the posterior prostatic fossa and seminal vesicle bed. Conclusion PSMA PET/CT identified LR in nearly one-fifth of patients undergoing PSMA imaging for biochemical recurrence following sRT. Although most recurrences were within the treated volume, their distribution highlights anatomical regions that may benefit from additional attention at the time of planning.

We report early toxicity outcomes after institutional implementation of prostate SBRT using 42.7 Gy in seven fractions delivered with either MR-guided adaptive SBRT (MRgSBRT) or CT-guided non-adaptive SBRT (CTgSBRT). Between July 2019 and May 2023, 216 patients received this regimen. Genitourinary (GU) and gastrointestinal (GI) toxicities were retrospectively assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Most patients had intermediate-risk disease (86%), and 14% had high-risk disease. Median prostate volume was 40 mL, and median baseline International Prostate Symptom Score (IPSS) was 8 among patients with available data. MRgSBRT and CTgSBRT were used in 100 (46%) and 116 (54%) patients, respectively. At a median follow-up of 19 months, 12- and 24-month grade ≥ 2 GU toxicity rates were 20.0% and 18.2%, while grade ≥ 2 GI toxicity rates were 3.5% and 3.6%, respectively. No statistically significant platform-related differences were detected; however, these comparisons were exploratory and potentially confounded by nonrandomized platform selection, treatment era, rectal-spacer use, adaptive workflow and differing PTV margins. On univariable analysis, baseline GU symptoms were associated with higher 12-month grade ≥ 2 GU toxicity (OR, 3.68; 95% CI, 1.52–10.37; p = 0.007), while prostate-volume category was not significantly associated with this endpoint.

In radiotherapy for cancer, organs surrounding the target tumor, known as organs-at-risk (OARs), should be protected from excessive radiation to avoid toxicity. Radiation exposure to multiple OARs can be summarized using matrix-valued dose-volume histograms (DVH), and understanding the causal relationship between DVHs and toxicity outcomes can improve treatment planning. Conventional causal models are not tailored to high-dimensional, highly correlated matrix-valued data. In this paper, we propose a Bayesian three-component joint model for a matrix-valued DVH exposure with a causal interpretation. Dimension reduction is achieved via multilinear principal component analysis (MPCA), which extracts information from matrices more efficiently than conventional PCA. A Hamiltonian Monte Carlo algorithm is adapted for estimation. We demonstrate the model's performance in estimating average causal effects through simulations. For interpretation, we map dose effects back to the original DVH matrix, illustrating that our model can correctly identify relevant effects in both simulation and application studies.

e17052 Background: Bone-targeting agents (BTAs) are guidelines-recommended to reduce SREs in patients with mCRPC and bone metastases. Despite this, BTAs remain underutilized, and the optimal duration of therapy remains undefined. This knowledge gap is particular relevant for patients with mCRPC receiving Ra-223, who are at high risk for SREs. Methods: Patients with mCRPC and bone metastases treated with Ra-223 at PM between 2015 and 2024 were retrospectively reviewed. We evaluated the association between BTA duration (categorized as ≤2 versus >2 years), BTA-related adverse events (AEs) leading to discontinuation, and SREs (defined as compression, pathological fracture, or bone metastases requiring radiotherapy or surgery). Results: Among 252 patients treated with Ra-223, 115 (45.6%) received BTAs with evaluable duration data. Ra-223 was administered for a median of 5 cycles (range 1-6). Median age was 73.6 years (range 51.5-93.4), median baseline PSA was 38.0 ng/mL (range 0.4-6277.0) and 65 patients (57.0%) presented with de novo metastases. All patients received prior androgen receptor pathway inhibitor therapy, 45.2% had prior Docetaxel. After a median follow-up of 20.4 months (range 1.2-60), median overall survival was 19.2 months (95%CI 16.6-23.3). Of 115 patients, 40 (34.8%) received zoledronic acid, 69 (60.0%) denosumab and 6 (5.2%) both. Median BTA duration was 20.4 months (range 0.3-115.2). BTA discontinuation occurred in 110 patients (95.7%), with AEs accounting for 37.2% (Table). Compared to ≤2 years, BTA duration >2 years was associated with numerically higher but non-signficant rates of AEs leading to discontinuation (34.9% vs 40.4%). Numerically higher SREs rates (57.6% vs 65.3%) in patients who received BTAs >2 years reflected a greater cumulative risk of SREs over time. Conclusions: In patients with mCRPC treated with Ra-223, BTAs were underutilized, BTA discontinuation due to AEs were frequent, while SRE rates remained high. Within the limitation of sample size, BTA duration >2 years was associated with numerically higher but non-significant increase in AE-related discontinuation. These findings support BTA use beyond 2 years in selected high-risk patients, however highlight the need for AE management and future prospective studies to define the optimal BTA duration. BTA duration p -value Reason for BTA discontinuation ≤2yrsn=63 (%) >2yrsn=47 (%) 0.74 AEs Hypocalcemia Anemia Osteonecrosis of jaw Bone pain Osteomyelitis Renal dysfunction 22 (34.9%) 11 (16.7%) 1 (1.5%) 4 (6.1%) 4 (6.1%) 1 (1.5%) 1 (1.5) 19 (40.4%) 7 (14.3%) 0 (0%) 5 (10.2%) 4 (8.2%) 3 (6.1%) 0 (0%) Disease progression / best supportive care 35 (55.6%) 21 (44.6%) Death 4 (6.3%) 4 (8.5%) Other 2 (3.2%) 3 (6.4%)

BACKGROUND AND OBJECTIVE:The PROFIT trial was designed to compare moderately hypofractionated (HF) radiotherapy versus conventional fractionation (CF) for patients with intermediate-risk prostate cancer (IR-PC). Similar efficacy and toxicity outcomes were previously reported. The aim of the current analysis was to evaluate differences in long-term patient-reported outcomes (PROs) between the HF and CF arms in PROFIT. METHODS:For the PROFIT phase 3 randomized clinical trial, patients with IR-PC (n = 1206) were enrolled from 14 sites in Canada, 12 in Australia, and one in France and randomized to receive 78 Gy in 39 fractions over 8 wk (CF) or 60 Gy in 20 fractions over 4 wk (HF). PROs were evaluated at baseline and 24 and 48 mo using the Expanded Prostate Cancer Index Composite, American Urological Association Symptom Score (AUASS), and the 12-item Short Form Health Survey (SF-12) comprising a physical component summary (PCS) and a mental component summary (MCS). A minimally important difference (MID) was defined as a deterioration in domain- or subdomain-specific health-related quality of life (HRQoL) score by ≥0.5 times the standard deviation at each time point in comparison to baseline. Statistical significance was set at p < 0.01. KEY FINDINGS AND LIMITATIONS:AUASS results were similar and stable over time in both arms (median 5 points, interquartile range 2-9; p > 0.2). There were no significant differences in scores for urinary, bowel, sexual, and hormonal domains or subdomains between the arms at any time point (p > 0.02). The greatest decline over time occurred in sexual domain, with a decrease of ≥10 points from baseline to 24 mo in both arms. SF-12 mean scores for both PSC and MSC were similar in the two arms and remained stable at all time points. The only significant differences in the proportion of patients reporting MIDs were for the bowel subdomains at 48 mo, with significant MID reductions favoring HF for both the bowel summary score (53% vs 44%; p = 0.01) and bowel function score (51% vs 39%; p = 0.001). Overall treatment satisfaction was high in both arms: ≥88% of patients were either satisfied or extremely satisfied with their treatment. CONCLUSIONS AND CLINICAL IMPLICATIONS:PRO results from the PROFIT trial suggest no significant differences in urinary, bowel, sexual, hormonal, and general HRQoL between CF and HF radiotherapy schedules. This study provides level 1 evidence supporting the use of moderate HF radiotherapy as standard treatment in patients with IR-PC. This trial is registered on ClinicalTrials.gov as NCT00304759.

PURPOSE:We evaluate the effectiveness of radiation therapy (RT) dose constraints on bone in reducing the incidence of radiation-associated fractures in patients with LE-STS treated with image guided RT and modern treatment planning techniques. We had established these constraints as bone avoidance objectives for RT planning in 2005 after observing a 4.5% rate of bone fracture in patients. The ultimate goal is to improve functional outcome following external beam radiation therapy (RT) combined with limb salvage surgery for lower extremity soft tissue sarcomas (LE-STS) which can be associated with significant long-term complications, such as bone fractures, which can lead to multiple surgeries or amputation. METHODS AND MATERIALS:We retrospectively analyzed a prospectively maintained database of all patients with LE-STS who received curative-intent RT that was planned using evidence-based bone avoidance objectives between January 2005 and December 2020 at our institution. Using a standard bone volume contoured 2 cm above and below the planning target volume, the following RT planning objectives were extracted for patients with and without a fracture: mean dose to bone, RT treatment volume, maximum dose to bone, and volume of bone irradiated to ≥40 Gy (V40). Fracture site dose was determined by comparing radiographic images and surgical reports to fracture location on the RT plan with isodose distribution. Patient and tumor factors, treatment details, and patient survival were extracted from medical records and compared between the fracture and non-fracture patient cohorts. The χ2 test was used to analyze categorical variables, a Student ttest was used to analyze continuous variables and t test was used to compare means. Survival was estimated using the method of Kaplan-Meier. RESULTS:Between January 2005 and December 2020, 700 eligible patients were assessed, 594 patients (84.9%) received preoperative RT, 103 (14.7%) received postop RT, and 3 (0.4%) both. At a median follow-up of 55 months, 10 patients (1.4%) developed radiation-associated fracture. Two of these patients developed a fracture after reirradiation of the extremity and 2 of the remaining 8 patients did not meet the radiation dose bone constraints. Of the full cohort, 14 patients (2%) had an intramedullary nail and there was only one fracture in this subgroup. Twenty patients (2.8%) in the entire cohort required bone resection necessitating replacement with a prosthesis or an allograft. The mean time to fracture was 41.7 months. Fracture management varied from conservative treatment to amputation. Local recurrence occurred in 44 patients (6.3%) and 248 patients (35.4%) developed metastasis. CONCLUSIONS:The overall fracture risk after RT is reduced with modern planning techniques using the radiation dose constraints to a bone volume contoured 2 cm above and below the planning target volume. RT treatment planning for LE-STS should include a focus on limiting radiation dose to the bone to minimize the risk of fracture. For high-risk patients, prophylactic intramedullary nailing of the femur may help prevent radiation-associated fractures.

BACKGROUND AND PURPOSE:Changing to next-line systemic therapy is the standard-of-care for patients with progressive metastatic castrate-resistant prostate cancer. However, to preserve systemic therapy options and minimize toxicity, stereotactic body radiation therapy (SBRT) is being increasingly considered for patients with limited disease progression ('oligoprogression'). Herein, we report clinical, toxicity and quality of life (QOL) outcomes for an oligoprogressive prostate cancer cohort from a prospective trial. MATERIALS AND METHODS:RADIANT (NCT04122469) was a single-arm, phase-II basket trial which included patients with metastatic prostate cancer on any systemic therapy ≥ 3 months, with radiographic evidence of oligoprogression in ≤ 5 sites. Analysis by disease site was planned a priori. Patients received SBRT in 1-5 fractions to all progressive sites and were maintained on their current systemic therapy. The primary endpoint was cumulative incidence of change in systemic therapy. Key secondary endpoints included local control, toxicity and health-related (HR) QOL. RESULTS:Thirty-two patients were analyzed; median age was 74.0 years, median PSA 6.7 µg/L, 25% with visceral metastases and a median of 2 prior systemic therapy lines. Median follow-up was 14.1 months (range 4.8-51.9 months). At 1-year, 55.1% of patients remained on the same systemic line and local control was 84.0%. The cumulative incidence of grade 2 toxicity was 25.0% at 1 year, with no grade 3+ toxicities. HRQOL was maintained, with no detriment following SBRT delivery. CONCLUSION:Among patients with oligoprogressive prostate cancer, SBRT is an effective and safe intervention, including in patients with aggressive clinicopathologic features. Larger, randomized trials are needed to validate these findings.

PURPOSE:Stereotactic body radiation therapy (SBRT) represents a novel, efficacious treatment for patients with kidney tumors who are medically inoperable or decline surgery. There is limited prospective data on the impact of kidney SBRT on renal function. METHODS AND MATERIALS:This was a prospective phase 2 single-arm clinical trial (clinicaltrials.gov NCT03747133) of kidney-directed SBRT in patients with primary or metastatic renal lesions who were medically inoperable or declined surgery. The primary outcome was the change in kidney function, assessed by the change in eGFR (estimated glomerular filtration rate) over 2 years. The a priori hypothesis was that eGFR (mL/min/1.73 m2) does not decrease over time and was analyzed using a 1 sample t-test for noninferiority with a fixed margin of -6.974 based on published data at the time of trial design. RESULTS:Thirty patients with 32 renal tumors enrolled, with a median (IQR) age of 76 (73-82), a Charlson comorbidity index of 8 (7-9), 93% with chronic kidney disease stage ≥2 (eGFR ≤60 mL/min/1.73 m2), and the majority with cT1b disease with a median tumor size of 43 mm. Twenty-six patients (87%) had primary kidney cancer, and the remainder had metastatic lesions from non-kidney cancer histologies. Median radiation dose was 35 Gy in 5 fractions. Median follow-up was 24.5 months (IQR, 20-36.2). Median (IQR) eGFR levels (mL/min/1.73 m2) were 47.5 (37.8-64.0) at baseline, 42.0 (35.2-54.2) at 1 year, and 39.5 (25.5-54.8) at 2 years. Eighteen of 30 patients were evaluable for eGFR at 2 years. Noninferiority was not established based on a mean reduction in eGFR between baseline and 2 years of -8.7 mL/min/1.73 m2 (95% 1-sided CI, -14.1, ∞; P = .71). Renal function decline was significantly associated with time, increasing age, baseline chronic kidney disease stages 3-4, and larger baseline tumor size on multivariable analysis. Local control was 96.7% at 2 years. CONCLUSIONS:Kidney-directed SBRT results in modest clinical renal function loss up to 2 years following SBRT, based on evaluable patients in our study. Technical advances may further improve the therapeutic ratio.

PURPOSE:Conventionally fractionated radiation therapy (CFRT) and hypofractionated RT (HFRT) are established treatments for intermediate-risk (IR) prostate cancer (PCa), with differing dose per fraction. However, their comparative patterns of failure remain unclear. This stuy aims to analyze the distinct relapse patterns of HFRT versus CFRT in terms of local progression-free survival (LPFS), pelvic lymph node metastasis-free survival (pnMFS), extrapelvic lymph node MFS (epnMFS), and bone MFS (bMFS). METHODS AND MATERIALS:Patients with IR PCa included in French and Australian centers in the "PROstate Fractionated Irradiation Trial (PROFIT)" study (NCT00304759), a phase 3, multicenter, randomized controlled trial. Using molecular positron emission tomography imaging, magnetic resonance imaging, and bone scintigraphy, the anatomic sites of relapse were retrospectively identified in biochemically relapsing patients after HFRT or CFRT. LPFS, pnMFS, epnMFS, and bMFS were compared between both treatment arms using Kaplan-Meier analyses. RESULTS AND LIMITATIONS:With a median follow-up of 6.4 years, 274 patients (130 HFRT and 144 CFRT) were included, among whom 35 (24.3%) in the HFRT arm and 28 (19.4%) in the CFRT arm experienced relapse. Median time to relapse varied by site: 4.9 years locally, 3.96 years for pelvic lymph nodes, 2.95 years for extrapelvic lymph nodes, and 3.6 years for bone metastasis. No significant differences were found between HFRT and CFRT arms in LPFS, pnMFS, epnMFS, or bMFS. CONCLUSIONS:Relapse rates after HFRT or CFRT are low, with no discernible variance in anatomical relapse patterns between treatments. Tailored management strategies considering these relapse patterns could optimize care of IR patients, including initial staging and microboosting of dominant lesions.

The incidence and predictors of brain metastases (BrM) from sarcoma remain poorly characterized. We aimed to determine the cumulative incidence (CuI) and risk factors for BrM. We retrospectively analyzed data from all sarcoma patients who presented to our center (2006–2023). CuI was calculated from initial presentation to BrM, stratified by key variables. Univariable (UVA) and multivariable competing risk regression analyses (MVA) were conducted to identify risk factors. Among 5110 sarcoma patients, 117 developed BrM. CuI rates were 1.8

Background:Intrathoracic soft tissue sarcomas are rare and heterogenous tumors with limited data guiding their management. Due to anatomical complexity and delayed diagnosis, treatment can be challenging. This study aimed to assess clinical outcomes and prognostic factors in intrathoracic soft tissue sarcoma patients treated at a high-volume referral sarcoma center. Methods:This bi-institutional retrospective cohort study (2007-2022) analyzed patients with histopathologically confirmed intrathoracic soft tissue sarcomas. Data from two prospective registries were used to assess overall survival (OS), local recurrence (LR), and distant metastasis (DM) via Kaplan-Meier, cumulative incidence, and multivariable Cox regression. Results:Among 49 patients (median age: 56 years, 55.1% male), 40 (81.6%) had localized and 9 (18.4%) had metastatic disease at diagnosis. The median follow-up was 15.6 months. The median OS was 37.1 months for localized, 5.9 months for metastatic cases. Among localized cases, 55% had recurrences, evenly split between local and distant. LR incidence was 39.4% at 12 months, 53.7% at 24 months; DM incidence was 38.8% and 53.4%. OS was worse in patients >65 years [hazard ratio (HR): 2.69, P=0.04] and with metastatic disease (HR: 4.84, P=0.02). DM risk was higher in grade 2 (HR: 19.38, P=0.03) and grade 3 tumors (HR: 12.65, P=0.02) and those in the lungs, pleura, or diaphragm (HR: 3.56, P=0.046). LR was not associated with grade, margin status, or perioperative therapy. Treatment modality had no impact on DM. Conclusions:Despite a small sample, this is the largest clinical cohort on intrathoracic soft tissue sarcomas, which carry high local and distant recurrence risks. Worse outcomes were linked to age >65 years, metastatic presentation, higher grade, and lung, pleura, or diaphragm location. Given their rarity, multi-institutional studies are needed to refine risk factors, treatment, and outcomes.

BACKGROUND:The association between acute and late toxicity following prostate radiotherapy has not been well studied using data from multiple randomised clinical trials and fractionation schedules. We aimed to characterise the relationship between acute and late genitourinary and gastrointestinal toxicity among patients receiving conventionally fractionated or moderately hypofractionated prostate radiotherapy. METHODS:This was an individual patient data meta-analysis that identified randomised phase 3 trials of conventionally fractionated or moderately hypofractionated prostate radiotherapy in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium that had individual-level acute and late toxicity data available and were available before Dec 1, 2023. Trials without individual patient data were excluded. Data were provided to MARCAP by study investigators. The associations between acute (≤3 months after radiotherapy) and late (>3 months after radiotherapy) grade 2 or greater genitourinary and gastrointestinal toxicities were assessed using adjusted generalised linear mixed models (adjusted for age, androgen deprivation therapy status, type of radiotherapy, radiation dose, and radiation schedule). In the subset of trials that collected Expanded Prostate Cancer Index Composite quality of life (QOL) evaluations, the association between acute genitourinary and gastrointestinal toxicity and decrements at least twice the minimal clinically important difference (MCID) for urinary and bowel QOL were also evaluated. FINDINGS:Six of 26 available trials met all the eligibility criteria. 6593 patients were included (conventionally fractionated: n=4248; moderately hypofractionated: n=2345). Median follow-up was 72 months (IQR 61-94). Acute grade 2 or greater genitourinary toxicity was associated with both late grade 2 or greater genitourinary toxicity (odds ratio 2·20 [95% CI 1·88-2·57], p<0·0001) and decrement at least twice the MCID in urinary QOL (1·41 [1·17-1·68], p=0·0002). Acute grade 2 or greater gastrointestinal toxicity was associated with both late grade 2 or greater gastrointestinal toxicity (2·53 [2·07-3·08], p<0·0001) and decrement at least twice the MCID in bowel QOL (1·52 [1·26-1·83], p<0·0001). INTERPRETATION:Acute toxicity following prostate radiotherapy was statistically significantly associated with late toxicity and with decrement in patient-reported QOL metrics. These data support efforts to evaluate whether interventions that reduce acute toxicity ultimately reduce the risk of late toxicity. FUNDING:National Institutes of Health and US Department of Defense.