PURPOSE:Stereotactic body radiation therapy (SBRT) with focal boost to the dominant intraprostatic lesion (DIL) provides a strategy to enhance outcomes in high-risk localized prostate cancer while minimizing toxicity. This study assessed late toxicity and quality of life (QOL) following CyberKnife-based SBRT with a simultaneous integrated boost in localized prostate cancer. METHODS AND MATERIALS:Patients with newly diagnosed, biopsy-proven unfavorable intermediate- to high-risk localized prostate cancer (at least one of the following: Gleason ≥ 4+3, MRI-defined T3a N0, PSA ≥ 20) with ≤2 MRI-defined DILs were enrolled. Participants received 36.25 Gy in 5 fractions with a simultaneous focal boost ≤47.5 Gy delivered using CyberKnife. All participants received androgen deprivation therapy. The current analysis reports RTOG-assessed late genitourinary (GU) and gastrointestinal (GI) toxicity, late International Prostate Symptom Score and urinary QOL, late International Index of Erectile Function 5-Questionnaire assessed sexual function, late EQ5D-5L QOL, and biochemical outcomes at 2 years. RESULTS:Between 2013 and 2023, 20 participants were enrolled with a median follow-up of 54 months (IQR, 24-108 months). The median D95 dose delivered to the DIL was 47.43 Gy. At 2 years, the cumulative rate of RTOG-assessed grade ≥2 GU and GI toxicity was 35% (95% CI, 15%-59%) and 5% (95% CI, 1%-25%), respectively. The prevalence of grade 2 GU and GI toxicity at 2 years was 0% and there was no late grade 3 GU and GI toxicity. There was no clinically significant worsening of EQ5D-5L-assessed QOL, International Prostate Symptom Score score, and urinary QOL scores at 2 years compared with baseline. There was a reduction in International Index of Erectile Function 5-Questionnaire scores for sexual function at 2 years (median 10; IQR, 5-18) from baseline (median 18; IQR, 6-22). There is one case of biochemical relapse reported to date. CONCLUSIONS:CyberKnife-based SBRT delivering 36.25 Gy to the prostate with a simultaneous integrated boost ≤47.5 Gy is well tolerated at 2 years. The cumulative rates of grade ≥2 GU and GI toxicity were 35% and 5%, respectively, consistent with other contemporary SBRT trials with and without focal boost.

OBJECTIVES:To describe the incidence, characteristics and mortality of men who present with complications of metastatic prostate cancer, a previously under-reported population. We investigate men who present with and without malignant ureteric obstruction (MUO) and skeletal-related events (SREs), collectively termed 'metastatic-related events' (MREs). PATIENTS AND METHODS:We used the English Cancer Registry linked to hospital administrative data to identify men diagnosed with metastatic prostate cancer between January 2015 and December 2022. Poisson regression models estimated adjusted relative risks (aRRs) of presenting with MREs. The cumulative incidences of overall and prostate cancer-specific death were estimated for each MRE subgroup (metastatic without MRE, MUO, SRE, and MUO and SRE in combination). RESULTS:Of 48 171 men diagnosed with primary metastatic disease, 4272 (8.9%) presented with MREs. Of these men, 2453 (57.4%) had MUO, 1738 (40.7%) had a SRE, and 81 (1.9%) had both. Men aged ≥80 years had the highest risk (9.8% [1604/16452]) of presenting with MREs. Men aged 70-79 years (8.0% [1470/18397]) (aRR 0.82, 95% confidence interval [CI] 0.77-0.88) and men aged 60-69 years (8.9% [916/10297]) (aRR 0.91, 95%CI 0.84-0.98) had lower risks. Men from the most deprived neighbourhoods (9.3% [706/7609]) (aRR 1.27, 95% CI 1.15-1.40) had greater risks of presenting with MREs than those from the least deprived neighbourhoods (8.0% [868/10865]). The proportion of men presenting with MREs varied across geographical regions, ranging from 4.6% (288/6233) to 11.7% (461/3951). The 5-year overall mortality for men presenting without MREs was 57.8% (95% CI 57.2-58.4%), compared to 77.1% (95% CI 74.9-79.2%) with MUO, 66.8% (95% CI 64.1-69.4%) with a SRE and 84.4% (95% CI 74.1-94.7%) with both. CONCLUSIONS:The risk of presenting with metastatic prostate cancer and MREs varies according to age, socioeconomic deprivation, and residential region. These men have poorer survival outcomes than men diagnosed without MREs at diagnosis.

PURPOSE:Advances in imaging have enabled identification of intraprostatic GTVs, creating opportunities for micro-boosting in prostate radiotherapy. However, variability exists in patient selection, target delineation, and treatment planning. This study aimed to characterize expert contouring variability and establish consensus guidance for GTV micro-boosting using a contour-based modified Delphi consensus. METHODS:International radiation oncologists with expertise in GTV micro-boosting participated in a two-part study comprising a contouring exercise and a two-round modified Delphi consensus. Participants contoured GTVs on two prostate cancer cases with mpMRI and PSMA-PET imaging, including one complex case with imaging discordance. Contouring agreement was assessed using Fleiss' kappa, intraclass correlation coefficients (ICC), and STAPLE analysis. Subsequently, participants completed iterative Delphi surveys addressing patient selection, imaging requirements, contouring practices, and treatment planning. Consensus and strong consensus were predefined as ≥75% and ≥90% agreement, respectively. RESULTS:Fifteen of 20 invited experts completed the study. Contouring agreement was high in the simpler case but substantially lower in the complex case. PSMA-PET-based GTVs were consistently larger than mpMRI-based GTVs. Overall, consensus or strong consensus was achieved for 43 of 131 statements (33%). Agreement was reached on key aspects of GTV delineation, including use of combined T2 and DWI/ADC sequences on mpMRI, eligibility of PI-RADS 4-5 and PROMISE 4-5 lesions for boosting, preferred use of PSMA-targeted tracers, and avoidance of CTV margins when PET and MRI information are used in combination. No consensus was achieved on SBRT micro-boosting outside clinical trials, margin expansion using single-modality imaging, or optimal dose prescriptions to the GTV or uninvolved prostate. CONCLUSION:This contour-based modified Delphi study demonstrates variability in GTVs delineation for complex cases and identifies areas of expert consensus that can inform standardized implementation of prostate GTVs micro-boosting.

PURPOSE:Modern technology has facilitated dose-escalated stereotactic body radiation therapy (SBRT) through real-time soft-tissue delineation and adaptive radiation therapy for locally advanced/unresectable pancreatic cancer (LAPC). The current study examined published prospective trials in SBRT for LAPC to inform clinical decision-making with support from the International Stereotactic Radiosurgery Society. METHODS AND MATERIALS:A systematic review and meta-analysis was conducted of all prospective trials in definitive SBRT (up to 6 fractions) for LAPC. Random-effects meta-analysis was performed, and metaregression was used to assess the effect of covariates on outcomes of interest, including local control (LC), progression-free survival (PFS), overall survival (OS), and toxicities. RESULTS:A total of 23 prospective studies were identified, including 901 patients. Most studies (n = 21, 91.3%) used systemic therapy before SBRT and delivered a median dose of 40 Gy in 5 fractions (range, 24-50 Gy in 3-6 fractions). The pooled 12- and 24-month LC estimate was 82% and 70%, respectively; 12-month PFS and OS rates were 35% and 63%, respectively; and 24-month PFS and OS rates were 15% and 28%, respectively. On univariable metaregression, SBRT with ≥5 fractions was associated with improved 12-month LC and OS. Inclusion of an elective clinical target volume was associated with improved 24-month PFS and OS. A higher biologically effective dose (BED10) was associated with improved 24-month LC and OS. Surgery was associated with improved 12- and 24-month OS and 12-month PFS. The pooled estimate for risk of any grade 3-4 toxicities was 2%, and that of grade 5 toxicities was 0.2% (7 events), mostly gastrointestinal bleeding. There were no predictors of grade 3-4 or 5 toxicities. CONCLUSIONS:Modern radiation therapy techniques allow safe delivery of high radiation doses for LAPC. SBRT provides excellent and durable LC with low rates of treatment-related grades ≥3 toxicities.

PURPOSE:Stereotactic Body Radiation Therapy (SBRT) schedules for prostate cancer are emerging as a standard treatment approach. However, although high efficacy is achieved in clinical trials, additional efforts at accurate treatment delivery are necessary to maximize the therapeutic ratio in the community setting. Kilovoltage Intrafraction Monitoring (KIM) is a technology developed to address the unmet clinical need of accurate intrafraction motion management without a requirement for additional hardware on standard linear accelerators. This paper describes the journey from bench to bedside of KIM. METHODS AND MATERIALS:The concept of KIM emerged in 2008 in a series of simulations, progressing to phantom experiments commencing in 2010, culminating in the first clinical trial starting in 2014. A series of technical innovations integrating rotational prostate movements, quality assurance, and dynamic multileaf collimator tracking were included within the multi-institutional Trans-Tasman Radiation Oncology Group 15.01 Stereotactic Prostate Adaptive Radiation therapy using KIM clinical trial for prostate SBRT. RESULTS:Submillimeter accuracy of KIM was observed in simulations, phantom experiments, and clinical trials. The Stereotactic Prostate Adaptive Radiation therapy using KIM trial demonstrated multicenter feasibility of use, a high rate of intrafraction motion triggering a gating event, and a significant dosimetric impact of KIM deployment for target volume coverage. KIM is being made available through commercialization with an industry partner, and through a 300-patient, 10-center clinical trial. CONCLUSIONS:The collaboration between researchers, clinicians, and industry has led to KIM being developed from a concept to clinical trials, enabling the safe delivery of prostate cancer SBRT in the presence of intrafraction motion. This journey provides a template for similar bench-to-bedside translational research.

Technological advances in online adaptive radiotherapy (oART) are set to revolutionise the treatment of prostate cancer (PCa). Yet, the need for a multi-disciplinary team oversight at every fraction remains a significant resource barrier to wider implementation. This practice-development paper explores the cost-consequence analysis and the operational implications of delegating online contouring responsibilities to therapeutic radiographers (RTTs) within an established MRI-guided online adaptive radiotherapy (oART) PCa service. Using a discrete-event simulation model informed by single-centre workflow data, the implications of RTT- and radiation oncologist (RO)-contoured workflows are discussed in terms of personnel costs, RO time, and patient throughput. With RTT online contouring generating substantial cost savings, demonstrating how reallocation of tasks can improve service efficiency and support sustainable oART. Highlighting the importance of workforce development and economic evidence to help to inform policy decisions, with the aim to broaden access to adaptive radiotherapy worldwide.

A steady rise in the number of patients receiving stereotactic body radiation therapy (SBRT) for primary prostate cancer is expected. Consequently, the current European Society for Radiotherapy and Oncology (ESTRO) 'how to' consensus has been developed to offer practical recommendations for the initiation and implementation of prostate SBRT in radiotherapy (RT) departments. A panel of fifteen experts in the field of prostate SBRT reviewed and analysed the literature and, through a Delphi process, answered a ten-item questionnaire addressing areas of controversy in prostate SBRT. Consensus was a priori defined as ≥75% agreement in each answer, while ≥90% agreement was defined as strong consensus. The aim of this 'how to' consensus recommendations is to define minimum requirements, common practices and additional options for prostate SBRT based on scientific evidence, expert opinion and consensus. This 'how to' clinical practice recommendations cover patient selection and follow-up process, treatment planning and delivery techniques in prostate SBRT.

BACKGROUND:Stereotactic body radiotherapy (SBRT) is effective for localised prostate cancer but increases genitourinary adverse events (AE). Focal boost to the dominant lesion may improve disease control. The DESTINATION study investigates whole gland dose de-escalation, with focal boost, using MR-guided adaptive radiotherapy (MRgART), to maintain cancer control whilst demonstrating acceptable AE. METHODS:DESTINATION is a prospective, phase II federated study that enrolled men with localised prostate cancer across three institutions (The Royal Marsden Hospital, Sunnybrook Health Sciences Centre, and The Netherlands Cancer Institute). Patients received MRgART with daily online replanning to deliver 30 Gy in 5 fractions to the whole prostate with no margin. The gross tumour volume (GTV) + 4 mm intra-prostatic margin received an isotoxic boost of 45 Gy. Acute AE were assessed using CTCAEv5 at baseline, end of treatment, 4 weeks, and 12 weeks post-treatment. Patient-reported outcomes were collected using IPSS, EPIC-26 and IIEF5. RESULTS:All 60 patients completed 12-weeks follow-up. Grade 2 genitourinary AE occurred in 55 % of patients by 12 weeks. Grade 2 gastrointestinal AE occurred in 11.7 %. Patient-reported outcomes demonstrated expected symptom flare at final fraction of treatment followed by gradual recovery. EPIC scores were consistently higher at NKI compared to RMH/SB, with sexual function decline during follow-up across all centres. CONCLUSION:The DESTINATION study demonstrates that dose de-escalation 5-fraction SBRT with isotoxic focal boost produces acute AE rates similar to or above the levels seen in the PACE-B trial. The focal boost may have offset any potential decrease in AE from whole gland de-escalation.

BACKGROUND:Prostate biopsy is a complex, multi-step procedure lacking standardisation across patient selection, tools, technique, and biopsy strategy, potentially influencing local treatment planning. An international consensus project was initiated to harmonise these aspects. METHODS AND ANALYSIS:A systematic review informed statement development. A modified Delphi process involving 34 international experts was conducted over three rounds. Panellists evaluated 96, 99, and 112 statements in Rounds 1-3, respectively, grouped into 36 stems. Statements were iteratively revised based on feedback and discussion. Consensus was assessed using a modified RAND appropriateness method. KEY FINDINGS AND LIMITATIONS:All experts completed the three rounds. Consensus was achieved for 29 of 36 stems (81%). Both biparametric and multiparametric magnetic resonance imaging were endorsed within the diagnostic pathway, provided imaging quality is adequate. Key elements of a targeted plus perilesional biopsy scheme were harmonised. For treatment planning, a targeted ± perilesional biopsy scheme was considered sufficient for most aspects of local treatment planning. However, additional contralateral sampling still seems necessary for specific indications, notably focal therapy candidate selection. Limitations include imbalances in specialty representation and heterogeneity in expertise across topics. CONCLUSION AND CLINICAL IMPLICATIONS:The ProBIOPSY consensus defines a contemporary, standardised framework for prostate biopsy. While targeted-based strategies are sufficient for most clinical scenarios, no single biopsy approach provides complete information for all treatment decisions, underscoring the need for indication-specific biopsy tailoring.

Prostate cancer poses a substantial clinical challenge and accounts for a large proportion of cancer-related deaths worldwide. The therapeutic landscape has undergone a large transformation in the past 5 years, resulting in improved patient outcomes. In this Seminar, we review the pathology, diagnostic strategies, and treatments for prostate cancer. Active surveillance is the preferred treatment option for patients with indolent prostate cancer. For those requiring treatment, local therapies provide effective cancer control. Systemic treatment is essential for advanced and metastatic cases, and a wide range of therapies are now available, including androgen deprivation therapy, chemotherapy, and emerging targeted agents such as lutetium-177-labelled prostate-specific membrane antigen radioligand therapy and PARP inhibitors. Considering toxicity profiles alongside patient preferences is important to facilitating shared decision making. Further research is needed to establish the most effective sequence and combination of treatments for metastatic prostate cancer.

Cancer treatment evolves, often under the selective pressures of clinical trials. Although some indications in radiation oncology are fading, new possibilities are emerging. Phase III randomized controlled trials remain the most immediate and influential drivers of evolution, sometimes changing practice overnight. Yet radiation oncology has increasingly struggled to keep pace in this sector. There are several important reasons why practice-defining phase III trials for stereotactic radiation therapy (SRT) (and for radiation oncology more broadly) are not being conducted as often as they should be. These headwinds include: (1) funding challenges and regulatory burdens; (2) phase III bypass and loss of equipoise; (3) nonaligned endpoints and patient-centered outcomes; and (4) value, equity, and opportunity costs. Corresponding solutions must be based on (1) diversified funding models; (2) more efficient trial designs; (3) patient-centered outcome priorities; and (4) consensus on evidence standards for funding and adoption. The continued evolution of SRT will require deliberate investment and collaboration, with an emphasis on robust, rigorous, patient-centered evidence.

308 Background: Risk stratification in localised prostate cancer (PCa) based on clinicopathological parameters is inadequate, leading to under- and over-treatment. We used CHHiP trial data to externally validate a previously-developed MMAI prognostic model with potential for cost-effective improved treatment personalisation. Methods: H&E slides from CHHiP translational substudy patients were centrally reviewed by a uro-pathologist between 2013 and 2015, with Gleason grade group (GGG) rescored using contemporary guidelines. GGG was reassigned in 52% of cases. We evaluated the locked ArteraAI prostate MMAI algorithm v1.2 which combines age, T-stage, and PSA with digital prostate biopsy H&E images. Multivariable cox regression analysis of biochemical/clinical recurrence (BCR; trial primary endpoint) and development of distant metastases (DM) were performed with models including age and MMAI as continuous (per 0.1 increase) and categorical (ArteraAI pre-validated 3-tier risk groups) variables. The additional prognostic value of MMAI beyond UK-recommended Cambridge Prognostic Group (CPG) and NCCN risk group models was assessed by change in Concordance Index and Likelihood Ratio Test (LRT). Results: Of 1854 patients with centrally-reviewed pathology, 1797 (97%) had clinical data and H&E with sufficient tumour for MMAI analysis. Median follow up was 14.3 years. Patients were classified as MMAI High (129, 7.2%), Intermediate (885, 49.2%) or Low (783, 43.6%). In univariable analysis, high MMAI score was significantly associated with increased BCR risk, as both a categorical variable (MMAI High risk hazard ratio (HR) = 5.07, 95%CI = 3.77-6.81, p=<0.001, MMAI Intermediate-risk HR = 1.90, 1.52-2.36, p=<0.001), and continuous variable (MMAI raw score HR = 1.55, 1.44-1.67, p=<0.001). MMAI was also significantly associated with DM. Addition of MMAI to CPG and NCCN multivariable models significantly improves discrimination (C-index) and overall fit (change in LRT) for BCR and DM (Table 1). Conclusions: ArteraAI MMAI improves prediction of BCR and DM in CHHiP over standard criteria. This first large-scale external validation in a contemporary UK cohort of localised PCa with rigorously standardized care will inform future prospective trials of MMAI biomarker-guided PCa treatment selection. Endpoint Model C index (MMAI risk group) ΔLRT χ² (p) C index (MMAI raw score) ΔLRT χ² (p) BCR CPG + ageCPG + age + MMAI 0.620.65+0.03 p=<0.001 55.6 p=<0.001 0.620.67+0.05 p=<0.001 67.5 p=<0.001 BCR NCCN + ageNCCN + age + MMAI 0.590.64+0.05 p=<0.001 67.2 p=<0.001 0.590.66+0.07 p=<0.001 80.9 p=<0.001 DM CPG + ageCPG + age + MMAI 0.650.71+0.06 p=0.001 35.3 p=<0.001 0.650.73+0.08p=<0.001 47.0 p=<0.001 DM NCCN + ageNCCN + age + MMAI 0.610.70+0.09 p=<0.001 43.4 p=<0.001 0.610.72+0.11 p=<0.001 55.8 p=<0.001 Total, n=1794. Events BCR, n = 426 (23.7%), DM, n = 121 (6.7%).