Search

Background and Introduction: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation., Materials and Methods: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC)., Results: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions., Conclusion: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAJF received grants from Accuray, AIRC, IBA and Fondazione IEO-CCM, lecture payments/honoraria from Bayer, Accuray, Astellas, IBA, IPSEN, Astra Zeneca, Tecnologie Avanzate, Recordati, and Novartis, and has board appointments at Astra Zeneca, Bayer, and Seagen. MG and PO are PIs of the ESTRO-EORTC 1811-E²-RADIatE OligoCare trial. MG is president-elect of ESTRO., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of interests The Division of Radiation Oncology of European Institute of Oncology (IEO) has received research funding from Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione IEO-CCM (Istituto Europeo di Oncologia-Centro Cardiologico Monzino) all outside the current project. BAJ-F has received speaker fees from Roche, Bayer, Janssen, Carl Zeiss, Ipsen, Accuray, Astellas, Elekta, and IBA AstraZeneca (all outside the current project). AVL has received speaker fees from AstraZeneca (outside the current project). SGi (in the last 3 years) reports personal honoraria for participation on advisory boards from Amgen and MSD; invited speaker fees for the European Society of Medical Oncology (ESMO), and the Swiss group for Clinical Cancer Research (SAKK), the German-speaking European School of Oncology, and the Swiss Academy of Multidisciplinary Oncology; a travel grant from AstraZeneca and Bayer; institutional honoraria for participation on advisory boards or independent data monitoring–steering committees from AAA International, Amgen, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DAIICHI Sankyo, Innomedica, Ipsen, Meister-ConCept, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, and Telixpharma; was an invited speaker for SAKK, American Society of Clinical Oncology Genitourinary, ESMO, PeerVoice, Silvio Grasso Consulting, and WebMD-Medscape; and has a patent for a research method for biomarker WO2009138392. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Stereotactic body radiation therapy is increasingly used for oligometastatic disease as well as palliation, but treatment protocols for nonspine bone and nodal metastases are lacking, with a wide variety of schedules applied., Methods and Materials: A prospective dose-escalation trial was initiated, involving 90 patients, among whom 52 (58%) had primary prostate tumors, 13 had breast tumors (14%), and 25 (28%) had other primary tumor types. All visible lymph node or nonspine bone oligometastases were treated in 3 consecutive cohorts: 5 × 7.0 Gy, 3 × 10.0 Gy, or 1 × 20.0 Gy., Results: Initial results revealed no dose-limiting toxicity after a median follow-up of 17.2 months. This update provides information on long-term toxicity, local failure (LF), and progression-free survival (PFS). After a median follow-up of 50 months, no new safety signals were observed. Grade 2 toxicity was 13%, 7% and 10% in the respective cohorts (P = .9), without grade 3 to 5 toxicities. LF rates were 9%, 3%, and 6% (P = .5) for the respective treatment groups, with an overall cumulative risk of LF of 7% (95% CI, 2-12) at 4 years. Median PFS was 16.5 months (95% CI, 9.8-21.5), and 4-year PFS was 21% (95% CI, 14-32). Median overall survival across groups was not reached (95% CI, 52.8 - not reached), 4-year OS was 68% (95% CI, 59-78). A subset of patients (23%) remained long-term disease-free, 37% had oligoprogressive disease at first recurrence and 40% developed polymetastatic relapse., Conclusions: The safe and effective use of dose-escalated single-fraction stereotactic body radiation therapy for bone and lymph node metastases is supported by this trial, especially considering patient-convenience and cost-effectiveness. Caution is needed when generalizing these outcomes beyond breast and prostate cancer, given their underrepresentation in our study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Conventional external beam radiotherapy (cEBRT) and stereotactic body radiotherapy (SBRT) are commonly used treatment options for relieving metastatic bone pain. The effectiveness of SBRT compared with cEBRT in pain relief has been a subject of debate, and conflicting results have been reported., Objective: To compare the effectiveness associated with SBRT vs cEBRT for relieving metastatic bone pain., Data Sources: A structured search was performed in the PubMed, Embase, and Cochrane databases on June 5, 2023. Additionally, results were added from a new randomized clinical trial (RCT) and additional unpublished data from an already published RCT., Study Selection: Comparative studies reporting pain response after SBRT vs cEBRT in patients with painful bone metastases., Data Extraction and Synthesis: Two independent reviewers extracted data from eligible studies. Data were extracted for the intention-to-treat (ITT) and per-protocol (PP) populations. The study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline., Main Outcomes and Measures: Overall and complete pain response at 1, 3, and 6 months after radiotherapy, according to the study's definition. Relative risk ratios (RRs) with 95% CIs were calculated for each study. A random-effects model using a restricted maximum likelihood estimator was applied for meta-analysis., Results: There were 18 studies with 1685 patients included in the systematic review and 8 RCTs with 1090 patients were included in the meta-analysis. In 7 RCTs, overall pain response was defined according to the International Consensus on Palliative Radiotherapy Endpoints in clinical trials (ICPRE). The complete pain response was reported in 6 RCTs, all defined according to the ICPRE. The ITT meta-analyses showed that the overall pain response rates did not differ between cEBRT and SBRT at 1 (RR, 1.14; 95% CI, 0.99-1.30), 3 (RR, 1.19; 95% CI, 0.96-1.47), or 6 (RR, 1.22; 95% CI, 0.96-1.54) months. However, SBRT was associated with a higher complete pain response at 1 (RR, 1.43; 95% CI, 1.02-2.01), 3 (RR, 1.80; 95% CI, 1.16-2.78), and 6 (RR, 2.47; 95% CI, 1.24-4.91) months after radiotherapy. The PP meta-analyses showed comparable results., Conclusions and Relevance: In this systematic review and meta-analysis, patients with painful bone metastases experienced similar overall pain response after SBRT compared with cEBRT. More patients had complete pain alleviation after SBRT, suggesting that selected subgroups will benefit from SBRT.

Purpose: Around 40% of men with intermediate-risk or high-risk prostate cancer will experience a biochemical recurrence after radical prostatectomy (RP). The aim of this review is to describe both toxicity and oncological outcomes following stereotactic body radiation therapy (SBRT) delivered to the prostate bed (PB)., Method: In april 2023, we performed a systematic review of studies published in MEDLINE or ClinicalTrials.gov according to Preferred Reporting Items for Systematic Reviews, using the keywords "stereotactic radiotherapy" AND "postoperative" AND "prostate cancer"., Results: A total of 14 studies assessing either adjuvant or salvage SBRT to the whole PB or macroscopic local recurrence (MLR) within the PB, and SBRT on radiorecurrent MLR within the PB were included. Doses delivered to either whole PB or MLR between 30 to 40 Gy are associated with a low rate of late grade ≥ 2 genitourinary (GU) toxicity, ranging from 2.2 to 15.1%. Doses above 40 Gy are associated with increased rate of late GU toxicity, raising up to 38%. Oncological outcomes should be interpreted with caution, due to both short follow-up, heterogeneous populations and androgen deprivation therapy (ADT) use., Conclusion: PB or MLR SBRT delivered at doses up to 40 Gy appears safe with relatively low late severe GU toxicity rates. Caution is needed with dose-escalated RT schedules above 40 Gy. Further prospective trials are eagerly awaited in this disease setting., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs., Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors., Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023., Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions)., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population., Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred., Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials., Competing Interests: Declaration of interests FA declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Varian, Elekta, Brainlabs, outside of this Policy Review. CBe declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis. CBe also declares support for attending meetings and travel from Pfizer and Eli Lilly, unrelated to this Policy Review. CBi declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from SPCC congress, unrelated to this Policy Review. BdB declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Debiopharma, Ipsen, and Astellas; support for attending meetings and travel from Debiopharma and Micropos medical; and leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, SAKK, and SASRO, unrelated to this Policy Review. BAJ-F declares grants or contracts from Italian Association for Cancer Research, FIEO-CCM and FUV, Accuray, and IBA Dosimetry; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Roche, Astellas, Ipsen, and Accuray; and participation on a data safety monitoring board or advisory board for Bayer, unrelated to this Policy Review. XG declares a grant from Varian paid to their institution; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Congress Care and Sanofi; and a leadership or fiduciary role in the board, society, committee, or advocacy group for RIZIV–INAMI and FANC–AFCN. YL declares grants or contracts from ImmunoSABR, EU Project, and HERO–VBHC; consulting fees paid to the institution by AstraZeneca; and a leadership or fiduciary role in the board, society, committee, or advocacy group of ESTRO, Belgian College of Oncology, and EORTC–ESTRO Radiation Infrastructure for Europe project, unrelated to this Policy Review. PO declares grants or contracts from Varian and Bayer; consulting fees from Bayer, AAA, Curium, Janssen, Telix, MSD, and Ferring; and support for attending meetings and travel from Ferring, unrelated to this Policy Review. SP declares personal fees from Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, and EQRx; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational event from AstraZeneca, Bayer, Guardant Health, Janssen, Merck Sereno, Roche, Takeda, and Pfizer; payment for expert testimony from Roche and Merck Sereno; support for attending meetings and travel from Janssen and Roche; participation on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Incyte, Janssen, Eli Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, and Seattle Genetics; and leadership or fiduciary role in the board, society, committee, or advocacy group of British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation, and ETOP–IBCSG Partners Foundation Board, unrelated to this Policy Review. SR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD Italia, Genetec, and Istituto Gentili Amgen; and participation on a data safety monitoring board or advisory board for Roche and AstraZeneca, unrelated to this Policy Review. UR declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Elekta and Accuray, unrelated to this Policy Review. MS declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, and Merck; participation on a data safety monitoring board or advisory board for Janssen, Ipsen, and Merck; and a leadership or fiduciary role in the board, society, committee, or advocacy group for ESMO, unrelated to this Policy Review. TZ declares grants or contracts from Varian Medical Systems and Debiopharm; consulting fees from Janssen and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Astellas, Debiopharm, Bayer, and Ferring; support for attending meetings and travel from Debiopharm; and participation on a data safety monitoring board or advisory board for SAKK scientific board and GFRU, unrelated to this Policy Review. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Context: Emerging evidence supports the use of stereotactic body radiation therapy (SBRT) as metastatic-directed therapy (MDT) for oligometastatic genitourinary cancers; however, the prospective data to guide its application as an alternative standard of care remain limited., Objective: To review prospective trials that assess the role of SBRT for patients with genitourinary cancers within a modern framework of oligometastatic disease (OMD) and to highlight clinical scenarios where SBRT may offer a benefit to patients with metastatic cancer., Evidence Acquisition: We performed a critical review of PubMed and clinicaltrials.gov in April 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, combined with expert input to identify prospective studies investigating the role of SBRT for oligometastatic prostate, renal, or bladder cancer., Evidence Synthesis: The most commonly studied application of SBRT has been for metachronous oligorecurrent hormone-sensitive prostate cancer (HSPC). Further prospective study is needed to define the role of SBRT in delaying time to next therapy or inducing synergy with other systemic therapies., Conclusions: SBRT has been associated with high rates of local control and minimal risk of toxicity with multiple trials assessing an MDT-alone approach for oligorecurrent HSPC. From a tumor-agnostic perspective, the clinical benefit of SBRT for OMD has been associated with the ability to extend overall survival. As methods of cancer detection and treatment evolve, expansion of studies that prospectively evaluate SBRT MDT, stratifying by tumor histology and oligometastatic state, is needed to inform optimal patient selection and treatment strategy., Patient Summary: We review outcomes from prospective trials assessing the role of stereotactic body radiation therapy (SBRT) for oligometastatic genitourinary cancers, which have predominantly investigated SBRT for oligorecurrent prostate cancer. Much work remains to define how SBRT alone compares with other standard of care treatments for prostate cancer or the role of SBRT in tumor control or delaying time to next therapy in oligometastatic renal and bladder cancer., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Although the management of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of new systemic agents, still few patients experience a long-term durable response. Stereotactic ablative radiotherapy (SABR) is nowadays commonly used as metastasis-directed therapy (MDT), but limited data exist on how best to implement this strategy as part of a multimodal approach., Objective: To evaluate the potential role of extracranial SABR in mRCC and to identify future therapeutic developments of SABR in different disease settings., Evidence Acquisition: A systematic review was conducted in May 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement on the PubMed database. Thirty-four studies were selected for inclusion in this systematic review., Evidence Synthesis: SABR has been used with four main goals: (1) eradication of the whole metastatic burden in synchronous and metachronous oligometastatic patients, resulting in a long-term local control (LC) rate of >90% and median progression-free survival (PFS) ranging between 8 and 15 mo; (2) eradication of oligoprogressive lesions, enabling an extension of the duration of the systemic therapy by approximately 9 mo; (3) improvement of the response to systemic therapy in polymetastatic patients, resulting in an overall response rate ranging from 17% to 56%; and (4) cytoreduction in polymetastatic mRCC patients, with LC rates ranging between 71% and 100%, and preservation of the renal function, but unclear PFS and overall survival impact. Overall, the combination of SABR and systemic agents has been associated with overall good tolerance, with grade ≥3 toxicity ranging from 0% to 13%., Conclusions: Current data highlight the role of SABR as an emerging MDT treatment option in both oligometastatic and oligoprogressive extracranial mRCC, able to ensure long-term disease control and delay the use of next-line systemic therapies. The use of SABR for cytoreduction in the de novo metastatic disease and as an immunological booster in the polymetastatic setting remains investigational and warrants further investigations., Patient Summary: Radiotherapy delivered with ablative doses (>6 Gy per fraction) is a promising treatment strategy for patients diagnosed with metastatic renal cell carcinoma. Excellent outcome results have been observed in patients with a limited number of metastases, improving metastasis-free survival by several months. For patients with a few metastases progressing under systemic therapy, radiotherapy allows an extension of the duration of the ongoing therapy by several months., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Published health-related quality of life (HRQOL) outcomes are lacking in patients treated for oligo-metastatic disease (OMD). The aim of this systematic review and individual patient data meta-analysis is to determine the effect of stereotactic body radiotherapy (SBRT) on HRQOL outcomes of patients with OMD., Methods: Studies screened included adults with extra-cranial OMD, defined as ≤ 5 metastases, SBRT intended as definitive treatment, and HRQOL as primary or secondary outcome. Primary outcome was change in HRQOL at 12-months from baseline in patients with OMD who received SBRT (versus not), reported as standardized mean difference (SMD)., Results: A total of 7556 publications were identified, four studies met inclusion criteria (2 single arm interventional studies and 2 randomised controlled trials [RCTs]), and individual patient data was available from 3 studies (175 patients). In the two RCTs, there was no SS difference in the SMD between patients who received SBRT and those that did not (0.09 [95 % CI -0.32, 0.5], P = 0.66). On meta-analysis of patients (N = 107) who received SBRT the SMDwas -0.23 (95 % CI [-0.42, -0.04], versus -0.25 (95 % CI [-0.57, 0.07]) in those who did not (N = 37) receive SBRT, demonstrating a small deterioration from baseline., Conclusion: In patients with OMD, there is no difference in HRQOL at 12-months from baseline between patients who received SBRT and those that did not. However, a small HRQOL deterioration was found in both groups of patients. More in-depth analysis of relevant HRQOL domains, in the setting of OMD, is required to better understand the potential impact of SBRT., Competing Interests: Declaration of Competing Interest RO – reports Varian Medical Systems Research Grant. PO – reports grant support from Varian and Bayer. Consultancies for AAA, Astella, Bayer, Curium, Janssen and Telix. LAD – reports current activity on Merck ITT clinical trial - ongoing. DP - reports research funding from the Ontario Insitute for Cancer Research, and a consultant role with Need Inc (digital oncology startup). SS – reports grant support from Varian. No conflicts of interest are reported by - ASB, JH, AB, RW, JR, RF, ZL, RP, NA., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Aim of this study is to report the results of the radiotherapy quality assurance program of the PEACE V-STORM randomized phase II trial for pelvic nodal oligorecurrent prostate cancer (PCa)., Material and Methods: A benchmark case (BC) consisting of a postoperative case with 2 nodal recurrences was used for both stereotactic body radiotherapy (SBRT, 30 Gy/3 fx) and whole pelvic radiotherapy (WPRT, 45 Gy/25 fx + SIB boost to 65 Gy)., Results: BC of 24 centers were analyzed. The overall grading for delineation variation of the 1st BC was rated as 'UV' (Unacceptable Variation) or 'AV' (Acceptable Variation) for 1 and 7 centers for SBRT (33%), and 3 and 8 centers for WPRT (46%), respectively. An inadequate upper limit of the WPRT CTV (n = 2), a missing delineation of the prostate bed (n = 1), and a missing nodal target volume (n = 1 for SBRT and WPRT) constituted the observed 'UV'. With the 2nd BC (n = 11), the overall delineation review showed 2 and 8 'AV' for SBRT and WPRT, respectively, with no 'UV'. For the plan review of the 2nd BC, all treatment plans were per protocol for WPRT. SBRT plans showed variability in dose normalization (Median D 90%  = 30.1 Gy, range 22.9-33.2 Gy and 30.6 Gy, range 26.8-34.2 Gy for nodes 1 and 2 respectively)., Conclusions: Up to 46% of protocol deviations were observed in delineation of WPRT for nodal oligorecurrent PCa, while dosimetric results of SBRT showed the greatest disparities between centers. Repeated BC resulted in an improved adherence to the protocol, translating in an overall acceptable contouring and planning compliance rate among participating centers., Competing Interests: Conflict of interest No competing interests concerning the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prostate cancer is the most commonly diagnosed cancer among men around the world. Radiotherapy is a standard of care treatment option for men with localized prostate cancer. Over the years, radiation delivery modalities have contributed to increased precision of treatment, employing radiobiological insights to shorten the overall treatment time, improving the control of the disease without increasing toxicities. Stereotactic body radiation therapy (SBRT) represents an extreme form of hypofractionated radiotherapy in which treatment is usually delivered in 1-5 fractions. This review assesses the main efficacy and toxicity data of SBRT in non-metastatic prostate cancer and discusses the potential to implement this scheme in routine clinical practice.

Background and Purpose: Between 30% and 47% of patients treated with definitive radiotherapy (RT) for prostate cancer are at risk of intraprostatic recurrence during follow-up. Re-irradiation with stereotactic body RT (SBRT) is emerging as a feasible and safe therapeutic option. However, no consensus or guidelines exist on this topic. The purpose of this ESTRO ACROP project is to investigate expert opinion on salvage SBRT for intraprostatic relapse after RT., Materials and Methods: A 40-item questionnaire on salvage SBRT was prepared by an internal committee and reviewed by a panel of leading radiation oncologists plus a urologist expert in prostate cancer. Following the procedure of a Delphi consensus, 3 rounds of questionnaires were sent to selected experts on prostate re-irradiation., Results: Among the 33 contacted experts, 18 (54.5%) agreed to participate. At the end of the final round, participants were able to find consensus on 14 out of 40 questions (35% overall) and major agreement on 13 questions (32.5% overall). Specifically, the consensus was reached regarding some selection criteria (no age limit, ECOG 0-1, satisfactory urinary flow), diagnostic procedures (exclusion of metastatic disease, SBRT target defined on the MRI) and therapeutic approach (no need for concomitant ADT, consideration of the first RT dose, validity of Phoenix criteria for salvage SBRT failure)., Conclusion: While awaiting the results of ongoing studies, our ESTRO ACROP Delphi consensus may serve as a practical guidance for salvage SBRT. Future research should address the existing disagreements on this promising approach., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors., Methods/design: Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study's primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples., Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials., Trial Registration: Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Importance: The oligometastatic paradigm postulates that patients with a limited number of metastases can be treated with ablative local therapy to each site of disease with curative intent. Stereotactic ablative radiotherapy (SABR) is a radiation technique that has become widely used in this setting. However, prospective data are limited and are mainly from single institutional studies., Objective: To conduct a meta-analysis to characterize the safety and clinical benefit of SABR in oligometastatic cancer., Data Sources: A comprehensive search was conducted in PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cumulative Index to Nursing and Allied Health Literature on December 23, 2019, that included prospective clinical trials and review articles that were published within the past 15 years., Study Selection: Inclusion criteria were single-arm or multiarm prospective trials including patients with oligometastatic cancer (ie, ≤5 sites of extracranial disease), and SABR was administered in less than or equal to 8 fractions with greater than or equal to 5 Gy/fraction., Data Extraction and Synthesis: The Population, Intervention, Control, Outcomes and Study Design; Preferred Reporting Items for Systematic Reviews and Meta-analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify eligible studies. Study eligibility and data extraction were reviewed by 3 authors independently. Random-effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted., Main Outcomes and Measures: Safety (acute and late grade 3-5 toxic effects) and clinical benefit (1-year local control, 1-year overall survival, and 1-year progression-free survival)., Results: Twenty-one studies comprising 943 patients and 1290 oligometastases were included. Median age was 63.8 years (interquartile range, 59.6-66.1 years) and median follow-up was 16.9 months (interquartile range, 13.7-24.5 months). The most common primary sites were prostate (22.9%), colorectal (16.6%), breast (13.1%), and lung (12.8%). The estimate for acute grade 3 to 5 toxic effect rates under the random-effects models was 1.2% (95% CI, 0%-3.8%; I2 = 50%; 95% CI, 3%-74%; and τ = 0.20%; 95% CI, 0.00%-1.43%), and the estimate for late grade 3 to 5 toxic effects was 1.7% (95% CI, 0.2%-4.6%; I2 = 54%; 95% CI, 11%-76%; and τ = 0.25%; 0.01%-1.00%). The random-effects estimate for 1-year local control was 94.7% (95% CI, 88.6%-98.6%; I2 = 90%; 95% CI, 86%-94%; and τ = 0.81%; 95% CI, 0.36%-2.38%]). The estimate for 1-year overall survival was 85.4% (95% CI, 77.1%-92.0%; I2 = 82%; 95% CI, 71%-88%; and τ = 0.72%; 95% CI, 0.30%-2.09%) and 51.4% (95% CI, 42.7%-60.1%; I2 = 58%; 95% CI, 17%-78%; and τ = 0.20%; 95% CI, 0.02%-1.21%) for 1-year progression-free survival., Conclusions and Relevance: In this meta-analysis, SABR appears to be relatively safe in patients with oligometastatic cancer with clinically acceptable rates of acute and late grade 3 to 5 toxic effects less than 13% and with clinically acceptable rates of 1-year local control overall survival, and progression-free survival. These findings are hypothesis generating and require validation by ongoing and planned prospective clinical trials.

Purpose: Oligorecurrent prostate cancer has historically been treated with indefinite androgen deprivation therapy (ADT), although many patients and providers opt to defer this treatment at the time of recurrence given quality-of-life and/or comorbidity considerations. Recently, metastasis-directed therapy (MDT) has emerged as a potential intermediary between surveillance and immediate continuous ADT. Simultaneously, advanced systemic therapy in addition to ADT has also been shown to improve survival in metastatic hormone-sensitive disease. This study aimed to compare the cost-effectiveness of treating oligorecurrent patients with upfront MDT before standard-of-care systemic therapy., Methods and Materials: A Markov-based cost-effectiveness analysis was constructed comparing 3 strategies: (1) upfront MDT → salvage abiraterone acetate plus prednisone (AAP) + ADT → salvage docetaxel + ADT; (2) upfront AAP + ADT → salvage docetaxel + ADT; and (3) upfront docetaxel + ADT → salvage AAP + ADT. Transition probabilities and utilities were derived from the literature. Using a 10-year time horizon and willingness-to-pay threshold of $100,000/quality-adjusted life year (QALY), net monetary benefit values were subsequently calculated for each treatment strategy., Results: At 10 years, the base case revealed a total cost of $141,148, $166,807, and $136,154 with QALYs of 4.63, 4.89, and 4.00, respectively, reflecting a net monetary benefit of $322,240, $322,018, and $263,407 for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively. In the probabilistic sensitivity analysis using a Monte Carlo simulation (1,000,000 simulations), upfront MDT was the cost-effective strategy in 53.6% of simulations. The probabilistic sensitivity analysis revealed 95% confidence intervals for cost ($75,914-$179,862, $124,431-$223,892, and $103,298-$180,617) and utility in QALYs (3.85-6.12, 3.91-5.86, and 3.02-5.22) for upfront MDT, upfront AAP + ADT, and upfront docetaxel + ADT, respectively., Conclusions: At 10 years, upfront MDT followed by salvage AAP + ADT, is comparably cost-effective compared with upfront standard-of-care systemic therapy and may be considered a viable treatment strategy, especially in patients wishing to defer systemic therapy for quality-of-life or comorbidity concerns. Additional studies are needed to determine whether MDT causes a sustained meaningful delay in disease natural history and whether any benefit exists in combining MDT with upfront advanced systemic therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Radiotherapy is an emerging treatment strategy for nodal oligorecurrent prostate cancer (PCa) patients. However, large heterogeneities exist in the RT regimens used, with series reporting the use of elective nodal radiotherapy (ENRT) strategies and others the delivery of focal treatments to the relapsing nodes with Stereotactic Body Radiotherapy (SBRT). In this systematic review of the literature we compared the oncological outcomes and toxicity of the different RT regimens for nodal oligorecurrent PCa patients, with the aim of defining the optimal RT target volume in this setting., Methods: We performed a systemic search on the Pubmed database to identify articles reporting on the use of ENRT or SBRT for oligometastatic PCa with nodal recurrence., Results: Twenty-two articles were analyzed, including four prospective phase II trials (3 with SBRT and 1 with ENRT). Focal SBRT, delivered with an involved node, involved site, and involved field modality, was the most commonly used strategy with 2-year progression-free survival (PFS) rates ranging from 16 to 58% and a very low toxicity profile. Improved PFS rates were observed with ENRT strategies (52-80% at 3 years) compared to focal SBRT, despite a slightly higher toxicity rate. One ongoing randomized phase II trial is comparing both modalities in patients with nodal oligorecurrent PCa., Conclusions: With a large variability in patterns of practice, the optimal RT strategy remains to be determined in the setting of nodal oligorecurrent PCa. Ongoing randomized trials and advances in translational research will help to shed light on the best management for these patients. .

Background: Stereotactic body radiotherapy (SBRT) and elective nodal radiotherapy (ENRT) are being investigated as metastasis-directed treatments in oligorecurrent prostate cancer (PC); however, comparative data are still lacking., Objective: To compare outcome and toxicity between both treatments. Primary endpoint was metastasis-free survival, adjusted for selected variables (aMFS)., Design, Setting, and Participants: This was a multi-institutional, retrospective analysis of 506 (SBRT: 309, ENRT: 197) patients with hormone-sensitive nodal oligorecurrent PC (five or fewer lymph nodes (LNs; N1/M1a), treated between 2004 and 2017. Median follow-up was 36 mo (interquartile range 23-56)., Intervention: SBRT was defined as a minimum of 5 Gy per fraction to each lesion with a maximum of 10 fractions. ENRT was defined as a minimum dose of 45 Gy in up to 25 fractions to the elective nodes, with or without a simultaneous boost to the suspicious node(s). The choice of radiotherapy (RT) was at the discretion of the treating physician, with treatments being unbalanced over the centers., Outcome Measurements and Statistical Analysis: In total, 506 patients from 15 different treatment centers were included. Primary treatment was radical prostatectomy, RT, or their combination. Nodal recurrences were detected by positron emission tomography/computer tomography (97%) or conventional imaging (3%). Descriptive statistics was used to summarize patient characteristics., Results and Limitations: ENRT was associated with fewer nodal recurrences compared with SBRT (p < 0.001). In a multivariable analysis, patients with one LN at recurrence had longer aMFS after ENRT (hazard ratio: 0.50, 95% confidence interval 0.30-0.85, p = 0.009). Late toxicity was higher after ENRT compared with that after SBRT (16% vs. 5%, p < 0.01). Limitations include higher use of hormone therapy in the ENRT cohort and nonstandardized follow-up., Conclusions: ENRT reduces the number of nodal recurrences as compared with SBRT, however at higher toxicity. Our findings hypothesize that ENRT should be preferred to SBRT in the treatment of nodal oligorecurrences. This hypothesis needs to be evaluated in a randomized trial., Patient Summary: This study investigated the difference between stereotactic and elective nodal radiotherapy in treating limited nodal metastatic prostate cancer. Nodal relapse was less frequent following elective nodal radiotherapy than following stereotactic body radiotherapy, and thus elective nodal radiotherapy might be the preferred treatment., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: Herein, we report the clinical outcomes of a multicenter study evaluating the role of SBRT in a cohort of patients affected by oligoprogressive castration-resistant prostate cancer (CRPC)., Materials and Methods: This is a retrospective multicenter observational study including eleven centers. Inclusion criteria of the current study were: (a) Karnofsky performance status > 80, (b) histologically proven diagnosis of PC, (c) 1-5 oligoprogressive metastases, defined as progressive disease at bone or nodes levels (detected by means of choline PET/CT or CT plus bone scan) during ADT, (d) serum testosterone level under 50 ng/ml during ADT, (e) controlled primary tumor, (f) patients treated with SBRT with a dose of at least 5 Gy per fraction to a biologically effective dose (BED) of at least 80 Gy using an alpha-to-beta ratio of 3 Gy, (g) at least 6 months of follow-up post-SBRT., Results: Eighty-six patients for a total of 117 lesions were treated with SBRT. The median follow-up was 30.7 months (range 4-91 months). The median new metastasis-free survival after SBRT was 12.3 months (95% CI 5.5-19.1 months). One- and two-year distant progression-free survival was 52.3% and 33.7%, respectively. Twenty-six out of 86 patients underwent a second course of SBRT due to further oligoprogressive disease: This resulted in a median systemic treatment-free survival of 21.8 months (95% CI 17.8-25.8 months). One-year systemic treatment-free survival was 72.1%., Conclusion: SBRT appears to be a promising approach in oligoprogressive castration-resistant prostate cancer. Further investigations are warranted.

Background: Bone metastases represent an important source of morbidity in cancer patients, mostly due to severe pain. Radiotherapy is an established symptomatic treatment for painful bone metastases, however, when conventional techniques are used, the effectiveness is moderate. Stereotactic body radiotherapy (SBRT), delivering very high doses in a limited number of fractions in a highly conformal manner, could potentially be more effective and less toxic., Methods: This is a phase III, randomized-controlled, single-blind, multicenter study evaluating the response rate of antalgic radiotherapy for painful bone metastases and the acute toxicity associated with this treatment. A total of 126 patients will be randomly assigned to receive either the standard schedule of a single fraction of 8.0 Gy delivered through three-dimensional conformal radiotherapy or a single fraction of 20.0 Gy delivered through SBRT. Primary endpoint is pain response at the treated site at 1 month after radiotherapy. Secondary endpoints are pain flare at 24-48-72 h after radiotherapy, duration of pain response, re-irradiation need, acute toxicity, late toxicity, quality of life and subsequent serious skeletal events. In a supplementary analysis, patient-compliance for a paper-and-pencil questionnaire will be compared with an electronic mode., Discussion: If a dose-escalated approach within the context of single fraction stereotactic body radiotherapy could improve the pain response to radiotherapy and minimize acute toxicity, this would have an immediate impact on the quality of life for a large number of patients with advanced cancer. Potential disadvantages of this technique include increased pain flare or a higher incidence of radiation-induced fractures., Trial Registration: The Ethics committee of the GZA Hospitals (B099201732915) approved this study on September 4th 2018. Trial registered on Clinicaltrials.gov ( NCT03831243 ) on February 5th 2019.

Objective: The primary objective of this study was to assess clinical outcomes in patients with oligometastatic prostate cancer recurrence after single or repeated salvage radiation treatment., Methods: Forty-nine consecutive prostate cancer patients diagnosed with oligometastatic recurrence on Ch-PET have been prospectively treated. Seven (23%) patients had castrate-resistant disease. Clinical outcomes were assessed using the Kaplan-Meier method. Potential prognostic factors were examined using univariate proportional hazards regression., Results: The treatments administered to the initial oligorecurrence sites were intensity-modulated radiotherapy (IMRT) ± ADT (26 patients; 53%) and stereotactic ablative radiotherapy (SABR) ± ADT (23 patients; 47%). With a median follow-up of 24 months (range 6-39), 24 patients developed a biochemical failure. Twenty out of the 24 relapsed patients underwent a second Ch-PET/CT. Seven patients presented poly-metastatic relapse and 10 oligometastatic diseases. Six of 10 patients with a second oligorecurrence were treated again with SABR. Overall, 102 lesions were treated. Local control was detected in 45 (91.8%) patients. No relevant (grade ≥ 2) toxicity was reported, and there was no grade 3 toxicity. On univariate analysis, none of the variables were significantly predicted for clinical disease-free survival. At last follow-up visit, 24 patients (40%) were free from biochemical failure and 37 (71%) patients were free from clinical disease. The 2-year OS and PCSS were 91.8% and 95.9% respectively., Conclusion: Salvage IMRT or SBRT of oligometastatic prostate cancer recurrence is associated with a prolonged cDFS. This may result in a longer time to develop castrate-resistant disease and a longer time without systemic therapies., (© 2019 John Wiley & Sons Ltd.)

Purpose: Nivolumab improves survival in patients with metastatic melanoma. Unfortunately, most patients do not respond to this treatment. Preclinical data indicate that radiation therapy could work synergistically with nivolumab and improve response rates., Methods and Materials: We conducted a phase 2 trial in 20 patients with inoperable or metastatic melanoma with ≥2 measurable lesions (Response Evaluation Criteria in Solid Tumors v1.1). Stereotactic body radiation therapy (SBRT) of 3 × 8 Gy to the largest lesion was delivered before the second nivolumab cycle. The primary endpoint was overall response rate (ORR) in the nonirradiated lesions (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included toxicity. An exploratory endpoint was mutant BRAF and NRAS circulating tumor DNA (ctDNA) on serial blood samples., Results: An ORR of 45% was noted with 3 complete and 6 partial responses. Three patients experienced stable disease and 7 had progressive disease as best response. All patients with a complete response in the nonirradiated lesions exhibited a local complete response in the irradiated lesion. Grade 1 to 2 treatment-related adverse events (AEs) occurred in 17 patients; 3 patients experienced grade 3 AEs (lymphopenia, gastroenteritis, and bullous pemphigoid). No grade 4 to 5 AEs occurred. ctDNA was detected in 8 patients, and changes corresponded to clinical response and suggested that a subset of patients with a low programmed death ligand-1 score only started responding after SBRT., Conclusions: We conclude that the combination treatment was well tolerated and led to an ORR of 45% in patients with metastatic or inoperable melanoma, similar to historical response rates of nivolumab monotherapy. Although underpowered, our data therefore do not indicate a substantial abscopal response. Nonetheless, serial ctDNA analyses suggest that a subset of patients responded only after the addition of SBRT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To report the results of a phase 1 trial evaluating the safety of the ipilimumab/radiation therapy combination in patients with metastatic melanoma., Patients and Methods: Thirteen patients with metastatic melanoma were enrolled. Trial treatment consisted of 4 cycles of ipilimumab in combination with concurrent dose-escalated high-dose radiation therapy to 1 lesion administered before the third cycle of ipilimumab., Results: Grade 3 or 4 ipilimumab-related adverse events occurred in 25% of patients. The maximum tolerated radiation therapy dose was not reached. Local control of the irradiated lesions was achieved in 11 of 12 irradiated patients (1 patient had progressive disease before irradiation and dropped out of the trial). Evaluation of the nonirradiated lesions demonstrated that 3 of 13 patients experienced clinical benefit, with 1 patient developing a partial response and 2 patients having confirmed stable disease. Immunomonitoring data showed that in patients without clinical benefit, factors linked to immunotolerance increased early after the initiation of ipilimumab, suggesting that early initiation of radiation therapy might be more effective if combined with ipilimumab., Conclusions: Our findings suggest that the combination of ipilimumab and high-dose radiation therapy is feasible and safe., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Prostate cancer is the most common non-cutaneous cancer in males. There are a number of options for patients with localized early stage disease, including active surveillance for low-risk disease, surgery, brachytherapy, and external beam radiotherapy. Increasingly, external beam radiotherapy, in the form of dose-escalated and moderately hypofractionated regimens, is being utilized in prostate cancer, with randomized evidence to support their use. Stereotactic body radiotherapy, which is a form of extreme hypofractionation, delivered with high precision and conformality typically over 1 to 5 fractions, offers a more contemporary approach with several advantages including being non-invasive, cost-effective, convenient for patients, and potentially improving patient access. In fact, one study has estimated that if half of the patients currently eligible for conventional fractionated radiotherapy in the United States were treated instead with stereotactic body radiotherapy, this would result in a total cost savings of US$250 million per year. There is also a strong radiobiological rationale to support its use, with prostate cancer believed to have a low α/β ratio and therefore being preferentially sensitive to larger fraction sizes. To date, there are no published randomized trials reporting on the comparative efficacy of stereotactic body radiotherapy compared to alternative treatment modalities, although multiple randomized trials are currently accruing. Yet, early results from the randomized phase III study of HYPOfractionated RadioTherapy of intermediate risk localized Prostate Cancer (HYPO-RT-PC) trial, as well as multiple single-arm phase I/II trials, indicate low rates of late adverse effects with this approach. In patients with low- to intermediate-risk disease, excellent biochemical relapse-free survival outcomes have been reported, albeit with relatively short median follow-up times. These promising early results, coupled with the enormous potential cost savings and implications for resource availability, suggest that stereotactic body radiotherapy will take center stage in the treatment of prostate cancer in the years to come.

Context: Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in patients affected by oligorecurrent prostate cancer disease limited to lymph nodes, a subgroup of patients who would otherwise be treated only with androgen deprivation therapy (ADT)., Objective: To perform a systematic review of SBRT for oligorecurrent prostate cancer limited to lymph nodes., Evidence Acquisition: We performed a systematic review of PubMed/Medline in October 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). We searched for studies reporting on biochemical or clinical progression and/or toxicity or complications of SBRT. Reports were excluded if these end points could not be ascertained or separately analyzed, or if insufficient details were provided., Evidence of Synthesis: A total of 363 patients from nine studies were collected. Of these patients, 211 were treated with SBRT for a total of 270 lymph nodes. With an alpha-beta ratio of 3 Gy, the biologically effective dose in fractionated SBRT was >100 Gy in all studies (range, 88-216 Gy). With a median follow-up of 19.23 mo, local control was achieved in 98.1% of patients. Median progression-free survival (defined as biochemical and/or radiological progression) was 22.5 mo (range, 11-30 mo). Information about ADT during SBRT was available in 281 patients, of whom 114 (40.5%) were on ADT during SBRT, and the duration of hormone therapy ranged from 1 to 17.5 mo. Median ADT-free survival was 32.8 mo (range, 25-44 mo). About toxicity, Common Terminology Criteria for Adverse Events toxicity scale was most used. Acute and/or late grade ≥2 toxicity was reported in only 5.6% of patients, and no patient developed grade 4 toxicity., Conclusions: SBRT seems to be promising in lymph node oligorecurrent prostate cancer, although there is a weak level of evidence to support such investigational treatment, which is currently based on retrospective studies of single-institution or pooled experiences. ADT-free survival is an interesting end point, which needs to be investigated., Patient Summary: We performed a systematic review to assess outcomes and toxicity of stereotactic body radiotherapy (SBRT) for patients affected by oligorecurrent prostate cancer limited to lymph nodes. We concluded that SBRT is a promising therapy in this setting, but it needs to be validated in randomized controlled trials., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The primary objective was to determine maximum tolerated radiation dose in patients with metastatic renal cell carcinoma on pazopanib treatment., Methods: Treatment-naïve patients received pazopanib according to standard of care. Stereotactic body radiotherapy (SBRT) was delivered concurrently to the largest metastatic lesion at day 8, 10 and 12. SBRT doses were escalated in 3 dose levels (24 Gy/3, 30 Gy/3 and 36 Gy/3). Dose level was assigned using Time-to-Event Continual Reassessment Method with the target dose-limiting toxicity rate set to 0.25., Results: Thirteen patients were included. One patient experienced dose limiting toxicity (DLT) at dose level 3 (grade 4 hypoglycemia). Maximum tolerated dose was not reached with a recommended dose of 36 Gy/3 having a probability of DLT of 11%. One-year local control was 83% (95% confidence interval 61-100) and 1-year progression-free survival was 28% (95% confidence interval 1-55)., Conclusions: SBRT in combination with pazopanib is well tolerated with good local control and response rates outside the radiation field., Trial Registration: This trial was retrospectively registered on clinicaltrials.gov( NCT02334709 ) on January 6th, 2015.

Background: The purpose of the study was to evaluate the prostate serum antigen (PSA) response, local control, progression-free survival (PFS), and toxicity of stereotactic body radiotherapy (SBRT) for lymph node (LN) oligorecurrent prostate cancer., Patients and Methods: Between May 2012 and October 2015, 124 lesions were treated in 94 patients with a median dose of 24 Gy in 3 fractions. Seventy patients were treated for a single lesion and 25 for > 1 lesion. In 34 patients androgen deprivation (AD) was combined with SBRT. We evaluated biochemical response according to PSA level every 3 months after SBRT: a 3-month PSA decrease from pre-SBRT PSA of more than 10% identified responder patients. In case of PSA level increase, imaging was performed to evaluate clinical progression. Toxicity was assessed every 6 to 9 months after SBRT., Results: Median follow-up was 18.5 months. In 13 patients (14%) Grade 1 to 2 toxicity was reported without any Grade 3 to 4 toxicity. Biochemical response, stabilization, and progression were observed in 64 (68%), 10 (11%), and 20 (21%) of 94 evaluable patients. Clinical progression was observed in 31 patients (33%) after a median time of 8.1 months. In-field progression occurred in 12 lesions (9.7%). Two-year local control and PFS rates were 84% and 30%, respectively. Age older than 75 years correlated with better biochemical response rate. Age older than 75 years, concomitant AD administered up to 12 months, and pelvic LN involvement correlated with longer PFS., Conclusion: SBRT is safe and offers good in-field control. At 2 years after SBRT, 1 of 3 patients is progression-free. Further investigation is warranted to identify patients who benefit most from SBRT and to define the optimal combination with AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates., Methods: The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon's two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment., Discussion: The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564).

Background: Antibodies blocking programmed cell death 1 (PD-1) have encouraging responses in patients with metastatic melanoma. Response to anti-PD-1 treatment requires pre-existing CD8+ T cells that are negatively regulated by PD-1-mediated adaptive immune resistance. Unfortunately, less than half of melanoma tumours have these characteristics. Combining anti-PD-1 treatment with other immunomodulating treatments to activate CD8+ T cells is therefore of vital importance to increase response rates and long-term survival benefit in melanoma patients. Both preclinical and retrospective clinical data support the hypothesis that radiotherapy increases the response rates to anti-PD-1 treatment by stimulating the accumulation and activation of CD8+ T cells in the tumour microenvironment. Combining radiotherapy with a PD-1 blocking antibody might therefore increase response rates and even induce long-term survival. The current phase II study will be testing these hypotheses and aims to improve local and distant tumour responses by exploiting the pro-immunogenic effects of radiotherapy in addition to anti-PD-1 treatment., Methods: The trial will be conducted in patients with metastatic melanoma. Nivolumab or pembrolizumab, both antibodies that target PD-1, will be administrated according to the recommended dosing schedule. Prior to the 2nd cycle, radiotherapy will be delivered in three fractions of 8 Gy to the largest FDG-avid metastatic lesion. The primary endpoint is the proportion of patients with a partial or complete response in non-irradiated metastases according to RECIST v1.1. Secondary endpoints include response rate according to immune related response criteria, metabolic response, local control and survival. To identify peripheral blood biomarkers, peripheral blood mononuclear cells and serum samples will be collected prospectively before, during and after treatment and subjected to flow cytometry and cytokine measurement., Discussion: The current phase II trial aims at exploring the suggested benefits of combining anti-PD-1 treatment and radiotherapy. The translational focus on immunologic markers might be suitable for predicting efficacy and monitoring the effect so to improve patient selection for future clinical applications. ClinicalTrials.gov Identifier NCT02821182.

Unlabelled: The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials., Patient Summary: This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival., (Copyright © 2015. Published by Elsevier B.V.)

Purpose: To assess the outcome of prostate cancer (PCa) patients diagnosed with oligometastatic disease at recurrence and treated with stereotactic body radiotherapy (SBRT)., Methods: Non-castrate patients with up to 3 synchronous metastases (bone and/or lymph nodes) diagnosed on positron emission tomography - computed tomography, following biochemical recurrence after local curative treatment, were treated with (repeated) SBRT to a dose of 50 Gy in 10 fractions or 30 Gy in 3 fractions. Androgen deprivation therapy-free survival (ADT-FS) defined as the time interval between the first day of SBRT and the initiation of ADT was the primary endpoint. ADT was initiated if more than 3 metastases were detected during follow-up even when patients were still asymptomatic. Secondary endpoints were local control, progression free survival (PFS) and toxicity. Toxicity was scored using the Common Terminology Criteria for Adverse Events., Results: With a median follow-up from time of SBRT of 2 years, we treated 50 patients with 70 metastatic lesions with a local control rate of 100%. The primary involved metastatic sites were lymph nodes (54%), bone (44%), and viscera (2%). The median PFS was 19 mo (95% CI: 13-25 mo) with 75% of recurring patients having ≤3 metastases. A 2nd and 3rd course of SBRT was delivered in 19 and 6 patients respectively. This results in a median ADT-FS of 25 months (20-30 mo). On univariate analysis, only a short PSA doubling time was a significant predictor for both PFS (HR: 0.90, 95% CI: 0.82 - 0.99) and ADT-FS (HR: 0.83; 95% CI: 0.71 - 0.97). Ten patients (20%) developed toxicity following treatment, which was classified as grade I in 7 and grade II in 3 patients., Conclusion: Repeated SBRT for oligometastatic prostate cancer postpones palliative androgen deprivation therapy with 2 years without grade III toxicity.

Prostate cancer (PC) is a radiosensitive tumor, and external beam radiotherapy (EBRT) has gained its place in the treatment of PC. The aim of this review is to provide the physician involved in the treatment of PC an overview of the current indications of EBRT, to focus on some recent developments in EBRT, and to highlight promising new indications for EBRT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: We investigated whether repeated stereotactic body radiotherapy (SBRT) of oligometastatic disease is able to defer the initiation of palliative androgen deprivation therapy (ADT) in patients with low-volume bone and lymph node metastases., Patients and Methods: Patients with up to 3 synchronous metastases (bone and/or lymph nodes) diagnosed on positron emission tomography, following biochemical recurrence after local curative treatment, were treated with (repeated) SBRT to a dose of 50 Gy in 10 fractions. Androgen deprivation therapy-free survival (ADT-FS) defined as the time interval between the first day of SBRT and the initiation of ADT was the primary end point. ADT was initiated if more than 3 metastases were detected during follow-up even when patients were still asymptomatic or in case of a prostate specific antigen elevation above 50 ng/mL in the absence of metastases. Secondary end points were local control, clinical progression-free survival, and toxicity. Toxicity was scored using the Common Terminology Criteria for Adverse Events., Results: We treated 24 patients with a median follow-up of 24 months. Ten patients started with ADT resulting in a median ADT-FS of 38 months. The 2-year local control and clinical progression-free survival was 100% and 42%, respectively. Eleven and 3 patients, respectively, required a second and third salvage treatment for metachronous low-volume metastatic disease. No grade 3 toxicity was observed., Conclusion: Repeated salvage SBRT is feasible, well tolerated and defers palliative ADT with a median of 38 months in patients with limited bone or lymph node PCa metastases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: The addition of stereotactic ablative radiotherapy (SABR) to standard of care for patients with oligometastatic prostate cancer has the potential of improving survival and delaying further metastases. The primary aim of this analysis is to report survival outcomes and pattern of recurrence of patients with hormone-sensitive (HSPC) and castrate-resistant (CRPC) oligometastatic prostate cancer treated with SABR. Methods: This is a single-center retrospective study of patients with oligometastatic prostate cancer treated in Iridium Network between 2014 and 2018. All patients with oligometastatic (≤3 active lesions) HSPC and CRPC treated with SABR were included. Data were collected using electronic records. Patterns of first progression following SABR were reported. Kaplan-Meier methods were used to determine survival outcomes. Results: Eighty-seven men received SABR to 115 metastases. Nineteen patients were castrate-resistant and 68 hormone-sensitive at the time of SABR. Median follow-up was 41.6 months. In 25% of patients, no decline from baseline PSA was recorded. Median bPFS was 11.7 months (95% CI 7.6 - 18.3) for HSPC as well as CRPC (95% CI 6.4 - 24.0) (p=0.27). Median DMFS was 21.8 (95% CI 16.9 - 43.2) versus 17.6 months (95% CI 6.7 - 26.2) for HSPC versus CRPC, respectively (p=0.018). Median OS was 72.6 months (95% CI 72.6 – not reached) for HSPC and not reached for CRPC (95% CI 35.4 months – not reached) (p=0.026). For the subgroup of oligorecurrent HSPC, short-term androgen-deprivation therapy was associated with improved bPFS (median 6.0 vs. 18.3 months, HR 0.31, p<0.001) and DMFS (median 15.8 vs 29.6 months, HR 0.5, p=0.06). Information on pattern of relapse was retrieved for 79 patients: 45% (36/79) of these patients were long-term disease-free (>18 months), 28% (22/79) of patients wmere oligoprogressive (≤3 new lesions) and 27% (21/79) developed a polymetastatic relapse. Conclusion: In this cohort, oligometastatic HSPC showed potential benefit from SABR with a median DMFS of 21.8 months. Well-selected patients with oligometastatic CRPC may also benefit from SABR. For patients with metachronous and repeat oligorecurrent HSPC, combining SABR with short-term androgen-deprivation therapy was associated with improved bPFS and DMFS. Overall, 36/87 (41%) of patients were still free from clinical relapse at 18 months. [ABSTRACT FROM AUTHOR]

Context The introduction of novel imaging modalities has increased the detection of oligometastatic prostate cancer (PCa) recurrence, potentially justifying the use of a metastasis-directed therapy (MDT) with surgery or radiotherapy (RT) rather than a systemic approach. Objective To perform a systematic review of MDT for oligometastatic PCa recurrence. Evidence acquisition This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We searched the Medline and Embase databases from 1946 to February 2014 for studies reporting on biochemical or clinical progression and/or toxicity or complications of MDT (RT or surgery). Reports were excluded if these end points could not be ascertained or separately analysed, or if insufficient details were provided. Methodological quality was assessed using an 18-item validated quality appraisal tool for case series. Evidence synthesis Fifteen single-arm case series reporting on a total of 450 patients met the inclusion criteria. Seven studies were considered of acceptable quality. Oligometastatic PCa recurrence was diagnosed with positron emission tomography with coregistered computed tomography in most of the patients (98%). Nodal, bone, and visceral metastases were treated in 78%, 21%, and 1%, respectively. Patients were treated with either RT (66%) or lymph node dissection (LND) (34%). Adjuvant androgen deprivation was given in 61% of patients ( n = 275). In the case of nodal metastases, prophylactic nodal irradiation was administered in 49% of patients ( n = 172). Overall, 51% of patients were progression free 1–3 yr after salvage MDT, with most of them receiving adjuvant treatment. For RT, grade 2 toxicity was observed in 8.5% of patients, with one case of grade 3 toxicity. In the case of LND, 11% and 12% of grade 2 and grade 3 complications, respectively, were reported. Conclusions MDT is a promising approach for oligometastatic PCa recurrence, but the low level of evidence generated by small case series does not allow extrapolation to a standard of care. Patient summary We performed a systematic review to assess complications and outcomes of treating oligometastatic prostate cancer recurrence with surgery or radiotherapy. We concluded that although this approach is promising, it requires validation in randomised controlled trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Currently available biomarkers for response to checkpoint inhibitors are incomplete and predominantly focus on tumor tissue analysis e.g., tumor mutational burden, programmed cell death-ligand 1 (PD-L1) expression. Biomarkers in peripheral blood would allow a more dynamic monitoring and could offer a way for sequential adaptation of treatment strategy. We conducted an in-depth analysis of baseline and on-treatment systemic immune features in a cohort of stage III/IV melanoma and stage IV urothelial cancer (UC) patients treated with anti-programmed cell death-1 (anti-PD-1) therapy combined with stereotactic body radiotherapy (SBRT) in a similar regimen/schedule. Baseline immunity was clearly different between these two cohorts, indicating a less active immune landscape in UC patients. This study also detected signatures of proliferation in the CD8+ T-cell compartment pre-treatment and early after anti-PD-1 initiation that were positively correlated with clinical outcome in both tumor types. In addition our data support the biological relevance of PD-1/PD-L1 expression on circulating immune cell subsets, especially in melanoma. (1) Background: Blockade of the PD-1/PD-L1 pathway has revolutionized the oncology field in the last decade. However, the proportion of patients experiencing a durable response is still limited. In the current study, we performed an extensive immune monitoring in patients with stage III/IV melanoma and stage IV UC who received anti-PD-1 immunotherapy with SBRT. (2) Methods: In total 145 blood samples from 38 patients, collected at fixed time points before and during treatment, were phenotyped via high-parameter flow cytometry, luminex assay and UPLC-MS/MS. (3) Results: Baseline systemic immunity in melanoma and UC patients was different with a more prominent myeloid compartment and a higher neutrophil to lymphocyte ratio in UC. Proliferation (Ki67+) of CD8+ T-cells and of the PD-1+/PD-L1+ CD8+ subset at baseline correlated with progression free survival in melanoma. In contrast a higher frequency of PD-1/PD-L1 expressing non-proliferating (Ki67−) CD8+ and CD4+ T-cells before treatment was associated with worse outcome in melanoma. In UC, the expansion of Ki67+ CD8+ T-cells and of the PD-L1+ subset relative to tumor burden correlated with clinical outcome. (4) Conclusion: This study reveals a clearly different immune landscape in melanoma and UC at baseline, which may impact immunotherapy response. Signatures of proliferation in the CD8+ T-cell compartment prior to and early after anti-PD-1 initiation were positively correlated with clinical outcome in both cohorts. PD-1/PD-L1 expression on circulating immune cell subsets seems of clinical relevance in the melanoma cohort. [ABSTRACT FROM AUTHOR]