Search

Background: Non-invasive and minimally invasive ablative treatments, including stereotactic body radiotherapy (SBRT), radiofrequency ablation, microwave ablation, and cryoablation, have emerged as key treatment options for managing renal cell carcinoma, especially for patients who are unsuitable for surgery. We aimed to compare the clinical efficacy and safety of these emerging treatment methods in patients with localised renal cell carcinoma., Methods: In this systematic review and meta-analysis, we searched PubMed (MEDLINE), Embase, and the Cochrane Library for publications between Jan 1, 2000, and March 1, 2024. Eligible articles were observational studies and randomised controlled trials including at least five adult patients (age ≥18 years) with primary and localised renal cell carcinoma treated with SBRT, radiofrequency ablation, microwave ablation, or cryoablation and that reported on local control outcomes. Two reviewers independently screened titles and abstracts and then full texts of eligible studies were independently evaluated by the same reviewers, with disagreements resolved via discussion or consultation with a third reviewer. Summary estimates were extracted from published reports manually using a standardised data extraction form. The primary endpoint was local control rate at 1 year, 2 years, and 5 years after start of treatment. A meta-analysis was conducted using a DerSimonian and Laird model to summarise local control rates. Publication bias was evaluated using funnel plots and Egger's test. We also recorded the frequency and severity of adverse events after treatment on the basis of the Common Terminology Criteria for Adverse Events (version 5.0) and Clavien-Dindo complication index. The study protocol was prospectively registered with PROSPERO, CRD42024511840., Findings: We identified 6668 records, of which 330 were assessed via full-text review, and 133 were included in our systematic review and meta-analysis. The eligible studies included data for 8910 patients (mean age 67·9 years [SD 7·3], 2518 [31·4%] of 8018 patients with available data were female and 5500 [68·6%] were male). Local control rates for SBRT were 99% (95% CI 97-100; I 2 =6%) at 1 year, 97% (95-99; I 2 =0%) at 2 years, and 95% (89-98; I 2 =42%) at 5 years; for radiofrequency ablation were 96% (94-98; I 2 =73%) at 1 year, 95% (92-98; I 2 =77%) at 2 years, and 92% (88-96; I 2 =78%) at 5 years; for microwave ablation were 97% (95-99; I 2 =74%) at 1 year, 95% (92-98; I 2 =77%) at 2 years, and 86% (75-94; I 2 =66%) at 5 years; and for cryoablation were 95% (93-96; I 2 =61%) at 1 year, 94% (91-96; I 2 =69%) at 2 years, and 90% (87-93; I 2 =74%) at 5 years. The proportion of patients who reported grade 3-4 adverse events was 3% (121 of 3726) after cryoablation, 2% (39 of 2503) after radiofrequency ablation, 1% (22 of 2069) after microwave ablation, and 2% (11 of 612) after SBRT. Risk of bias was moderate in most studies (70 [53%] of 133) and no publication bias was observed., Interpretation: All investigated ablative methods continue to represent effective treatment choices in renal cell carcinoma, and these findings support multi-disciplinary discussions of these treatment methods, along with surgery and surveillance, to individualise treatment decisions in these patients. Future research should aim to conduct randomised controlled trials across larger patient populations to further elucidate the long-term oncological and survival outcomes associated with these treatments., Funding: None., Competing Interests: Declaration of interests SR reports receiving personal fees from AstraZeneca, Sanofi, Knight Pharmaceuticals, Verity Pharma, and Tersera, and grants from Knight Therapeutics, AstraZeneca, and Varian. AS reports receiving honoraria from Bristol Meyers Squib. CJDW reports receiving personal fees from Janssen Oncology, Nanostics, Precision Point Specialty, Sesen Bio, AbbVie, Astellas, Bayer, EMD Serono, Haymarket Media, Healing and Cancer Foundation, Knight Therapeutics, Merck, Science & Medicine Canada, TerSera Canada, and Tolmar Pharmaceuticals Canada, and grants from Knight Therapeutics, Bayer, and Tolmar Pharmaceuticals Canada. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Purpose: Stereotactic body radiotherapy (SBRT) carries potentially higher risks for ultracentral (UC) NSCLC with limited prospective data to guide decision making. We conducted a secondary analysis from a randomized trial of SBRT and conventionally hypofractionated radiation (CRT) to assess these risks., Materials and Methods: Patients (n = 233) with medically inoperable stage I NSCLC were recruited from 2014 to 2020. Patients with UC targets directly overlapping the proximal bronchial tree (PBT) were identified. The primary objective was the occurrence of related grade 3-5 toxicity > 3 months following radiation. Secondary endpoints included local control, survival, and evaluation of PBT dose and its association with late toxicity., Results: Thirty UC tumors were identified (23 - SBRT 60 Gy/8 fractions, 7 - CRT 60 Gy/15 fractions). Median age was 72 years, and median tumor size was 2.8 cm. Most patients (67 %) had histologically confirmed NSCLC. At a median follow-up of 2.9 years, 3 and 1 patients developed grade 3 and 5 toxicity respectively (all SBRT). 3-year local control was 85 %. Mean PBT dose (converted to 2 Gy dose equivalents) was higher in patients with grade ≥ 3 toxicity, particularly for 4 cc (105.5 vs 51.8 Gy, p = 0.0004), 5 cc (84 vs 46.1 Gy, p = 0.003), and volumetric doses (V65 - V100Gy). The patient with grade 5 toxicity had the highest 5 cc dose (117 Gy), V90Gy (8.2 cc), and V100Gy (7 cc)., Conclusions: SBRT for UC NSCLC provides good local control but carries a high rate of late grade 3-5 toxicity. An apparent association between toxicity and PBT volumetric dose was observed, which should be considered if SBRT is offered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the effectiveness and safety of salvage stereotactic ablative body radiotherapy (SABR) for recurrent renal cell carcinoma (RCC) after thermal ablation (TA)., Materials and Methods: This study was a multi-institutional retrospective analysis of patients with recurrent RCC following TA who received SABR between 2016 and 2020. The primary study outcome was freedom from local failure, evaluated radiographically based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Distant failure, cancer-specific survival (CSS), overall survival (OS), treatment-related toxicity and renal function changes following SABR were the secondary outcomes. The Kaplan-Meier method was used to estimate freedom from local and distant failure, CSS and OS., Results: Seventeen patients with 18 biopsy-confirmed RCCs were included, with a median (interquartile range [IQR]) age at time of SABR of 75.2 (72.6-68.7) years, a median (IQR) tumour size of 3.5 (1.9-4.1) cm and follow-up (reverse Kaplan-Meier method) of 3.36 (95% confidence interval [CI] 1.6-4.1) years. Six of the 17 patients had a solitary kidney. Five patients had failed repeat TA prior to SABR. The median (IQR) time from TA procedure to SABR was 3.03 (1.5-5.1) years. No patient experienced local progression, with a local control rate of 100%. Four patients, two with baseline metastatic disease, experienced distant progression. The distant progression-free survival, CSS and OS at 3 years were 72.1% (95% CI 51.9%-100%), 92.3% (95% CI 78.9%-100%) and 82.1% (95% CI 62.1%-100%), respectively. The median (IQR) glomerular filtration rate before SABR was 58 (40-71) mL/min, and at last follow-up, it was 48 (33-57) mL/min. No patient experienced grade 3+ toxicity or went on to develop end-stage renal disease., Conclusion: The results showed that SABR appears to be an effective and safe salvage strategy in patients with recurrent RCC following TA., (© 2024 BJU International.)

Traditionally, renal cell carcinoma (RCC) was considered a radioresistant tumor, thereby limiting definitive radiation therapy management options. However, several recent studies have demonstrated that stereotactic body radiation therapy (SBRT) can achieve high rates of local control for the treatment of primary RCC. In the setting of expanding use of SBRT for primary RCC, it is crucial to provide guidance on practical considerations such as patient selection, fractionation, target delineation, and response assessment. This is particularly important in challenging scenarios where a paucity of evidence exists, such as in patients with a solitary kidney, bulky tumors, or tumor thrombus. The Radiosurgery Society endorses this case-based guide to provide a practical framework for delivering SBRT to primary RCC, exemplified by 3 cases. This article explores topics of tumor size and dose fractionation, impact on renal function and treatment in the setting of a solitary kidney, and radiation's role in the management of inferior vena cava tumor thrombus. Additionally, we review existing evidence and expert opinion on target delineation, advanced techniques such as magnetic resonance imaging guided SBRT, and SBRT response assessment., Competing Interests: Disclosures Rohann J. M. Correa reports research funding from Droplet Biosciences. Alan Dal Pra reports research support from Veracyte. Tugce Kutuk reports a travel stipend from GammaTile. Simon S. Lo reports research support from Elekta AB and the Kuni Foundation, travel support from the Japanese Society for Radiation Oncology, and leadership roles as a member of the ICON Gamma Knife Expert Group, American College of Radiology, and the Radiosurgery Society. Alexander Louie reports honoraria from AstraZeneca and serves on an AstraZeneca advisory board. Sarah P. Psutka reports grants from the National Institutes on Aging, Bladder Cancer Advisory Network, and PRIME Education, as well as serving on advisory or data safety monitoring boards for Janssen, Merck, Immunity Bio, and CG Oncology, and leadership roles for European Urology journal, Bladder Cancer journal, and American Urological Association. Shankar Siva reports research funding from Merck-Sharp-Dohme, Bayer Pharmaceuticals, and Varian Medical Systems. Karin A. Skalina reports a leadership role with the Radiosurgical Society. Anand Swaminath reports honoraria from AstraZeneca and Bristol Myers Squibb, as well as serving on an AstraZeneca advisory board. Chad Tang reports consulting fees from Telix Pharmaceutical, as well as advisory board service for Siemens Healthineer, Lantheus Pharmaceutical, and Bayer, as well as clinical trial research support from Merck and Myriad. Rituraj Upadhyay reports payment or honoraria and travel support from Varian Medical Systems. Nicholas G. Zaorsky reports support from the American Cancer Society – Tri State CEOs Against Cancer Clinician Scientist Development Grant, CSDG-20-013-01-CCE and the Department of Defense, as well as remuneration from the American College of Radiation Oncology for chart review and accreditation of radiation oncology facilities nationally and remuneration from Spring Nature for the textbook Absolute Clinical Radiation Oncology Review; he was supported by the National Institutes of Health Grant LRP 1 L30 CA231572-01. All other authors report no disclosures., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy., Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone., Design, Setting, and Participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023., Intervention: Personalized SBRT, 27.5 to 50 Gy in 5 fractions., Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life., Results: Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively., Conclusions and Relevance: In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone., Trial Registration: ClinicalTrials.gov Identifier: NCT01730937.

Background and Objective: Renal function preservation is particularly important following nonoperative treatment of localized renal cell carcinoma (RCC) since patients are often older with medical comorbidities. Our objective was to report long-term renal function outcomes after stereotactic ablative radiotherapy (SABR) including patients with a solitary kidney., Methods: Patients with primary RCC treated with SABR with ≥2 yr of follow-up at 12 International Radiosurgery Consortium for Kidney institutions were included. Renal function was measured by estimated glomerular filtration rate (eGFR)., Key Findings and Limitations: In total, 190 patients (56 with a solitary kidney) underwent SABR and were followed for a median of 5.0 yr (interquartile range [IQR]: 3.4-6.8). In patients with a solitary kidney versus bilateral kidneys, pre-SABR eGFR (mean [standard deviation]) was 61.1 (23.2) versus 58.0 (22.3) ml/min (p = 0.32) and the median tumor size was 3.65 cm (IQR: 2.59-4.50 cm) versus 4.00 cm (IQR: 3.00-5.00 cm; p = 0.026). At 5 yr after SABR, eGFR decreased by -14.5 (7.6) and -13.3 (15.9) ml/min (p = 0.67), respectively, and there were similar rates of post-SABR dialysis (3.6% [n = 2/56] vs 3.7% [n = 5/134]). A multivariable analysis demonstrated that increasing tumor size (odds ratio [OR] per 1 cm: 1.57; 95% confidence interval [CI]: 1.14-2.16, p = 0.0055) and baseline eGFR (OR per 10 ml/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) were associated with an eGFR decline of ≥15 ml/min at 1 yr., Conclusions and Clinical Implications: With long-term follow-up after SABR, kidney function decline remains moderate, with no observed difference between patients with a solitary kidney and bilateral kidneys. Tumor size and baseline eGFR are dominant factors predictive of long-term renal function decline., Patient Summary: With long-term follow-up, stereotactic ablative radiotherapy (SABR) yields moderate long-term renal function decline and low dialysis rates even in patients with a solitary kidney. SABR thus represents a promising noninvasive, nephron-sparing option for patients with localized renal cell carcinoma., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To conduct an international survey of radiation oncologists treating primary renal cell carcinoma (RCC) with SABR to ascertain the general patterns of SABR use, common dose/treatment/follow-up details, and expected outcomes., Materials and Methods: A 51-question survey was created containing the following themes: prevalence and clinical scenarios in which RCC SABR is used, dose-fractionation schedules, treatment delivery details, follow-up/outcome assessments, and implementation barriers. The survey was distributed widely across multiple influential radiation oncology societies and social media, and ran from January to April 2023., Results: A total of 255 respondents participated, mostly from academic centers within Europe/North America. Of these, 40 % (n = 102) currently offer SABR (50 % having begun within the last 3 years). Common barriers in non-users included lack of referrals by urologists and lack of supportive practice guidelines. Of respondents who do offer SABR, 77 % treat both small (4 cm or less) and large (>4 cm) renal masses. Dose-fractionation strategies varied from 27-52 Gy (3-5 fractions) for multifraction regimens, and 15-34 Gy for single fractions. Apart from treatment for medically inoperable disease, scenarios in which SABR was likely to be offered were for recurrence post surgery/thermal ablation and for oligometastatic kidney lesions. Uncommon scenarios included RCC with renal vein/inferior vena cava thrombosis, and as cytoreductive therapy in metastatic RCC. Expected local control outcomes were generally above 70 %, higher for small versus large renal masses., Conclusions: SABR is a relatively newer indication for primary RCC, offered by less than 50% of respondents, with both consistent and variable practice patterns observed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Taplin: none, Hannan: none, Lo: Kuni Foundation – research funding; Radiosurgery Society – Member of Board of Directors; ACR – assistant councillor and chair of CARROS nomination committee, Morgan: none, Ali: none, Sigurdson: none, Guckenberger: none, Swaminath: Bristol-Myers Squibb – honoraria., (© 2024 The Author(s).)

Brain metastases are frequent in neuropathology practices; however, the literature on their distribution is frequently derived from imaging studies. This work examined metastases of lung cancer to the brain through the lens of pathology specimens. All brain surgical pathology cases accessioned from 2011-2020 were retrieved from a regional laboratory. Specimens were classified by neuroanatomical location, diagnostic category, and diagnosis with a hierarchical free text string-matching algorithm. All reports classified as probable metastasis per algorithm were reviewed by a pathologist. Lung biomarkers and selected immunostains were retrieved with text parsing and reviewed. Among 4,625 cases of brain surgical resection specimens, 854 were classified as probable metastasis by the algorithm. On report review, 538/854 cases were confirmed as metastasis with a known primary site. The 538 cases were from 511 patients and 234/511 patients had lung primaries. Small cell lung cancer lesions were most frequently found in the cerebellum (17/30). Lesions from lung adenocarcinoma (59/164) and non-small cell carcinoma-not otherwise specified (NSCLC-NOS) (15/34) were most commonly found in the frontal lobe. Squamous cell carcinoma lesions were most commonly found in the frontal and occipital lobes (8/27). 72/234 cases were reported as NSCLC-NOS and could be further subclassified using immunostaining (41/72). Lung biomarker data were retrieved in ~38% of cases. PD-L1 positivity was dependent on neuroanatomical distribution (p = 0.04); other examined biomarkers were not. The distribution of lung tumours metastatic to the brain is dependent on the lung cancer subtype (p<0.001). The reporting of histologic subtype could be further optimized in the local environment., Competing Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/St. Joseph’s Healthcare Hamilton/Hamilton Regional Laboratory Medicine Program. The above does not in any way limit adherence to the PLOS ONE data availability policy, as found here: https://journals.plos.org/plosone/s/data-availability. There is no financial conflict of interest. There are no conflicts for the other authors., (Copyright: © 2024 Bonert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials., Methods: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes., Results: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively)., Conclusions: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets., (© 2024. The Author(s).)

Purpose: The use of stereotactic body radiation therapy for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (NCT03306680) aimed to determine the maximally tolerated dose of stereotactic body radiation therapy for ultracentral non-small cell lung carcinoma, using a time-to-event continual reassessment methodology., Methods and Materials: Patients with T1-3N0M0 (≤6 cm) non-small cell lung carcinoma were eligible. The maximally tolerated dose was defined as the dose of radiation therapy associated with a ≤30% rate of grade (G) 3 to 5 prespecified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume; tumors with endobronchial invasion were excluded. This primary analysis occurred 2 years after completion of accrual., Results: Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range, 65-87) and 17 (57%) were female. Planning tumor volume was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%), and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range, 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia. The latter had computed tomography findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% CI, 52.3%-85.3%), progression-free survival 66.1% (95% CI, 46.1%-80.2%), local control 89.6% (95% CI, 71.2%-96.5%), regional control 96.4% (95% CI, 77.2%-99.5%), and distant control 85.9% (95% CI, 66.7%-94.5%). Quality-of-life scores declined numerically over time, but the decreases were not clinically or statistically significant., Conclusions: Sixty Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the prespecified acceptability criteria and results in excellent control for ultracentral tumors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Stereotactic body radiotherapy (SBRT) is widely used for stage I medically inoperable non-small cell lung cancer (NSCLC), yet varied results from randomized clinical trials (RCTs) and concerns in treating centrally located tumors persist., Objective: To examine whether SBRT would improve local control (LC) compared with hypofractionated conventional radiotherapy (CRT)., Design Setting and Participants: This phase 3 RCT was conducted in 16 Canadian centers. Patients with medically inoperable stage I (≤5 cm) NSCLC were randomized 2:1 to SBRT of 48 Gy in 4 fractions (peripheral NSCLC) or 60 Gy in 8 fractions (central NSCLC) vs CRT of 60 Gy in 15 fractions. Data were collected from May 2014 to January 2020, and data were analyzed from July 2022 to July 2023., Interventions: SBRT or CRT., Main Outcomes and Measures: The primary objective was to determine the effectiveness of SBRT compared with CRT based on LC at 3 years. Secondary outcomes included event-free survival, overall survival, and toxic effects. All radiation plans were subject to real-time/final review. Local failures were centrally adjudicated. The study was designed to detect a 3-year LC improvement of SBRT from 75% to 87.5%. The target sample size was 324 patients., Results: Of 233 included patients, 119 (51.1%) were male, and the mean (SD) age was 75.4 (7.7) years; the median (IQR) follow-up was 36.1 (26.4-52.8) months. A total of 154 patients received SBRT and 79 received CRT. The 3-year LC was 87.6% (95% CI, 81.9%-93.4%) for SBRT and 81.2% (95% CI, 71.9%-90.5%) for CRT (hazard ratio [HR], 0.61; 95% CI, 0.31-1.20; P  = .15). The HR was 1.02 (95% CI, 0.72-1.45; P  = .87) for event-free survival and 1.18 (95% CI, 0.80-1.76; P  = .40) for overall survival. Minimal acute toxic effects were observed. Among those randomized to SBRT, late grade 3 or 4 toxic effects occurred in 5 of 45 (11%) with central NSCLC and 2 of 109 (1.8%) with peripheral NSCLC; among those randomized to CRT, in 1 of 19 (5%) with central NSCLC and 1 of 60 (2%) with peripheral NSCLC. One patient who received SBRT for an ultracentral lesion (target overlapping proximal bronchus) experienced a possible treatment-related grade 5 event (hemoptysis)., Conclusions and Relevance: This RCT compared lung SBRT with hypofractionated CRT that included central/ultracentral tumors. No difference was detected in LC between groups. Severe toxic effects were limited, including patients with central tumors. The trial provides important prospective data evaluating SBRT; however, further research is necessary to determine if SBRT is more effective than CRT for peripheral and central NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT03924869., Competing Interests: Conflict of Interest Disclosures: Dr Swaminath reported personal fees from AstraZeneca, Bristol Myers Squibb, and Eisai outside the submitted work. Dr Bujold reported grants from Ontario Clinical Oncology Group during the conduct of the study. Dr Gabos reported personal fees from AstraZeneca outside the submitted work. Dr Mehiri reported grants from Ontario Clinical Oncology Group during the conduct of the study. Dr Louie reported personal fees from AstraZeneca outside the submitted work. Dr Whelan reported nonfinancial support from Exact Science outside the submitted work. No other disclosures were reported., (Copyright 2024 Swaminath A et al. JAMA Oncology.)

Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published.

Purpose: SABR is increasingly used to treat renal cell carcinoma (RCC). However, the optimal method to assess treatment response is unclear. We aimed to quantify changes in both volume and maximum linear size of tumors after SABR and evaluate the utility of the 2 approaches in treatment response assessment., Methods and Materials: We retrospectively studied patients with RCC treated with SABR at our institution between 2013 and 2020. All available follow-up computed tomography scans were aligned, and tumors were contoured on all scans. Volume and maximum linear size were measured at each follow-up, relative to these measurements at the time of computed tomography simulation., Results: Twenty-four patients with 25 tumors were included. Median follow-up was 32 months (range, 16-67). Nineteen tumors (76%) had 30% volumetric response at a median time of 7 months after SABR, and 12 tumors (48%) had 30% decrease in maximum linear size at a median time of 16 months. Eighteen tumors (72%) decreased in volume on first follow-up scan and continued to shrink, and 5 tumors (20%) displayed transient growth after SABR (average 24% increase in volume). Compared with T1a tumors, T1b or larger tumors were more likely to have transient growth (8% vs 33%; P = .16) and had higher average relative volume 24 months after SABR (0.47 vs 0.8; P = .022)., Conclusions: Volume measurement results in more pronounced and earlier change compared with linear size measurement when assessing response to SABR. These findings may provide guidance when assessing treatment response for patients with RCC treated with SABR., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: The role of stereotactic ablative radiotherapy (SABR) for gynecologic malignant tumors has yet to be clearly defined despite recent clinical uptake., Objective: To evaluate the outcomes of SABR in patients with oligometastatic and oligoprogressive gynecologic cancers., Design, Setting, and Participants: In this retrospective pooled analysis, patients with oligometastatic and oligoprogressive gynecologic cancers receiving SABR at 5 institutions from Canada and the US were studied. Data were collected from January 2011 to December 2020, and data were analyzed from January to December 2023., Exposure: Stereotactic ablative radiotherapy., Main Outcomes and Measures: Cumulative incidence of local and distant recurrence, chemotherapy-free survival (CFS), and overall survival (OS) probabilities after SABR were calculated using Kaplan-Meier methods. Univariable and multivariable analysis was conducted using Cox regression methods., Results: A total of 215 patients with 320 lesions meeting criteria were included in the analysis; the median (range) age at primary diagnosis was 59 (23-86) years. The median (range) follow-up from SABR was 18.5 (0.1-124.5) months. The primary site included the endometrium (n = 107), ovary (n = 64), cervix (n = 30), and vulva or vagina (n = 14). Local cumulative incidence of recurrence was 13.7% (95% CI, 9.4-18.9) and 18.5% (95% CI, 13.2-24.5) at 1 and 5 years, respectively. Distant cumulative incidence of recurrence was 48.5% (95% CI, 41.4-55.1) and 73.1% (95% CI, 66.0-79.0) at 1 and 5 years, respectively. OS was 75.7% (95% CI, 69.2-81.1) and 33.1% (95% CI, 25.3-41.1) at 1 and 5 years, respectively. The median CFS was 21.7 months (95% CI, 15.4-29.9). On multivariable analysis, local recurrence was significantly associated with nodal metastasis, lesion size, biologically effective dose, treatment indication, institution, and primary disease type. Distant progression-free survival was associated with nodal targets and lesion size. OS and CFS were significantly associated with lesion size., Conclusions and Relevance: In this study, SABR appeared to have excellent local control with minimal toxic effects in this large patient group, and certain patients may achieve durable distant control and OS as well. It may be possible to delay time to chemotherapy in select patient subtypes and therefore reduce associated toxic effects. Prospective multicenter trials will be critical to establish which characteristics procure the greatest benefit from SABR use and to define the ideal time to implement SABR with other oncologic treatments.

Competing Interests: Intérêts concurrents:: Christopher Wallis a reçu des honoraires de services conseils des sociétés Janssen Oncology, Nanostics Inc., Precision Point Specialty LLC, Sesen Bio; des honoraires ou des frais de voyage des sociétés AbbVie, Astellas, AstraZeneca, Bayer, EMD Serono, Haymarket Media, Janssen, Knight Therapeutics, Merck, Science & Medicine Canada, TerSera Canada, Tolmar Pharmaceuticals Canada et de la Fondation Healing and Cancer Foundation; du financement de recherche de la part des sociétés Knight Therapeutics, Tolmar Pharmaceuticals et Bayer. Aly-Khan Lalani a reçu des honoraires ou des frais de service conseil des sociétés AbbVie, Astellas Pharma, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche/Genentech et TerSera, et du financement de recherche des sociétés Bristol Myers Squibb, BioCanRx, EMD Serono, Ipsen, Novartis et Roche. Anand Swaminath a reçu des honoraires des sociétés Bristol Myers Squibb, Eisai, et AstraZeneca, et occupe un poste à titre bénévole au sein du conseil consultatif médical de l’Association canadienne du cancer du rein.

Competing Interests: Competing interests: Christopher Wallis has received consulting fees from Janssen Oncology, Nanostics, Inc., Precision Point Specialty LLC, Sesen Bio; honoraria or travel fees from AbbVie, Astellas, AstraZeneca, Bayer, EMD Serono, Haymarket Media, Healing and Cancer Foundation, Janssen, Knight Therapeutics, Merck, Science & Medicine Canada, TerSera Canada, and Tolmar Pharmaceuticals Canada; research funding from Knight Therapeutics, Tolmar Pharmaceuticals and Bayer. Aly-Khan Lalani has received honoraria and/or consultancy fees from AbbVie, Astellas Pharma, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche/Genentech and TerSera, and research funding from Bristol Myers Squibb, BioCanRx, EMD Serono, Ipsen, Novartis and Roche. Anand Swaminath has received honoraria from Bristol Myers Squibb, Eisai, and AstraZeneca, and holds a voluntary position on the medical advisory board for Kidney Cancer Canada.

Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.

Introduction: First-line systemic therapy (ST) options for advanced hepatocellular carcinoma (HCC) include tyrosine kinase inhibitors and immunotherapy (IO). Evolving data suggest prolonged overall survival (OS) when ST is combined with stereotactic body radiation therapy (SBRT), although evidence is significantly limited in HCC populations. We hypothesized that advanced HCC patients in the National Cancer Database (NCDB) would have improved OS when receiving ST+SBRT vs ST alone., Methods: Stage III/IV HCC patients diagnosed from 2010-2020 and treated with first-line ST±SBRT were identified from the NCDB. The primary endpoint was OS from date of diagnosis stratified by the receipt of SBRT (ST+SBRT vs ST alone). Survival was estimated using Kaplan-Meier methodology and compared via log-rank. Multivariate analysis (MVA) was performed by Cox regression., Results: Of 10,505 eligible patients with stage III disease, 115 (1.1%) received ST+SBRT and 10,390 (98.9%) received ST alone. Of 9,617 eligible patients with stage IV disease, 127 (1.3%) received ST+SBRT and 9,490 (98.7%) received ST alone. Median follow-up time was 6.8 months. Baseline characteristics were similar between cohorts. Patients with stage III disease receiving ST+SBRT had improved median OS (12.62 months vs 8.38 months) and higher rates of survival at 1-year (53.0% vs 38.7%) and 2-years (27.0% vs 20.7%) compared to those receiving ST alone (log-rank P =0.0054). Similarly, patients with stage IV disease receiving ST+SBRT had improved median OS (11.79 months vs 5.72 months) and higher rates of survival at 1-year (49.6% vs 26.2%) and 2-years (23.6% vs 12.0%) (log-rank P <0.0001). On MVA, receipt of SBRT predicted improved OS (HR=0.748, 95%CI 0.588-0.951; P =0.0178) and receipt of IO trended towards improved OS (HR=0.859, 95%CI 0.735-1.003; P =0.0538)., Conclusion: In advanced HCC, patients receiving ST+SBRT had improved OS compared to those receiving ST alone. Prospective clinical trials are warranted to better identify HCC populations which may benefit from combined modality therapy., 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 © 2023 Piening, Swaminath, Dombrowski, Teague, Al-Hammadi and Shahi.)

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization., Competing Interests: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.The corresponding author (MB) retains the copyright on the computer code that was written outside of his employment relationship with McMaster University/St. Joseph’s Healthcare Hamilton/Hamilton Regional Laboratory Medicine Program. The above does not in any way limit adherence to the PLOS ONE data availability policy, as found here: https://journals.plos.org/plosone/s/data-availability. There is no financial conflict of interest. There are no conflicts for the other authors., (Copyright: © 2023 Bonert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

For much of the past two decades, the treatment options for patients with stage III NSCLC were mostly stagnant. In the past 5 years, ongoing innovations have dovetailed alongside advances in biomarker testing, novel therapeutics, precision surgery, and radiotherapy, all of which are leading to an increase in more personalized option for the treatment. This review article will focus on several completed and ongoing initiatives involving treatment of patients with stage III NSCLC. First, it will tackle the progress made in curative treatment of unresectable stage III NSCLC, starting with PACIFIC, and branching out into topics such as concurrent immunotherapy and chemoradiation, intensification of consolidative immunotherapy, dual immunotherapy consolidation, and a reflection on those subpopulations that may not benefit from consolidative immunotherapy. Second, there will be discussion of novel strategies in the setting of resectable stage III disease, most notably neoadjuvant therapy using combined chemoimmunotherapy and immunotherapy alone before surgical resection. Third, it will delve into recent data evaluating adjuvant immunotherapy for resectable stage III NSCLC, including adjuvant targeted therapy (for those harboring driver mutations) and postoperative radiotherapy. Finally, a look to future trials/initiatives will be interspersed throughout the review, to reveal the ongoing efforts being made to continue to improve outcomes in this group of patients., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Fluoro-2-deoxyglucose positron-emission tomography (FDG-PET/CT) is now considered a standard investigation for the staging of new cases of stage III NSCLC. However, there is not published level 3 evidence demonstrating the impact of FDG-PET/CT on appropriate therapy in this setting. Using retrospective population-based data, we sought to examine the role and timing that FDG-PET/CT scans play in influencing treatment choice, as well as survival in patients diagnosed with stage III NSCLC., Materials and Methods: A retrospective cohort of patients diagnosed with stage III NSCLC from 2009-2017 in Ontario were identified from the IC/ES (formerly Institute of Clinical Evaluative Sciences) database. FDG-PET/CT utilization over time, trends in mediastinal biopsy technique and usage, the impact of FDG-PET/CT on overall survival (OS), and its influence on use of concurrent chemoradiotherapy (CRT) were explored. The impact of timing of pre-treatment FDG-PET/CT on OS was also analyzed (≤28 days prior to treatment, 29-56 days prior, and >56 days prior)., Results: Between 2007 and 2017, a total of 13 796 people were diagnosed with stage III NSCLC in Ontario. FDG-PET/CT utilization increased over time with 0% of cases in 2007 and 74% in 2017 with pre-treatment FDG-PET/CT scans. The number of patients who received a mediastinal biopsy similarly increased in this timeframe increasing from 41% to 53%. More patients with pre-treatment FDG-PET/CT scans received curative-intent therapy than those who did not: 23% vs 13% for CRT (p<0.001), and 23% vs 10% for surgery (p<0.001). Median OS was longer in those with FDG-PET/CT scans prior to treatment (17 vs 11 months), as was 5-year survival (22% vs 14%, p<0.001), and this held true on both univariate and multivariate analyses. Timing of FDG-PET/CT scan relative to treatment was not associated with differences in OS., Conclusion: Improvements in OS were seen in this cohort of stage III NSCLC patients who underwent a pre-treatment FDG-PET/CT scan. This can likely be attributed to stage-appropriate therapy due to more complete staging using FDG-PET/CT. This study stresses the importance of complete staging for suspected stage III NSCLC using FDG-PET/CT, and a need for continued advocacy for increased access to FDG-PET/CT scans., 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 © 2023 Beers, Pond, Wright, Tsakiridis, Okawara and Swaminath.)

Localized renal cell carcinoma is primarily managed surgically, but this disease commonly presents in highly comorbid patients who are poor operative candidates. Less invasive techniques, such as cryoablation and radiofrequency ablation, are effective, but require percutaneous or laparoscopic access, while generally being limited to cT1a tumors without proximity to the renal pelvis or ureter. Active surveillance is another management option for small renal masses, but many patients desire treatment or are poor candidates for active surveillance. For poor surgical candidates, a growing body of evidence supports stereotactic ablative radiotherapy (SABR) as a safe and effective non-invasive treatment modality. For example, a recent multi-institution individual patient data meta-analysis of 190 patients managed with SABR estimated a 5.5% five-year cumulative incidence of local failure with one patient experiencing grade 4 toxicity, and no other grade ≥3 toxic events. Here, we discuss the recent developments in SABR for the management of localized renal cell carcinoma, highlighting key concepts of appropriate patient selection, treatment design, treatment delivery, and response assessment.

Purpose: Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial., Methods and Materials: Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power., Results: A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P = .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P = .49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P = .03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups., Conclusions: Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context., Methods: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement., Results: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data., Conclusions: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Purpose: Immunotherapy (IO) has significantly improved outcomes in metastatic renal cell carcinoma (mRCC). Preclinical evidence suggests that responses to IO may be potentiated via immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in patients with mRCC receiving IO + SRT versus IO alone., Methods and Materials: Patients with mRCC receiving first-line IO ± SRT were identified from the NCDB. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS stratified by the receipt of SRT (IO + SRT vs IO alone). Secondary endpoints included OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test., Results: Of 644 eligible patients, 63 (9.8%) received IO + SRT, and 581 (90.2%) received IO alone. Median follow-up time was 17.7 months (range, 2-24 months). Sites treated with SRT included the brain (71.4%), lung/chest (7.9%), bones (7.9%), spine (6.3%), and other (6.3%). OS was 74.4% versus 65.0% at 1 year and 71.0% versus 59.4% at 2 years for the IO + SRT and IO alone groups, respectively, although this difference did not reach statistical significance (log-rank P  = .1077). In patients with BM, however, 1-year OS (73.0% vs 54.7%) and 2-year OS (70.8% vs 51.4%) was significantly higher in those receiving IO + SRT versus IO alone, respectively (pairwise P  = .0261). Timing of SRT (before or after IO) did not influence OS (log-rank P  = .3185)., Conclusions: Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Factors such as International mRCC Database Consortium risk stratification, oligometastatic tumor burden, SRT dose/fractionation, and utilization of doublet therapy should be considered in future analyses to better identify patients who may benefit from combined IO + SRT. Further prospective studies are warranted., (© 2023 The Authors.)

Background: Radiotherapy (RT) is used as monotherapy in poor performance patients with unresected locally advanced non-small cell lung cancer (LA-NSCLC), but their outcomes are not well-described. As novel therapies are increasingly considered in this space, it is important to understand contemporary outcomes of RT alone. Here, in this retrospective cohort study we analyzed LA-NSCLC outcomes of RT alone in Ontario, Canada, and contrasted them against those of standard of care (SoC) treatment of concurrent chemo-radiotherapy (cCRT)., Methods: Ontario provincial databases were searched through the Institute of Clinical Evaluative Sciences (IC/ES) for stage III NSCLC patients diagnosed between 2007 and 2017. Surgical patients were excluded, and all patients that received RT without or with chemotherapy were selected. Patients were divided in groups of RT dose received (<40 Gy, 40-55.9 Gy, and ≥56 Gy) and whether they underwent diagnostic 18 F-deoxy-glucose (FDG)-positron emission tomography (PET)., Results: Five thousand five hundred and seventy-seven stage III patients that received chest RT without surgery between January 2007 and March 2017 were included in this analysis. Within this group, 39.8% (2,225) received RT alone, 47.4% (2,645) cCRT and 12.6% (707) received sequential chemo-radiotherapy (sCRT). Median OS with RT alone in three dose groups <40/40-55.9/≥56 Gy was 7.2, 8.5 and 13.3 months compared to 16.5, 15.8 and 22 months for cCRT patients. Higher RT dose and PET utilization were independently associated with improved survival in multivariate analysis., Conclusions: Radiation monotherapy remains a widely used treatment modality in LA-NSCLC. RT dose and utilization of FDG-PET imaging are associated with improved survival in this group. These findings help improve clinical decision making and serve as basis for future trials., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-925/coif). Greg Pond declares receiving consulting fees from profound Medical and Merck. He also received honoraria from Astra-Zeneca for educational events; received honorarium from Takeda for DSMB (Data Safety Monitoring Board or Advisory Board) membership. He has a close family member who is an employee of Roche Canada, and who owns stock in Roche Ltd. The other authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for primary renal cell carcinoma, for which long-term data are awaited. The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma., Methods: This study was an individual patient data meta-analysis, for which patients undergoing SABR for primary renal cell carcinoma across 12 institutions in five countries (Australia, Canada, Germany, Japan, and the USA) were eligible. Eligible patients had at least 2 years of follow-up, were aged 18 years or older, had any performance status, and had no previous local therapy. Patients with metastatic renal cell carcinoma or upper-tract urothelial carcinoma were excluded. SABR was delivered as a single or multiple fractions of greater than 5 Gy. The primary endpoint was investigator-assessed local failure per the Response Evaluation Criteria in Solid Tumours version 1.1, and was evaluated using cumulative incidence functions., Findings: 190 patients received SABR between March 23, 2007, and Sept 20, 2018. Single-fraction SABR was delivered in 81 (43%) patients and multifraction SABR was delivered in 109 (57%) patients. Median follow-up was 5·0 years (IQR 3·4-6·8). 139 (73%) patients were men, and 51 (27%) were women. Median age was 73·6 years (IQR 66·2-82·0). Median tumour diameter was 4·0 cm (IQR 2·8-4·9). 96 (75%) of 128 patients with available operability details were deemed inoperable by the referring urologist. 56 (29%) of 190 patients had a solitary kidney. Median baseline estimated glomerular filtration rate (eGFR) was 60·0 mL/min per 1·73 m 2 (IQR 42·0-76·0) and decreased by 14·2 mL/min per 1·73 m 2 (IQR 5·4-22·5) by 5 years post-SABR. Seven (4%) patients required dialysis post-SABR. The cumulative incidence of local failure at 5 years was 5·5% (95% CI 2·8-9·5) overall, with single-fraction SABR yielding fewer local failures than multifraction (Gray's p=0·020). There were no grade 3 toxic effects or treatment-related deaths. One (1%) patient developed an acute grade 4 duodenal ulcer and late grade 4 gastritis., Interpretation: SABR is effective and safe in the long term for patients with primary renal cell carcinoma. Single-fraction SABR might yield less local failure than multifraction, but further evidence from randomised trials is needed to elucidate optimal treatment schedules. These mature data lend further support for renal SABR as a treatment option for patients unwilling or unfit to undergo surgery., Funding: None., Competing Interests: Declaration of interests SS reports honoraria from AstraZeneca and Varian Medical Systems; and research funding from Varian Medical Systems, Bayer Pharmaceuticals, and Merck Sharp & Dohme, outside of the submitted work. AM reports royalties and licenses from Elsevier Clinical Pathway that is directed to his institution; and honoraria and travel support from Accuray, outside of the submitted work. RH reports research funding from the American Cancer Society. AVL reports speaker's bureau and advisory activities with AstraZeneca. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: Long-term randomized data assessing the effect of ablative therapies in patients with oligometastases are lacking. The Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases (SABR-COMET) randomized phase 2 trial was originally designed with 5 years of follow-up, but the trial was amended in 2016 to extend follow-up to 10 years. Herein we report oncologic outcomes beyond 5 years., Methods and Materials: Patients were eligible if they had a controlled primary tumor and 1 to 5 metastases, with all metastases amenable to SABR. Patients were randomized in a 1:2 ratio between palliative standard-of-care treatment (control arm) versus SABR to all metastases plus standard of care (SABR arm). The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), toxicity, quality of life (using the Functional Assessment of Cancer Therapy: General [FACT-G]), and time to new metastases., Results: Ninety-nine patients were randomized between 2012 and 2016 (n = 33 in arm 1 vs n = 66 in arm 2). Primary tumor sites included lung (n = 18), breast (n = 18), colon (n = 18), prostate (n = 16), and other (n = 29). Eight-year OS was 27.2% in the SABR arm versus 13.6% in the control arm (hazard ratio, 0.50; 95% confidence interval, 0.30-0.84; P = .008). Eight-year PFS estimates were 21.3% versus 0.0%, respectively (hazard ratio, 0.45; 95% confidence interval, 0.28-0.72; P < .001). Rates of grade ≥ 2 acute or late toxic effects were 30.3% versus 9.1% (P = .019), with no new grade 3 to 5 toxic effects. FACT-G quality of life scores declined over time in both arms, but there were no differences in quality of life scores between arms. The use of systemic therapy overall was similar between arms, but patients in the SABR arm were less likely to require cytotoxic chemotherapy (33.3% vs 54.6%, respectively, P = .043)., Conclusions: SABR achieved durable improvements in OS and PFS, with no new major toxicity signals with extended follow-up. A minority of patients randomized to the SABR arm (21.3%) achieved > 5 years of survival without recurrence., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer., Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines., Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target., Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Objectives: To conduct a cost-effectiveness analysis of stereotactic body radiotherapy (SBRT) versus radiofrequency ablation (RFA) in the non-surgical management of early stage renal cell carcinoma (RCC) according to Consolidated Health Economic Evaluation Reporting Standards (CHEERS) criteria in the Canadian healthcare system., Methods: A Markov state transition model was constructed for initial local treatment with RFA or SBRT for early stage, kidney confined, medically inoperable RCC in a hypothetical cohort. Incremental cost effectiveness ratios (ICER) were then calculated to compare the two treatments. The analysis was conducted over 5-year time horizon from the perspective of a publicly funded health system in Canada. Secondary analyses were conducted to assess the effect of small versus large size (< 4 cm vs. > 4 cm) RCC on ICERs. Multiple one-way deterministic sensitivity analysis were conducted. Discounting of 1.5% per year was applied., Results: Over 5 years, SBRT economically dominated RFA with a gain of 4.103 quality-adjusted life years (QALYs) and a cost of $16,097, compared with 3.607 QALYs at a cost of $18,324 for RFA. The ICER was $4490 CAD less per QALY for SBRT in the base case analysis (BCE). In patients with small tumors (T1a), SBRT compared with RFA was more effective and marginally more costly, resulting in an ICER of $2207 CAD per QALY gained, while for larger tumors (T1b), SBRT was less costly and more effective than RFA, resulting in an ICER of -$22904. Sensitivity analysis demonstrated significant variability in the cost-effectiveness of SBRT versus RFA when parameters were varied, with rates of distant metastasis following RFA or SBRT having the greatest implications on ICERs., Conclusion: Overall, SBRT used as a primary treatment for RCC shows promising effectiveness at an overall reduction in cost compared with RFA in the Canadian healthcare system. The use of SBRT appears to be cost-effective for larger tumors as well as smaller tumors. The validity of these conclusions are highly sensitive to the accuracy of local and distant progression rates reported in previous studies, and may be adjusted as the available data on SBRT and RFA continues to evolve and mature., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: There is increasing interest in using stereotactic body radiation therapy (SBRT) in areas of oligoprogressive metastatic disease (OPD). Our main objective was to investigate the impact of SBRT on overall survival (OS) and the incidence of systemic therapy treatment switches in this population., Methods: A retrospective institutional review of patients treated with SBRT for OPD was performed. Patients were included if they received SBRT for 1-3 discrete progressing metastases, using a dose of at least 5 Gy per fraction. The study aimed to calculate progression-free survival (PFS), overall survival (OS), local control (LC), and incidence of treatment switch (TS). PFS and OS were calculated using the Kaplan-Meier methodology, while LC and TS were determined using cumulative incidence., Results: Eighty-one patients with a total of 118 lesions were treated with SBRT from July 2014 to November 2020. The Median SBRT dose was 40 (18-60) Gy in 5 (2-8) fractions. Patients had primarily kidney, lung, or breast cancer. Most patients were treated with a tyrosine kinase inhibitor (TKI) (30.9%) or chemotherapy (29.6%) before OPD. The median follow-up post-SBRT was 14 months. Median OS and PFS were 25.1 (95% CI 11.2-39.1) months and 7.8 (95% CI 4.6-10.9) months, respectively. The cumulative incidence of local progression of treated lesions was 5% at 1 year and 7.3% at 2 years. Sixty patients progressed after SBRT and 17 underwent additional SBRT. Thirty-eight patients (47%) changed systemic therapy following SBRT; the cumulative incidence of TS was 28.5% at 6 months, 37.4% at 1 year, and 43.9% at 2 years., Conclusions: SBRT effectively controls locally progressing lesions but distant progression still occurs frequently. A sizeable number of patients can be salvaged by further SBRT or have minimally progressing diseases that may not warrant an immediate initiation/switch in systemic therapy. Further prospective studies are needed to validate this benefit.

Introduction: The comparative effectiveness of radiofrequency ablation (RFA), radiation therapy (RT), transarterial chemoembolization (TACE) and transarterial radioembolization with Yttrium-90 (Y90) relative to one another for the treatment of hepatocellular carcinoma (HCC) is unclear. The aim of this systematic review and network meta-analysis is to compare RFA to RT to TACE to Y90 in the treatment of HCC., Methods: Pubmed, Embase and Cochrane CENTRAL were searched up until April 19, 2021. Observational analyses with propensity score matched (PSM) cohort analyses and randomized controlled trials (RCT) reporting on two or more treatments relative to one another with respect to overall survival (OS) and/or progression free survival (PFS) were included. Survival data were extracted from Kaplan-Meier survival curves, and meta-analyzed using a multivariate network meta-analysis., Results: After exclusions, 24 RCTs or PSM observational studies reporting on 5549 patients were included. While 1-year OS was greater for Y90 than TACE (RR 0.85, 95% CI: 0.72-0.99), all other 1-year OS comparisons across the 4 modalities yielded similar OS, and there were no differences across any modalities in 2-year and 3-year OS. TACE had a modest PFS advantage relative to RFA (RR 0.81, 95% CI: 0.68-0.95) and RT (RR 0.65, 95% CI: 0.51-0.83) at 2 years., Conclusion: All modalities assessed resulted in similar OS, which explains the current heterogenous practice patterns. This conclusion may assist in decision making based on administrative and patient costs, and implementation of these modalities. Other factors such as toxicity rate specific to individual patients could not be assessed using network meta-analysis and may also play a role in selection of modality. Further studies, ideally using PSM cohort analyses or RCT study design, reporting on OS, PFS, local control, complete response and toxicity are needed prior to drawing definitive conclusions.

Background: For the local management of pulmonary malignancies, surgical resection and stereotactic body radiation therapy (SBRT) are mutually exclusive treatments. This study aims to assess the effectiveness of SBRT on reducing tumor viability at a histologic level in the context of pulmonary metastases., Methods: This protocol describes an open-label unblinded single-arm prospective Phase 2 trial to determine the effects of dual treatment of pulmonary metastasis amenable to curative resection using neoadjuvant SBRT followed by surgical resection, the Post SBRT Pulmonary Metastasectomy (PSPM) trial. Sample size require 39 patients, with an anticipated study duration of 30-36 months. Following completion of SBRT, eligible patients will be assessed at the 4-6-week mark by the treating radiation oncologist and thoracic surgeon with a post-treatment computed tomography (CT) of the chest. Patients with no disease progression will undergo scheduled surgical resection of all metastatic tumors at 8-12 weeks post SBRT. Patients will then be evaluated postoperatively at 30 days, and every 6 months for a total of 36 months with surveillance CT scans. Patients will also undergo sequential serologic evaluation of circulating tumor DNA (ctDNA) levels throughout their respective treatment pathway. The primary outcome of this study is the rate of complete pathologic response (pCR) following SBRT, assess using the International Association for the Study of Lung Cancer (IASLC) multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. Secondary outcomes include overall survival (OS), disease free survival (DFS), local recurrence rates, cancer histology effects on pCR and treatment related complications, and treatment effect on ctDNA levels. Primary and secondary outcomes will be analyzed using Fisher's Exact test and Student's t -test based on data type. Cox-proportional hazard ratios will be used to evaluate OS and DFS, using the log rank test., Discussion: In evaluating the effect of SBRT on pulmonary metastasis at a histologic level, this trial may increase the use of this modality in selected patients who would otherwise only undergo surgery for disease that has already metastasized. Also, the trial provides secondary benefits of evaluating the abscopal effects of radiation on pulmonary metastatic disease, and serves as a platform for more comprehensive large-scale research in this field., Trial Registration: ClinicalTrials.gov identifier: NCT04160143 (HiREB: 7925)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-232/coif). The authors have no conflicts of interest to declare., (2022 Translational Cancer Research. All rights reserved.)

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone., Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories., Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P  = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P  = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P  = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P  = .63)., Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need., (© 2022 The Author(s).)

Background: Research from the International Cancer Benchmarking Partnership (ICBP) demonstrates that international variation in lung cancer survival persists, particularly within early stage disease. There is a lack of international consensus on the critical contributing components to variation in lung cancer outcomes and the steps needed to optimise lung cancer services. These are needed to improve the quality of options for and equitable access to treatment, and ultimately improve survival., Methods: Semi-structured interviews were conducted with 9 key informants from ICBP countries. An international clinical network representing 6 ICBP countries (Australia, Canada, Denmark, England, Ireland, New Zealand, Northern Ireland, Scotland & Wales) was established to share local clinical insights and examples of best practice. Using a modified Delphi consensus model, network members suggested and rated recommendations to optimise the management of lung cancer. Calls to Action were developed via Delphi voting as the most crucial recommendations, with Good Practice Points included to support their implementation., Results: Five Calls to Action and thirteen Good Practice Points applicable to high income, comparable countries were developed and achieved 100% consensus. Calls to Action include (1) Implement cost-effective, clinically efficacious, and equitable lung cancer screening initiatives; (2) Ensure diagnosis of lung cancer within 30 days of referral; (3) Develop Thoracic Centres of Excellence; (4) Undertake an international audit of lung cancer care; and (5) Recognise improvements in lung cancer care and outcomes as a priority in cancer policy., Conclusion: The recommendations presented are the voice of an expert international lung cancer clinical network, and signpost key considerations for policymakers in countries within the ICBP but also in other comparable high-income countries. These define a roadmap to help align and focus efforts in improving outcomes and management of lung cancer patients globally.

Background: Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy., Objective: To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy., Design, Setting, and Participants: A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled., Intervention: Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward., Outcome Measurements and Statistical Analysis: Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest., Results and Limitations: The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71-98%). The median PFS after SRT was 9.3 mo (95% CI 7.5-15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32-68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6-17.4 mo). One-year OS was 92% (95% CI 82-100%). There were no grade 3-5 SRT-related toxicities., Conclusions: LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr., Patient Summary: The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Stereotactic Body Radiotherapy (SBRT) has shown effectiveness in treating bone metastases to alleviate pain. The benefit of SBRT may be further harnessed especially when radiating disease from primary malignancies with low alpha-beta ratios in order to maximize the magnitude and durability of pain relief. However, such an approach has not been studied in a prospective trial. We look to assess single-fraction SBRT for painful non-spinal bone metastases from radioresistant primaries., Methods: Forty patients will be enrolled on an open label, phase II single arm trial to receive a single fraction of SBRT (15-20 Gray) to all sites of bone metastases requiring treatment for pain relief. Eligible patients will include those with primary malignancies consisting of prostate cancer, breast cancer, renal cell carcinoma, or melanoma. The primary endpoint is pain response at 3 months post-treatment using the Brief Pain Inventory. Secondary endpoints include pain response at 1 month and 6 months post-treatment, toxicity, patient-reported quality of life, re-irradiation or salvage surgery, and local control., Discussion: This study will evaluate the efficacy of single-fraction SBRT on painful bone metastases from primary cancers with low alpha-beta ratios. These data will be valuable to promote future randomized trials and support clinical implementation. Trial registration Clinicaltrials.gov, NCT04177056. Date of registration: November 26, 2019. https://clinicaltrials.gov/ct2/show/NCT04177056., (© 2021. The Author(s).)

Importance: Unresected locally advanced non-small cell lung cancer (LA-NSCLC) shows poor survival outcomes even after aggressive concurrent chemoradiotherapy. Whether metformin, a diabetes agent that inhibits the mitochondria oxidative phosphorylation chain, could improve radiotherapy and chemotherapy response in LA-NSCLC remains to be studied., Objective: To examine whether metformin, given concurrently with chemoradiotherapy and as consolidation treatment, could improve outcomes in patients with LA-NSCLC., Design, Setting, and Participants: The Ontario Clinical Oncology Group Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy (OCOG-ALMERA) study was a multicenter phase 2 randomized clinical trial. Patients were stratified for stage IIIA vs IIIB LA-NSCLC and use of consolidation chemotherapy. The trial was designed to enroll 96 patients with unresected LA-NSCLC who did not have diabetes. The trial was conducted from September 24, 2014, to March 8, 2019., Interventions: Patients were randomized to platinum-based chemotherapy, concurrent with chest radiotherapy (60-63 Gy), with or without consolidation chemotherapy or the same treatment plus metformin, 2000 mg/d, during chemoradiotherapy and afterward for up to 12 months., Main Outcomes and Measures: The primary outcome was the proportion of patients who experienced a failure event (ie, locoregional disease progression, distant metastases, death, and discontinuation of trial treatment or planned evaluations for any reason within 12 months). Proportions were compared using a 2-sided Fisher exact test. Conventional progression-free and overall survival were estimated using the Kaplan-Meier method. Adverse events were graded with Common Terminology Criteria for Adverse Events, version 4.03. All randomized patients were included in an intention-to-treat analysis., Results: The trial was stopped early due to slow accrual. Between 2014 and 2019, 54 patients were randomized (26 in experimental arm and 28 in control arm). Participants included 30 women (55.6%); mean (SD) age was 65.6 (7.6) years. Treatment failure was detected in 18 patients (69.2%) receiving metformin within 1 year vs 12 (42.9%) control patients (P = .05). The 1-year progression-free survival rate was 34.8% (95% CI, 16.6%-53.7%) in the metformin arm and 63.0% (95% CI, 42.1%-78.1%) in the control arm (hazard ratio, 2.42; 95% CI, 1.14-5.10) The overall survival rates were 47.4% (95% CI, 26.3%-65.9%) in the metformin arm and 85.2% (95% CI, 65.2%-94.2%) in the control arm (hazard ratio, 3.80; 95% CI, 1.49-9.73). More patients in the experimental arm vs control arm (53.8% vs 25.0%) reported at least 1 grade 3 or higher adverse event., Conclusions and Relevance: In this randomized clinical trial, the addition of metformin to chemoradiotherapy was associated with worse treatment efficacy and increased toxic effects compared with combined modality therapy alone. Metformin is not recommended in patients with LA-NSCLC who are candidates for chemoradiotherapy., Trial Registration: ClinicalTrials.gov Identifier: NCT02115464.

Introduction: Preclinical evidence demonstrates the immunogenic potential of stereotactic body radiotherapy (SBRT). There is growing interest in investigating this interplay with the immune system in metastatic renal cell carcinoma (mRCC). Cytoreduction with SBRT and combination therapy with SBRT and checkpoint inhibitor immuno-oncology agents (IO) are two potential therapeutic strategies in mRCC. In this review, we summarize the current clinical evidence for the use of cytoreductive SBRT to primary kidney and combination SBRT with IO., Methods: A literature review for articles and abstracts published between January 2000 and March 2020 was conducted through the PubMed, the American Society of Clinical Oncology (ASCO), and the American Society of Radiation Oncology (ASTRO) databases. Evaluation of studies followed the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) criteria., Results: A total of three articles for cytoreductive SBRT and one article and three abstracts for combination SBRT and IO in mRCC met inclusion criteria for this review. Evidence for SBRT to primary kidney is limited by small series and pilot studies. Outcomes vary widely due to small patient numbers and study heterogeneity. Local control ranges from 85-100% and one- and two-year overall survival ranges from 38-71% and 19-53%, respectively. Combination SBRT and IO are tolerable for patients with early data, suggesting grade 3-4 adverse event rates of 0-24%. Long-term survival data is not yet available., Conclusions: Cytoreductive SBRT and combination SBRT with IO therapy represent promising treatment strategies in mRCC. The evidence for clinical benefit is currently limited and requires further study with well-designed, randomized controlled trials.

Introduction: Treatment algorithms for small cell lung cancer (SCLC) are determined largely by the Veterans Affairs Lung Cancer Staging Group (VALCSG) staging (limited (LS) versus extensive (ES) stage). Relapse occurs frequently; however, patterns of relapse, in particular the competing risk of thoracic and central nervous system relapse, are not well described. This study describes patterns of relapse in SCLC patients treated at a large tertiary institution in Ontario, Canada., Materials and Methods: A retrospective cohort of SCLC patients treated at the Juravinski Cancer Centre was reviewed. Data were abstracted from the medical record on demographic, disease, treatment and outcome variables. The primary outcome was a description of the patterns of relapse stratified by disease stage. Multivariate analysis was performed to identify prognostic variables for thoracic and CNS relapse., Results: Two hundred and twenty nine patients were treated during the study period (LS-83, ES-146). Relapse occurred in the majority of patients (isolated thoracic-28%, isolated CNS-9%, extrathoracic-9%, thoracic/extrathoracic-14%, systemic and CNS-13%). The median OS was consistent with published data (LS-21.8 months, ES-8.9 months). ES disease and elevated LDH were prognostic for increased thoracic relapse, whereas poor PS and older age were prognostic for lower central nervous system (CNS) relapse., Discussion: Thoracic relapse and CNS relapse represent competing risks for patients with SCLC. Decisions about incorporating thoracic or CNS radiation are complex. More research is needed to incorporate performance status and LDH into treatment algorithms.

Adaptive MR-guided radiotherapy (MRgRT) is a new treatment paradigm and its role as a non-invasive treatment option for renal cell carcinoma is evolving. The early clinical experience to date shows that real-time plan adaptation based on the daily MRI anatomy can lead to improved target coverage and normal tissue sparing. Continued technological innovations will further mitigate the challenges of organ motion and enable more advanced treatment adaptation, and potentially lead to enhanced oncologic outcomes and preservation of renal function. Future applications look promising to make a positive clinical impact and further the personalization of radiotherapy in the management of renal cell carcinoma., Competing Interests: AB reports personal fees from ViewRay Inc., outside the submitted work. AS has received honoraria from Bristol Myers Squibb, AstraZeneca, and Eisai, and trial funding in kind from Bristol Myers Squibb. BK, CT, LK and WC are members of the Elekta MR-Linac Consortium, and Elekta financially supports projects in the member institutes. BK and WC have received travel support from Elekta., (Copyright © 2021 Keller, Bruynzeel, Tang, Swaminath, Kerkmeijer and Chu.)

Purpose: The phase 2 randomized study SABR-COMET demonstrated that in patients with controlled primary tumors and 1 to 5 oligometastatic lesions, SABR was associated with improved progression-free survival (PFS) compared with standard of care (SoC), but with higher costs and treatment-related toxicities. The aim of this study was to assess the cost-effectiveness of SABR versus SoC in this setting., Methods and Materials: A Markov model was constructed to perform a cost-utility analysis from the Canadian health care system perspective. Utility values and transition probabilities were derived from individual-level data from the SABR-COMET trial. One-way, 2-way, and probabilistic sensitivity analyses were performed. Costs were expressed in 2018 CAD. A separate analysis based on US payer's perspective was performed. An incremental cost-effectiveness ratio (ICER) at a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) was used., Results: In the base case scenario, SABR was cost-effective at an ICER of $37,157 per QALY gained. This finding was most sensitive to the number of metastatic lesions treated with SABR (ICER: $28,066 per QALY for 2, increasing to $64,429 per QALY for 5), difference in chemotherapy use (ICER: $27,173-$53,738 per QALY), and PFS hazard ratio (HR) between strategies (ICER: $31,548-$53,273 per QALY). Probabilistic sensitivity analysis revealed that SABR was cost-effective in 97% of all iterations. Two-way sensitivity analysis demonstrated a nonlinear relationship between the number of lesions and the PFS HR. To maintain cost-effectiveness for each additional metastasis, the HR must decrease by approximately 0.047. The US cost analysis yielded similar results, with an ICER of $54,564 (2018 USD per QALY) for SABR., Conclusions: SABR is cost-effective for patients with 1 to 5 oligometastatic lesions compared with SoC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Metastatic lesions of the heart are rare but have the potential to cause significant morbidity. We describe the case of a patient with renal cell carcinoma who presented with shortness of breath and palpitations and was found to have a metastatic myocardial lesion causing arrythmia. He received stereotactic body radiation therapy (SBRT) to alleviate symptoms and provide local control. SBRT planning was executed using a four-dimensional computed tomography (4DCT) scan to account for respiratory and cardiac motion. Images from a planning magnetic resonance imaging (MRI) scan and a gated diagnostic MRI scan of the heart were fused with the 4DCT to assist with delineating the tumour. A dose of 30 Gy in five fractions was delivered without incident. The patient's cardiac MRI at two months post-treatment showed stability of his cardiac lesion. He subsequently died of distant disease progression, without any recurrence of his cardiac symptoms. SBRT may be considered for patients who present with a symptomatic metastatic cardiac lesion.

Purpose: Metastatic epidural spinal cord compression (MESCC) is a devastating complication of advanced malignancy, which can result in neurologic complications and significant deterioration in overall function and quality of life. Most patients are not candidates for optimal surgical decompression and as a result, receive urgent 3D conformal radiotherapy (3DCRT) to prevent or attempt to reverse neurologic progression. Multiple trials indicate that response and ambulatory rates after 3DCRT are inferior to surgery. The advent of stereotactic body radiation therapy (SBRT) has created a method with which a "radiosurgical decompression" boost may facilitate improve outcomes for MESCC patients., Methods: We are conducting a pilot study to investigate SBRT boost after urgent 3D CRT for patients with MESCC. The aim of the study is to establish feasibility of this two-phase treatment regimen, and secondarily to characterize post-treatment ambulation status, motor response, pain control, quality of life and survival., Discussion: We describe the study protocol and present a case report of one patient. A quality assurance review was conducted after the first seven patients, and resultant dose-constraints were revised to improve safety and feasibility of planning through more conservative organ at risk constraints. There have been no severe adverse events (grade 3-5) to date. We have illustrated clinical and dosimetric data of an example case, where a patient regained full strength and ambulatory capacity., Conclusions: Our study aims to determine if SBRT is a feasible option in addition to standard 3DCRT for MESCC patients, with the goal to consider future randomized trials if successful. Having a robust quality assurance process in this study ensures translatability going forward if future trials with multicenter and increased patient representation are to be considered., Trial Registration: clinicaltrials.gov; registration no. NCT03529708; https://clinicaltrials.gov/ct2/show/NCT03529708 ; First posted May 18, 2018.

Purpose: Patients with larger (T1b, >4 cm) renal cell carcinoma (RCC) not suitable for surgery have few treatment options because thermal ablation is less effective in this setting. We hypothesize that SABR represents an effective, safe, and nephron-sparing alternative for large RCC., Methods and Materials: Individual patient data from 9 institutions in Germany, Australia, USA, Canada, and Japan were pooled. Patients with T1a tumors, M1 disease, and/or upper tract urothelial carcinoma were excluded. Demographics, treatment, oncologic, and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes., Results: Ninety-five patients were included. Median follow-up was 2.7 years. Median age was 76 years, median tumor diameter was 4.9 cm, and 81.1% had Eastern Cooperative Oncology Group performance status of 0 to 1 (or Karnofsky performance status ≥70%). In patients for whom operability details were reported, 77.6% were defined as inoperable as determined by the referring urologist. Mean baseline estimated glomerular filtration rate (eGFR) was 57.2 mL/min (mild-to-moderate dysfunction), with 30% of the cohort having moderate-to-severe dysfunction (eGFR <45mL/min). After SABR, eGFR decreased by 7.9 mL/min. Three patients (3.2%) required dialysis. Thirty-eight patients (40%) had a grade 1 to 2 toxicity. No grade 3 to 5 toxicities were reported. Cancer-specific survival, overall survival, and progression-free survival were 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, 64.9% at 4 years, respectively. Local, distant, and any failure at 4 years were 2.9%, 11.1%, and 12.1% (cumulative incidence function with death as competing event). On multivariable analysis, increasing tumor size was associated with inferior cancer-specific survival (hazard ratio per 1 cm increase: 1.30; P < .001)., Conclusions: SABR for larger RCC in this older, largely medically inoperable cohort, demonstrated efficacy and tolerability and had modest impact on renal function. SABR appears to be a viable treatment option in this patient population., (Copyright © 2020 Elsevier Inc. All rights reserved.)