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Purpose: To explore whether prostate motion mitigation using the rectal distension-mediated technique is safe and effective in stereotactic ablative radiation therapy (SABR) salvage treatment of intraprostatic cancer recurrences following initial radiotherapy for primary prostate cancer., Materials and Methods: Between July 2013 and December 2020, 30 patients received salvage SABR for 68 Ga- PSMA-11 PET/CT-detected intra-prostatic relapses. Median time from primary RT to salvage reirradiation was 70.2 (IQR, 51.3-116.0) months. Median PSA at retreatment was 3.6 ng/mL (IQR, 1.9-6.2). Rectal distension-mediated SABR was achieved with a 150-cm 3 air-inflated endorectal balloon and a Foley catheter loaded with 3 beacon transponders was used for urethra visualization and on-line tracking. MRI-based planning employed a 2-mm expansion around the planned target volume (PTV), reduced to 0-mm at the interface with critical organs at risk (OARs). Volumetric Modulated Arc Therapy (VMAT) permitted a 20% dose reduction of the urethra. VMAT simultaneous integrated boost (SIB) of the dominant intraprostatic lesion was deployed when indicated. Median SABR dose was 35 Gy (7 Gy per fraction over 5 consecutive days; range 35-40 Gy). Toxicity assessment used CTCAE v.4 criteria., Results: Median follow-up was 44 months (IQR, 18-60). The actuarial 3- and 4-year biochemical relapse free survival was 53.4% and 47.5%, respectively. Intraprostatic post-salvage relapse by PSMA PET/CT was 53.3%. Acute grade 2 and 3 genitourinary (GU) toxicities were 20% and 0%, respectively. There were no instances of acute grade ≥2 rectal (GI) toxicity. Late grade 2 and 3 GU toxicities occurred in 13.3% and 0% of patients, respectively. There were no instances of grade ≥2 late rectal toxicity. Patient-reported QOL measures showed an acute transient deterioration in the urinary domain 1 month after treatment but returned to baseline values at 3 months. The median IPSS scores rose over baseline (≥5 points in 53% of patients) between month 6 and 12 post-treatment as a result of urinary symptoms flare, eventually receding at 18 months. The bowel domain metrics had no appreciable changes over time., Conclusion: Pursuit of local control in intraprostatic failures is feasible and can be achieved with an acceptably low toxicity profile associated with effective OAR sparing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Greco, Pares, Pimentel, Louro, Nunes, Kociolek, Marques and Fuks.)

Purpose: The present study explores PSA density (PSA-D) as predictor of biochemical and local failure in organ-confined prostate cancer at 3-6 months after hypofractionated stereotactic ablative radiotherapy (SABR)., Methods and Materials: A cohort of 219, hormone-naïve, NCCN intermediate-risk prostate cancer patients were derived from a phase 2 study of 5 × 9 Gy prostate cancer SABR. PSA-D was calculated at 3 and 6 months by dividing serum PSA by the MR-derived prostate CTV, while the slope of the 3-6 months curve was used to express the kinetics of PSA-D decay., Results: The median follow-up was 60.3 (range 46-76) months, and the actuarial 7-year bRFS was 98.0% for intermediate-risk favorable (FIR) patients versus 84.5% for the unfavorable (UIR) subgroup (P = 0.02). Fourteen patients developed a Phoenix-defined biochemical PSA relapse (bRFS) at a median of 34.2 months, 11 confirmed with 68 Ga-PSMA PET/CT scan that revealed tracer uptake at the site of dominant intraprostatic pretreatment lesion in 8 patients. The 3-month PSA-D concertation (cut-off 0.08 ng/ml 2 ) and 3-6 months decay slope (cut-off -0.45) values were predictive of long-term bRFS. A dual adverse PSA-D permutation was detected in 25/148 UIR patients, exhibiting 47.5% 7-year bRFS compared with 94.1% for the remaining 123 UIR patients with favorable PSA-D kinetics (P = 0.0006). Intraprostatic local relapse in patients with a 3-month PSA-D > 0.080 ng/ml 2 was 11.0% vs. 1.7% for patients with PSA-D ≤ 0.080 ng/ml 2 (P = 0.01) and 2.3% vs. 4.3%, respectively, for nodal progression (P = 0.68)., Conclusions: Early post-treatment PSA-D kinetics transcends pre-treatment risk stratification of tumor relapse and adds a nuance in the biological characterization of intermediate-risk prostate cancer phenotypes. The dual adverse PSA-D algorithm may serve as a tool to validate current search of classifiers of radioresistance in prostate cancer with therapeutic implications., Competing Interests: Conflict of interest statement Patents not related to this work for Zvi Fuks (US10413533B2, US20170333413A1, US20180015183A1, AN 62880797). Patent not related to this work for Carlo Greco (AN 62880797). All other authors have declared no conflicts of interest to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: To explore whether the rectal distension-mediated technique, harnessing human physiology to achieve intrafractional prostate motion mitigation, enables urethra sparing by inverse dose painting, thus promoting dose escalation with extreme hypofractionated stereotactic ablative radiotherapy (SABR) in prostate cancer., Materials and Methods: Between June 2013 and December 2018, 444 patients received 5 × 9 Gy SABR over 5 consecutive days. Rectal distension-mediated SABR was employed via insertion of a 150-cm 3 air-inflated endorectal balloon. A Foley catheter loaded with 3 beacon transponders was used for urethra visualization and online tracking. MRI-based planning using Volumetric Modulated Arc Therapy - Image Guided Radiotherapy (VMAT-IGRT) with inverse dose painting was employed in delivering the planning target volume (PTV) dose and in sculpting exposure of organs at risk (OARs). A 2-mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. All plans fulfilled D mean ≥45 Gy. Target motion ≥2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of the planned dose delivery., Results: Patient compliance to the rectal distension-mediated immobilization protocol was excellent, achieving reproducible daily prostate localization at a patient-specific retropubic niche. Online tracking recorded ≤1-mm intrafractional target deviations in 95% of treatment sessions, while target realignment in ≥2-mm deviations enabled treatment completion as scheduled in all cases. The cumulative incidence rates of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) toxicities were 5.3% and 1.1%, respectively. The favorable toxicity profile was corroborated by patient-reported quality of life (QOL) outcomes. Median prostate-specific antigen (PSA) nadir by 5 years was 0.19 ng/ml. The cumulative incidence rate of biochemical failure using the Phoenix definition was 2%, 16.6%, and 27.2% for the combined low/favorable-intermediate, unfavorable intermediate, and high-risk categories, respectively. Patients with a PSA failure underwent a 68 Ga-labeled prostate-specific membrane antigen ( 68 Ga-PSMA) scan showing a 20.2% cumulative incidence of intraprostatic relapses in biopsy International Society of Urological Pathology (ISUP) grade ≥3., Conclusion: The rectal distension-mediated technique is feasible and well tolerated. Dose escalation to 45 Gy with urethra-sparing results in excellent toxicity profiles and PSA relapse rates similar to those reported by other dose-escalated regimens. The existence of intraprostatic recurrences in patients with high-risk features confirms the notion of a high α/β ratio in these phenotypes resulting in diminished effectiveness with hypofractionated dose escalation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Greco, Pares, Pimentel, Louro, Nunes, Kociolek, Stroom, Vieira, Mateus, Cardoso, Soares, Marques, Freitas, Coelho and Fuks.)

Purpose: Early positron emission tomography-derived metrics post-oligometastasis radioablation may predict impending local relapses (LRs), providing a basis for a timely ablation., Methods and Materials: Positron emission tomography data of 623 lesions treated with either 24 Gy single-dose radiation therapy (SDRT) (n = 475) or 3 ×  9 Gy stereotactic body radiation therapy (SBRT) (n = 148) were analyzed in a training data set (n = 246) to obtain optimal cutoffs for pretreatment maximum standardized uptake value (SUV max ) and its 3-month posttreatment decline (ΔSUV max ) in predicting LR risk, validated in a data set unseen to testing (n = 377)., Results: At a median of 21.7 months, 91 lesions developed LRs: 39 of 475 (8.2%) after SDRT and 52 of 148 (35.1%) after SBRT. The optimal cutoff values were 12 for SUV max and -75% for ΔSUV max . Bivariate SUV max /ΔSUV max permutations rendered a 3-tiered LR risk stratification of dual-favorable (low risk), 1 adverse (intermediate risk) and dual-adverse (high risk). Actuarial 5-year local relapse-free survival rates were 93.9% versus 89.6% versus 57.1% ( P < .0001) and 76.1% versus 48.3% versus 8.2% ( P < .0001) for SDRT and SBRT, respectively. The SBRT area under the ROC curve was 0.71 (95% CI, 0.61-0.79) and the high-risk subgroup yielded a 76.5% true positive LR prediction rate., Conclusions: The SBRT dual-adverse SUV max /ΔSUV max category LR prediction power provides a basis for prospective studies testing whether a timely ablation of impending LRs affects oligometastasis outcomes., (© 2021 The Authors.)

Background and Purpose: To quantitate the accuracy, reproducibility and prostate motion mitigation efficacy rendered by a target immobilization method used in an intermediate-risk prostate cancer dose-escalated 5×9Gy SBRT study., Material and Methods: An air-inflated (150 cm 3 ) endorectal balloon and Foley catheter with three electromagnetic beacon transponders (EBT) were used to mitigate and track intra-fractional target motion. A 2 mm margin was used for PTV expansion, reduced to 0 mm at the interface with critical OARs. EBT-detected ≥ 2 mm/5 s motions mandated treatment interruption and target realignment prior to completion of planned dose delivery. Geometrical uncertainties were measured with an in-house ESAPI script., Results: Quantitative data were obtained in 886 sessions from 189 patients. Mean PTV dose was 45.8 ± 0.4 Gy (D95 = 40.5 ± 0.4 Gy). A mean of 3.7 ± 1.7 CBCTs were acquired to reach reference position. Mean treatment time was 19.5 ± 12 min, 14.1 ± 11 and 5.4 ± 5.9 min for preparation and treatment delivery, respectively. Target motion of 0, 1-2 and >2 mm/10 min were observed in 59%, 30% and 11% of sessions, respectively. Temporary beam-on hold occurred in 7.4% of sessions, while in 6% a new reference CBCT was required to correct deviations. Hence, all sessions were completed with application of the planned dose. Treatment preparation time > 15 min was significantly associated with the need of a second reference CBCT. Overall systematic and random geometrical errors were in the order of 1 mm., Conclusion: The prostate immobilization technique explored here affords excellent accuracy and reproducibility, enabling normal tissue dose sculpting with tight PTV margins., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: Ultra-high single-dose radiotherapy (SDRT) represents a potential alternative to curative extreme hypofractionated stereotactic body radiotherapy (SBRT) in organ-confined prostate cancer., Objective: To compare toxic effect profiles, prostate-specific antigen (PSA) responses, and quality-of-life end points of SDRT vs extreme hypofractionated SBRT., Design, Setting, and Participants: The PROSINT single-institution phase 2 randomized clinical trial accrued, between September 2015 and January 2017, 30 participants with intermediate-risk prostate cancer to receive SDRT or extreme hypofractionated SBRT. Androgen deprivation therapy was not permitted. Data were analyzed from March to May 2020., Interventions: Patients were randomized in a 1:1 ratio to receive 5 × 9 Gy SBRT (control arm) or 24 Gy SDRT (test arm)., Main Outcomes and Measures: The primary end point was toxic effects; the secondary end points were PSA response, PSA relapse-free survival, and patient-reported quality of life measured with the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaires., Results: A total of 30 men were randomized; median (interquartile range) age was 66.3 (61.2-69.9) and 73.6 (64.7-75.9) years for the SBRT and SDRT arms, respectively. Time to appearance and duration of acute and late toxic effects were similar in the 2 trial arms. Cumulative late actuarial urinary toxic effects did not differ for grade 1 (hazard ratio [HR], 0.41; 90% CI, 0.13-1.27) and grade 2 or greater (HR, 1.07; 90% CI, 0.21-5.57). Actuarial grade 1 late gastrointestinal (GI) toxic effects were comparable (HR, 0.37; 90% CI, 0.07-1.94) and there were no grade 2 or greater late GI toxic effects. Declines in PSA level to less than 0.5 ng/mL occurred by 36 months in both study arms. No PSA relapses occurred in favorable intermediate-risk disease, while in the unfavorable category, the actuarial 4-year PSA relapse-free survival values were 75.0% vs 64.0% (HR, 0.76; 90% CI, 0.17-3.31) for SBRT vs SDRT, respectively. The EPIC-26 median summary scores for the genitourinary and GI domains dropped transiently at 1 month and returned to pretreatment scores by 3 months in both arms. The IPSS-derived transient late urinary flare symptoms occurred at 9 to 18 months in 20% (90% CI, 3%-37%) of patients receiving SDRT., Conclusions and Relevance: In this randomized clinical trial among patients with intermediate-risk prostate cancer, SDRT was safe and associated with low toxicity, and the tumor control and quality-of-life end points closely match the SBRT arm outcomes. Further studies are encouraged to explore indications for SDRT in the cure of prostate cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02570919.

Background and Purpose: While favourable long-term outcomes have been reported in organ-confined prostate cancer treated with 5 × 7-8 Gy extreme hypofractionation, dose escalation to 5 × 9-10 Gy improved local control but was associated with unacceptable rates of late rectal and urinary toxicities. The purpose of this study was to explore the feasibility of intra-fractional prostate immobilization in reducing toxicity, to promote dose escalation with extreme hypofractionated radiotherapy in prostate cancer., Material and Methods: 207 patients received 5 consecutive fractions of 9 Gy. An air-inflated (150 cm 3 ) endorectal balloon and an intraurethral Foley catheter with 3 beacon transponders were used to immobilize the prostate and monitor intra-fractional target motion. VMAT-IGRT with inverse dose-painting was employed in delivering the PTV dose and in sculpting exposure of normal organs at risk to fulfil dose-volume constraints., Results: Introduction of air-filled balloon induced repeatable rectum/prostate complex migration from its resting position to a specific retropubic niche, affording the same 3D anatomical configuration daily. Intra-fractional target deviations ≤1 mm occurred in 95% of sessions, while target realignment in ≥2 mm deviations enabled treatment completion as scheduled. Nadir PSA at median 54 months follow-up was 0.19 ng/mL, and bRFS was 100%, 92.4% and 71.4% in low-, intermediate- and high-risk categories, respectively. Late Grade 2 GU and GI toxicities were 2.9% and 2.4%, respectively. No adverse changes in patient-reported quality of life scores were observed., Conclusion: The unique spatial configuration of this prostate motion mitigation protocol enabled precise treatment planning and delivery that optimized outcomes of ultra-high 5 × 9 Gy hypofractionated radiotherapy of organ-confined prostate cancer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The current oligometastatic (OM) model postulates that the disease evolves dynamically with sequential emergence of OM (SOM) lesions requiring successive rounds of SOM ablation to afford tumor cure. The present phase 2 study explores the ablative efficacy of 24 Gy single-dose radiation therapy (SDRT), its feasibility in diverse OM settings, and the impact of radioablation on polymetastatic (PM) dissemination., Methods and Materials: One hundred seventy-five consecutive patients with 566 OM or SOM lesions underwent periodic positron emission tomography/computed tomography (PET/CT) imaging to stage the disease before treatment, determine tumor response, and monitor timing of PM conversion after SDRT. When 24 Gy SDRT was restricted by dose or volume constraints of serial normal organs, radioablation was diverted to a nontoxic 3×9 Gy SBRT schedule., Results: SOM/SOMA occurred in 42% of the patients, and 24 Gy SDRT was feasible in 76% of the lesions. Despite 92% actuarial 5-year OM ablation by 24 Gy SDRT, respective PM-free survival (PMFS) was 26%, indicating PM conversion dominates over effective OM radioablation in many patients. Multivariate analysis of OM metrics derived from staging PET/CT scanning before first treatment predicted PMFS outcome after SDRT. Bivariate analysis of dichotomized high versus low baseline metric combinations of CT-derived tumor load (cutoff at 14.8 cm 3 ) and PET-derived metabolic SUV max (cutoff at 6.5) yielded a 3-tiered PMFS categorization of 89%, 58% and 17% actuarial 5-year PMFS in categories 1, 2, and 3, respectively (P < .001), defining OM disease as a syndrome of diverse clinical and prognostic phenotypes., Conclusion: Long-term risk of PM dissemination, predicted by preablation PET/CT staging, provides guidelines for phenotype-oriented OM therapy. In categories 1 and 2, radioablation should be a primary therapeutic element when pursuing tumor cure, whereas in the PM-prone category 3, radioablation should be a component of multimodal trials addressing primarily the risk of PM dissemination. PET/CT baseline staging also provides a platform for discovery of pharmacologically accessible PM drivers as targets for new phenotype-oriented treatment protocols., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primary organ-confined prostate cancer is curable with external-beam radiotherapy. However, prostate cancer expresses a unique radiobiological phenotype, and its ablation requires doses at the high-end range of clinical radiotherapy. At this dose level, normal tissue radiosensitivity restricts the application of curative treatment, and mandates the use of the most advanced high-precision treatment delivery techniques to spare critical organs at risk. The efficacy and tolerance of dose-escalated conventional fractionated radiotherapy and of the biological equivalent doses of moderate and extreme hypofractionation are reviewed. Current studies indicate that novel risk-adapted techniques to spare normal organs at risk are still required to deploy high-biological equivalent dose extreme hypofractionation, while affording preservation of quality of life and cost-effectiveness., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: To review the recent evolution of spine SBRT with emphasis on single dose treatments., Background: Radiation treatment of spine metastases represents a challenging problem in clinical oncology, because of the high risk of inflicting damage to the spinal cord. While conventional fractionated radiation therapy still constitutes the most commonly used modality for palliative treatment, notwithstanding its efficacy in terms of palliation of pain, local tumor control has been approximately 60%. This limited effectiveness is due to previous lack of technology to precisely target the tumor while avoiding the radiosensitive spinal cord, which constitutes a dose-limiting barrier to tumor cure., Materials and Methods: A thorough review of the available literature on spine SBRT has been carried out and critically assessed., Results: Stereotactic body radiotherapy (SBRT) emerges as an alternative, non-invasive high-precision approach, which allows escalation of tumor dose, while effectively sparing adjacent uninvolved organs at risk. Engaging technological advances, such as on-line Cone Beam Computed Tomography (CBCT), coupled with Dynamic Multi-Leaf Collimation (DMLC) and rapid intensity-modulated (IMRT) beam delivery, have promoted an interactive image-guided (IGRT) approach that precisely conforms treatment onto a defined target volume with a rapid dose fall-off to collateral non-target tissues, such as the spinal cord. Recent technological developments allow the use of the high-dose per fraction mode of hypofractionated SBRT for spinal oligometastatic cancer, even if only a few millimeters away from the tumor., Conclusion: Single-dose spine SBRT, now increasingly implemented, yields unprecedented outcomes of local tumor ablation and safety, provided that advanced technology is employed.