Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

MRI-guided radiotherapy in twenty fractions for localised prostate cancer; results from the MOMENTUM study.

Background and purpose: MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac. Materials and methods: Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Results: Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months. Conclusion: This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.

Development of Prostate Bed Delineation Consensus Guidelines for Magnetic Resonance Image-Guided Radiotherapy and Assessment of Its Effect on Interobserver Variability.

PURPOSE: The use of magnetic resonance imaging (MRI) in radiotherapy planning is becoming more widespread, particularly with the emergence of MRI-guided radiotherapy systems. Existing guidelines for defining the prostate bed clinical target volume (CTV) show considerable heterogeneity. This study aimed to establish baseline interobserver variability (IOV) for prostate bed CTV contouring on MRI, develop international consensus guidelines, and evaluate its effect on IOV. METHODS AND MATERIALS: Participants delineated the CTV on 3 MRI scans, obtained from the Elekta Unity MR-Linac, as per their normal practice. Radiation oncologist contours were visually examined for discrepancies, and interobserver comparisons were evaluated against simultaneous truth and performance level estimation (STAPLE) contours using overlap metrics (Dice similarity coefficient and Cohen's kappa), distance metrics (mean distance to agreement and Hausdorff distance), and volume measurements. A literature review of postradical prostatectomy local recurrence patterns was performed and presented alongside IOV results to the participants. Consensus guidelines were collectively constructed, and IOV assessment was repeated using these guidelines. RESULTS: Sixteen radiation oncologists' contours were included in the final analysis. Visual evaluation demonstrated significant differences in the superior, inferior, and anterior borders. Baseline IOV assessment indicated moderate agreement for the overlap metrics while volume and distance metrics demonstrated greater variability. Consensus for optimal prostate bed CTV boundaries was established during a virtual meeting. After guideline development, a decrease in IOV was observed. The maximum volume ratio decreased from 4.7 to 3.1 and volume coefficient of variation reduced from 40% to 34%. The mean Dice similarity coefficient rose from 0.72 to 0.75 and the mean distance to agreement decreased from 3.63 to 2.95 mm. CONCLUSIONS: Interobserver variability in prostate bed contouring exists among international genitourinary experts, although this is lower than previously reported. Consensus guidelines for MRI-based prostate bed contouring have been developed, and this has resulted in an improvement in contouring concordance. However, IOV persists and strategies such as an education program, development of a contouring atlas, and further refinement of the guidelines may lead to additional improvements.

Recommendations for improved reproducibility of ADC derivation on behalf of the Elekta MRI-linac consortium image analysis working group.

BACKGROUND AND PURPOSE: The apparent diffusion coefficient (ADC), a potential imaging biomarker for radiotherapy response, needs to be reproducible before translation into clinical use. The aim of this study was to evaluate the multi-centre delineation- and calculation-related ADC variation and give recommendations to minimize it. MATERIALS AND METHODS: Nine centres received identical diffusion-weighted and anatomical magnetic resonance images of different cancerous tumours (adrenal gland, pelvic oligo metastasis, pancreas, and prostate). All centres delineated the gross tumour volume (GTV), clinical target volume (CTV), and viable tumour volume (VTV), and calculated ADCs using both their local calculation methods and each of the following calculation conditions: b-values 0-500 vs. 150-500 s/mm2, region-of-interest (ROI)-based vs. voxel-based calculation, and mean vs. median. ADC variation was assessed using the mean coefficient of variation across delineations (CVD) and calculation methods (CVC). Absolute ADC differences between calculation conditions were evaluated using Friedman's test. Recommendations for ADC calculation were formulated based on observations and discussions within the Elekta MRI-linac consortium image analysis working group. RESULTS: The median (range) CVD and CVC were 0.06 (0.02-0.32) and 0.17 (0.08-0.26), respectively. The ADC estimates differed 18% between b-value sets and 4% between ROI/voxel-based calculation (p-values < 0.01). No significant difference was observed between mean and median (p = 0.64). Aligning calculation conditions between centres reduced CVC to 0.04 (0.01-0.16). CVD was comparable between ROI types. CONCLUSION: Overall, calculation methods had a larger impact on ADC reproducibility compared to delineation. Based on the results, significant sources of variation were identified, which should be considered when initiating new studies, in particular multi-centre investigations.

Comparing adaptation strategies in MRI-guided online adaptive radiotherapy for prostate cancer: Implications for treatment margins.

PURPOSE: To quantify the difference in accuracy of adapt-to-position (ATP), adapt-to-rotation (ATR) and adapt-to-shape (ATS) workflows used in MRI-guided online adaptive radiotherapy for prostate carcinoma (PCa) by evaluating the margins required to accommodate intra-fraction motion of the clinical target volumes for prostate (CTVpros), prostate including seminal vesicles (CTVpros + sv) and gross tumor volume (GTV). MATERIALS AND METHODS: Clinical delineations of the CTVpros, CTVpros + sv and GTV of 24 patients with intermediate- and high-risk PCa, treated using ATS on a 1.5 T MR-Linac, were used for analysis. Delineations were available pre- and during beam-on. To simulate ATP and ATR workflows, we automatically generated the structures associated with these workflows using rigid transformations from the planning-MRI to the daily online MRIs. Clinical GTVs were analyzed as ATR GTVs and only ATP GTVs were simulated. Planning target volumes (PTVs) were generated with isotropic margins ranging 0.0-5.0 mm. The volumetric overlap was calculated between these PTVs and their corresponding clinical delineation on the MRI acquired during beam-on and averaged over all treatment fractions. RESULTS: The PTV margin required to cover > 95% of the CTVpros was equal (2.5 mm) for all workflows. For the CTVpros + sv, this margin increased to 5.0, 4.0 and 3.5 mm in the ATP, ATR and ATS workflow, respectively. GTV coverage improved from ATP to ATR for margins up to 4.0 mm. CONCLUSION: ATP, ATR and ATS workflows ensure equal coverage of the CTVpros for the current clinical margins. For the CTVpros + sv, ATS showed optimal performance. GTV coverage improves by additional adaptations to prostate rotations.

From once-weekly to semi-weekly whole prostate gland stereotactic radiotherapy with focal boosting: Primary endpoint analysis of the multicenter phase II hypo-FLAME 2.0 trial.

BACKGROUND AND PURPOSE: The hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days. MATERIAL AND METHODS: Patients with intermediate- and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). RESULTS: Between August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade ≥3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL. CONCLUSION: Semi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule. Registration number ClinicalTrials.gov: NCT04045717.

An ESTRO-ACROP guideline on quality assurance and medical physics commissioning of online MRI guided radiotherapy systems based on a consensus expert opinion.

OBJECTIVE: The goal of this consensus expert opinion was to define quality assurance (QA) tests for online magnetic resonance image (MRI) guided radiotherapy (oMRgRT) systems and to define the important medical physics aspects for installation and commissioning of an oMRgRT system. MATERIALS AND METHODS: Ten medical physicists and two radiation oncologists experienced in oMRgRT participated in the survey. In the first round of the consensus expert opinion, ideas on QA and commissioning were collected. Only tests and aspects different from commissioning of a CT guided radiotherapy (RT) system were considered. In the following two rounds all twelve participants voted on the importance of the QA tests, their recommended frequency and their suitability for the two oMRgRT systems approved for clinical use as well as on the importance of the aspects to consider during medical physics commissioning. RESULTS: Twenty-four QA tests were identified which are potentially important during commissioning and routine QA on oMRgRT systems compared to online CT guided RT systems. An additional eleven tasks and aspects related to construction, workflow development and training were collected. Consensus was found for most tests on their importance, their recommended frequency and their suitability for the two approved systems. In addition, eight aspects mostly related to the definition of workflows were also found to be important during commissioning. CONCLUSIONS: A program for QA and commissioning of oMRgRT systems was developed to support medical physicists to prepare for safe handling of such systems.

Genomic Classifiers in Personalized Prostate Cancer Radiation Therapy Approaches: A Systematic Review and Future Perspectives Based on International Consensus.

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa.

Magnetic Resonance-Guided Adaptive Radiation Therapy for Prostate Cancer: The First Results from the MOMENTUM study-An International Registry for the Evidence-Based Introduction of Magnetic Resonance-Guided Adaptive Radiation Therapy.

PURPOSE: Magnetic resonance (MR)-guided radiation therapy (MRgRT) is a new technique for treatment of localized prostate cancer (PCa). We report the 12-month outcomes for the first PCa patients treated within an international consortium (the MOMENTUM study) on a 1.5T MR-Linac system with ultrahypofractionated radiation therapy. METHODS AND MATERIALS: Patients treated with 5 × 7.25 Gy were identified. Prostate specific antigen-level, physician-reported toxicity (Common Terminology Criteria for Adverse Events [CTCAE]), and patient-reported outcomes (Quality of Life Questionnaire PR25 and Quality of Life Questionnaire C30 questionnaires) were recorded at baseline and at 3, 6, and 12 months of follow-up (FU). Pairwise comparative statistics were conducted to compare outcomes between baseline and FU. RESULTS: The study included 425 patients with localized PCa (11.4% low, 82.0% intermediate, and 6.6% high-risk), and 365, 313, and 186 patients reached 3-, 6-, and 12-months FU, respectively. Median prostate specific antigen level declined significantly to 1.2 ng/mL and 0.1 ng/mL at 12 months FU for the nonandrogen deprivation therapy (ADT) and ADT group, respectively. The peak of genitourinary and gastrointestinal CTCAE toxicity was reported at 3 months FU, with 18.7% and 1.7% grade ≥2, respectively. The QLQ-PR25 questionnaire outcomes showed significant deterioration in urinary domain score at all FU moments, from 8.3 (interquartile range [IQR], 4.1-16.6) at baseline to 12.4 (IQR, 8.3-24.8; P = .005) at 3 months, 12.4 (IQR, 8.3-20.8; P = .018;) at 6 months, and 12.4 (IQR, 8.3-20.8; P = .001) at 12 months. For the non-ADT group, physician- and patient-reported erectile function worsened significantly between baseline and 12 months FU. CONCLUSIONS: Ultrahypofractionated MR-guided radiation therapy for localized PCa using a 1.5T MR-Linac is effective and safe. The peak of CTCAE genitourinary and gastrointestinal toxicity was reported at 3 months FU. Furthermore, for patients without ADT, a significant increase in CTCAE erectile dysfunction was reported at 12 months FU. These data are useful for educating patients on expected outcomes and informing study design of future comparative-effectiveness studies.

Advancing the treatment of localized prostate cancer with MR-guided radiotherapy.

External beam radiotherapy (EBRT) is an important cornerstone in the treatment of localized prostate cancer. Current image-guided radiotherapy (IGRT) techniques allow for more accurate and precise delivery of radiation treatment by the use of imaging before each fraction. Magnetic resonance guided radiotherapy (MRgRT) is the next step in IGRT with hybrid systems combining linear accelerators with MRI-scanners. With MRgRT, it is possible to visualize pelvic anatomy in great detail and subsequently perform replanning of the radiation dose distribution before each radiotherapy fraction. This technique has the potential to increase the therapeutic window of EBRT, by improved normal tissue sparing due to margin reduction and more accurate target dose delivery. This is particularly promising for prostate cancer, with its biology lending itself to ultra-hypofractionation, reducing radiotherapy treatment to as little as five fractions. Also, recent studies have shown that focal dose escalation to the intraprostatic tumor to high ablative doses can substantially increase disease-free survival. In this article, we discuss these unique opportunities as well as the potential future benefits of MRgRT in prostate cancer treatment.

Trends and variation in the use of radiotherapy in non-metastatic prostate cancer: A 12-year nationwide overview from the Netherlands.

PURPOSE: This population-based study describes nationwide trends and variation in the use of primary radiotherapy for non-metastatic prostate cancer in The Netherlands in 2008-2019. METHODS: Prostate cancer patients were selected from the Netherlands Cancer Registry (N = 103,059). Treatment trends were studied over time by prognostic risk groups. Multilevel analyses were applied to identify variables associated with external beam radiotherapy (EBRT) and brachy-monotherapy versus no active treatment in low-risk disease, and EBRT versus radical prostatectomy in intermediate and high-risk disease. RESULTS: EBRT use remained stable (5-6%) in low-risk prostate cancer and increased from 21% to 32% in intermediate-risk, 37% to 45% in high-risk localized and 50% to 57% in high-risk locally advanced disease. Brachy-monotherapy decreased from 19% to 6% and from 15% to 10% in low and intermediate-risk disease, respectively, coinciding an increase of no active treatment from 55% to 73% in low-risk disease. Use of EBRT or brachy-monotherapy versus no active treatment in low-risk disease differed by region, T-stage and patient characteristics. Hospital characteristics were not associated with treatment in low-risk disease, except for availability of brachy-monotherapy in 2008-2013. Age, number of comorbidities, travel time for EBRT, prognostic risk group, and hospital characteristics were associated with EBRT versus prostatectomy in intermediate and high-risk disease. CONCLUSION: Intermediate/high-risk PCa was increasingly managed with EBRT, while brachy-monotherapy in low/intermediate-risk PCa decreased. In low-risk PCa, the no active treatment-approach increased. Variation in treatment suggests treatment decision related to patient/disease characteristics. In intermediate/high-risk disease, variation seems furthermore related to the treatment modalities available in the diagnosing hospitals.

Adaptive magnetic resonance image guided radiation for intact localized prostate cancer how to optimally test a rapidly emerging technology.

Introduction: Prostate cancer is a common malignancy for which radiation therapy (RT) provides an excellent management option with high rates of control and low toxicity. Historically RT has been given with CT based image guidance. Recently, magnetic resonance (MR) imaging capabilities have been successfully integrated with RT delivery platforms, presenting an appealing, yet complex, expensive, and time-consuming method of adapting and guiding RT. The precise benefits of MR guidance for localized prostate cancer are unclear. We sought to summarize optimal strategies to test the benefits of MR guidance specifically in localized prostate cancer. Methods: A group of radiation oncologists, physicists, and statisticians were identified to collectively address this topic. Participants had a history of treating prostate cancer patients with the two commercially available MRI-guided RT devices. Participants also had a clinical focus on randomized trials in localized prostate cancer. The goal was to review both ongoing trials and present a conceptual focus on MRI-guided RT specifically in the definitive treatment of prostate cancer, along with developing and proposing novel trials for future consideration. Trial hypotheses, endpoints, and areas for improvement in localized prostate cancer that specifically leverage MR guided technology are presented. Results: Multiple prospective trials were found that explored the potential of adaptive MRI-guided radiotherapy in the definitive treatment of prostate cancer. Different primary areas of improvement that MR guidance may offer in prostate cancer were summarized. Eight clinical trial design strategies are presented that summarize options for clinical trials testing the potential benefits of MRI-guided RT. Conclusions: The number and scope of trials evaluating MRI-guided RT for localized prostate cancer is limited. Yet multiple promising opportunities to test this technology and potentially improve outcomes for men with prostate cancer undergoing definitive RT exist. Attention, in the form of multi-institutional randomized trials, is needed.

How Advanced Imaging Will Guide Therapeutic Strategies for Patients with Newly Diagnosed Prostate Cancer in the Years to Come.

In recent years, clinical use of novel advanced imaging modalities in prostate cancer detection, staging, and therapy has intensified and is currently reforming clinical guidelines. In the future, advanced imaging technologies will continue to develop and become even more accurate, which will offer new opportunities for improving patient selection, surgical treatment, and radiotherapy, with the potential to guide prostate cancer therapy.

Magnetic Resonance Imaging-guided Adaptive Radiotherapy for Urological Cancers: What Urologists Should Know.

Magnetic resonance imaging (MRI)-guided radiotherapy allows for online adaptation of the radiation plan on the basis of anatomical and functional changes during treatment. MRI-guided radiotherapy holds significant promise for broadening the therapeutic window for multiple urological cancers.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Patterns of Failure Following External Beam Radiotherapy With or Without an Additional Focal Boost in the Randomized Controlled FLAME Trial for Localized Prostate Cancer.

BACKGROUND: Focal dose escalation in external beam radiotherapy (EBRT) showed an increase in 5-yr biochemical disease-free survival in the Focal Lesion Ablative Microboost in Prostate Cancer (FLAME) trial. OBJECTIVE: To analyze the effect of a focal boost to intraprostatic lesions on local failure-free survival (LFS) and regional + distant metastasis-free survival (rdMFS). DESIGN, SETTING, AND PARTICIPANTS: Patients with intermediate- or high-risk localized prostate cancer were included in FLAME, a phase 3, multicenter, randomized controlled trial. INTERVENTION: Standard treatment of 77 Gy to the entire prostate in 35 fractions was compared to an additional boost to the macroscopic tumor of up to 95 Gy during EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: LFS and rdMFS, measured via any type of imaging, were compared between the treatment arms using Kaplan-Meier and Cox regression analyses. Dose-response curves were created for local failure (LF) and regional + distant metastatic failure (rdMF) using logistic regression. RESULTS AND LIMITATIONS: A total of 571 patients were included in the FLAME trial. Over median follow-up of 72 mo (interquartile range 58-86), focal boosting decreased LF (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14-0.78) and rdMF (HR 0.58, 95% CI 0.35-0.93). Dose-response curves showed that a greater dose to the tumor resulted in lower LF and rdMF rates. CONCLUSIONS: A clear dose-response relation for LF and rdMF was observed, suggesting that adequate focal dose escalation to intraprostatic lesions prevents undertreatment of the primary tumor, resulting in an improvement rdMF. PATIENT SUMMARY: Radiotherapy is a treatment option for high-risk prostate cancer. The FLAME trial has shown that a high dose specifically targeted at the tumor within the prostate will result in better disease outcome, with less likelihood of regional and distant disease spread. The FLAME trial is registered on ClinicalTrials.gov as NCT01168479.