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Introduction For patients with locally advanced cutaneous squamous cell carcinoma (LA-cSCC), radiotherapy alone (RT) is often the only treatment option with modest tumor response. We report the outcomes of using combination of programmed cell death protein-1 (PD-1) inhibitor and RT in the treatment of inoperable LA-cSCC. The study presents the efficacy and safety data for the patients with LA-cSCC treated with this combination. Methods During the period 2018-2020, a total of 7 patients with biopsy proven inoperable LA-cSCC were treated with combination of PD-1 inhibitor cemiplimab and concurrent RT (Cem-RT). The patients were followed up for safety and efficacy of the Cem-RT regimen and the primary endpoints were objective tumor response and toxicity. Results The median age of patients was 68 years (range, 64-94). All patients had ECOG performance score 0-1. Six patients initially received cemiplimab and concurrent RT was added to PD-1 inhibitor when there was an inadequate therapeutic response. One patient received concurrent Cem-RT. RT with PD-1 antibody was well tolerated. Six patients developed grade ≤2 dermatitis and 1 patient (patient no. 3) developed acute grade 3 skin reaction. During the post-RT follow up, 3 patients discontinued cemiplimab due to significant toxicities. At the time of reporting , 5 patients remain in complete remission. One patient developed lung metastasis and is currently receiving best supportive care. Conclusions The Cem-RT combination was safe and well tolerated with significant tumor response suggesting Cem-RT may be a viable therapeutic option for LA-cSCC. Our hypothesis generating data support the rationale for future prospective studies.

Cardiac tachyarrhythmias are a major cause of morbidity and mortality. Treatments for these tachyarrhythmias include antiarrhythmic drugs, catheter ablation, surgical ablation, cardiac implantable electronic devices, and cardiac transplantation. Each of these treatment approaches is effective in some patients but there is considerable room for improvement, particularly with respect to the most common of the tachydysrhythmias, atrial fibrillation, and the most dangerous of the tachydysrhythmias, ventricular tachycardia (VT) or ventricular fibrillation. Noninvasive stereotactic ablative radiation therapy is emerging as an effective treatment for refractory tachyarrhythmias. Animal models have shown successful ablation of arrhythmogenic myocardial substrates with minimal short-term complications. Studies of stereotactic radioablation involving patients with refractory VT have shown a reduction in VT recurrence and promising early safety data. In this review, we provide the background for the application of stereotactic arrhythmia radioablation therapy along with promising results from early applications of the technology. Résumé: Les tachyarythmies cardiaques sont une cause importante de morbidité et de mortalité. Les traitements employés comprennent des antiarythmiques, l’ablation par cathéter, l’ablation par chirurgie, l’implantation de dispositifs cardiaques électroniques et la transplantation cardiaque. Toutes ces démarches thérapeutiques sont efficaces dans certains cas, mais les traitements peuvent encore être largement améliorés, en particulier en ce qui concerne la fibrillation auriculaire, qui est la tachyarythmie la plus fréquente, et la tachycardie ventriculaire (TV, aussi appelée fibrillation ventriculaire), qui est la tachyarythmie la plus dangereuse. La radiochirurgie stéréotaxique non invasive se démarque de plus en plus comme traitement efficace des tachyarythmies réfractaires. Des substrats myocardiques arythmogènes ont pu être réséqués avec succès sur des modèles animaux, l’intervention n’ayant entraîné que des complications minimales de courte durée. Dans le cadre d’études menées auprès de patients présentant une TV réfractaire, la radiochirurgie stéréotaxique a permis de réduire le risque de récurrence de la TV, et les premières données sur l’innocuité du traitement sont encourageantes. Dans notre revue, nous précisons le cadre d’application de la radiochirurgie stéréotaxique visant à réséquer le tissu responsable de l’arythmie, et nous présentons les résultats prometteurs des premières applications de la technologie à cette fin.

Background and purpose Prospective data evaluating the role of adjuvant radiotherapy (RT) for Merkel Cell Carcinoma(MCC) is lacking. To better understand the efficacy of adjuvant RT, a population-based patterns of failure study was conducted. Methods We identified MCC patients treated from 1988 to 2018.Primary outcome measures were recurrence-free survival (RFS), overall survival (OS) and MCC-specific survival (MCC-SS). Charlson Co-morbidity Index (CCI) was also calculated. Results 217 patients with mean age 79 (range: 33-96) were analyzed. The median follow-up was 40 months. Treatments were: surgery(S) alone (n=101, 45%) or S+RT(n=116, 55%).Local recurrence (LR) was low in stage I (n=6, 6.5%) with clear margin of ≥1 cm, negative sentinel lymph node biopsy (SLNB) without high-risk factors, irrespective of adjuvant RT. Tumor size ≥2 cm (HR:2.95; p=0.024) and immunosuppression(HR:3.98; p=0.001) were associated with high risk of nodal failure. Adjuvant RT was associated with significant reduction in regional failure (HR:0.36; p=0.002). Distant metastases (DM) were infrequent in stage I (4/90) and stage II (4/34), compared to stage III (32/93). Adjuvant RT improvedRFS but did not influence MCC-SS and OS. CCI was a significant predictor of OS. Conclusions Adjuvant RT improvedRFS, withoutimpact on MCC-SS and OS. Co-morbidity rather than RT influenced OS. Adjuvant RT may be avoided instage I patients with negative SLNB and no associated high-risk factors. Prophylactic RNI could be considered in stage II with high risk features, inspite of negative SLNB. Stage III patients benefited from adjuvant RNI, but no impact on prevention of DM.

PURPOSE To determine safety and efficacy of postoperative spine stereotactic body radiation therapy (SBRT) in the published literature, and to present practice recommendations on behalf of the International Stereotactic Radiosurgery Society. METHODS AND MATERIALS A systematic review of the literature was performed, specific to postoperative spine SBRT, using PubMed and Embase databases. A meta-analysis for 1-year local control (LC), overall survival (OS), and vertebral compression fracture probability was conducted. RESULTS The literature search revealed 251 potentially relevant articles after duplicates were removed. Of these 56 were reviewed in-depth for eligibility and 12 met all the inclusion criteria for analysis. 7 studies were retrospective, 2 prospective observational and 3 were prospective phase 1 and 2 clinical trials. Outcomes for a total of 461 patients and 499 spinal segments were reported. Ten studies used a magnetic resonance imaging (MRI) scan fused to computed tomography (CT) simulation for treatment planning, and 2 investigations reported on all patients receiving a CT-myelogram at the time of planning. Meta-analysis for 1 year LC and OS was 88.9% and 57%, respectively. The crude reported vertebral compression fracture rate was 5.6%. One case of myelopathy was described in a patient with a previously irradiated spinal segment. One patient developed an esophageal fistula requiring surgical repair. CONCLUSIONS Postoperative spine SBRT delivers a high 1-year LC with acceptably low toxicity. Patients who may benefit from this include those with oligometastatic disease, radioresistant histology, paraspinal masses, or those with a history of prior irradiation to the affected spinal segment. The International Stereotactic Radiosurgery Society recommends a minimum interval of 8 to 14 days after invasive surgery before simulation for SBRT, with initiation of radiation therapy within 4 weeks of surgery. An MRI fused to the planning CT, or the use of a CT-myelogram, are necessary for target and organ-at-risk delineation. A planning organ-at-risk volume (PRV) of 1.5 to 2 mm for the spinal cord is advised.

Purpose To present interobserver variability in thecal sac (TS) delineation based on contours generated by 8 radiation oncologists experienced in spine stereotactic body radiation therapy and to propose contouring recommendations to standardize practice. Methods and Materials In the setting of a larger contouring study that reported target volume delineation guidelines specific to sacral metastases, 8 academically based radiation oncologists with dedicated spine stereotactic body radiation therapy programs independently contoured the TS as a surrogate for the cauda equina and intracanal spinal nerve roots. Uniform treatment planning simulation computed tomography datasets fused with T1, T2, and T1 post gadolinium magnetic resonance imaging for each case were distributed to each radiation oncologist. All contours were analyzed and agreement was calculated using both Dice similarity coefficient and simultaneous truth and performance level estimation with kappa statistics. Results A fair level of simultaneous truth and performance level estimation agreement was observed between practitioners, with a mean kappa agreement of 0.38 (range, 0.210.55) and the mean Dice similarity coefficient (± standard deviation, with range) was 0.43 (0.36 ± 0.1 to -0.53 ±0.1). Recommendations for a reference TS contour, accounting for the variations in practice observed in this study, include contouring the TS to encompass all the intrathecal spinal nerve roots, and caudal to the termination of the TS, the bony canal can be contoured as a surrogate for the extra thecal nerves roots that run within it. Conclusions This study shows that even among high-volume practitioners, there is a lack of uniformity when contouring the TS. Further modifications may be required once dosimetric data on nerve tolerance to ablative doses, and pattern of failure analyses of clinical data sets using these recommendations, become available. The contouring recommendations were designed as a guide to enable consistent and safe contouring across general practice.

Purpose Metastatic complications are responsible for 90% of cancer-associated mortality. Magnetic resonance imaging (MRI) can be used to observe the brain's microstructure and potentially correlate changes with metastasis occurrence. Diffusion weighted imaging (DWI) is an MRI technique that utilizes the kinetics of water molecules within the body. The aim of this study is to use DWI to characterize diffusion changes within brain metastases in cancer patients pre- and post-stereotactic radiosurgery (SRS). Methods We retrospectively analyzed 113 metastases from 13 patients who underwent SRS for brain metastasis recurrence. Longitudinal apparent diffusion coefficient (ADC) maps were registered to Gd-T1 images and CT, and clinical metastasis ROIs from all SRS treatments were retrospectively transferred onto these ADC maps for analysis. Metastases were characterized based on pre-SRS diffusion pattern, primary cancer site, and post-SRS outcome. ADC values were calculated pre- and post-SRS. Results ADC values were significantly elevated (980.2 × 10-6mm2s-1and 1040.3 × 10-6mm2s-1pre- and post-SRS, respectively) when compared to healthy brain tissue (826.8 × 10-6mm2s-1) for all metastases. Three identified pre-SRS patterns were significantly different before SRS and within 6 months post-SRS. No significant differences were observed between different primaries pre-SRS. Post-SRS, Lung metastases ADC decreased by 86.2 × 10-6mm2s-1, breast metastases increased by 116.7 × 10-6mm2s-1, and genitourinary metastases showed no significant ADC change. SRS outcomes showed ADC variability pre-treatment but no significant differences pre- and post-SRS, except at 6-9 months post-SRS where progressing metastases were elevated when compared to other response groups. Conclusion This study provided a unique opportunity to characterize diffusion changes in brain metastases before their manifestation on standard Gd-T1 images and post-SRS. Identified patterns may improve early detection of brain metastases as well as predict their response to treatment.

Background Vertebral compression fracture (VCF) is a challenging and not infrequent complication observed following spine stereotactic body radiation therapy (SBRT). Objective To summarize the data from the multiple studies that have been published, addressing the risk and predictive factors for VCF post-SBRT. Methods A systematic literature review was conducted. Studies were selected if they specifically addressed risk factors for post-SBRT VCF in their analyses. Results A total of 11 studies were identified, reporting both the risk of VCF post-SBRT and an analysis of risk factors based on univariate and multivariate analysis. A total of 2911 spinal segments were treated with a crude VCF rate of 13.9%. The most frequently identified risk factors on multivariate analysis were: lytic disease (hazard ratio [HR] range, 2.76-12.2), baseline VCF prior to SBRT (HR range, 1.69-9.25), higher dose per fraction SBRT (HR range, 5.03-6.82), spinal deformity (HR range, 2.99-11.1), older age (HR range, 2.15-5.67), and more than 40% to 50% of vertebral body involved by tumor (HR range, 3.9-4.46). In the 9 studies that specifically reported on the use of post-SBRT surgical procedures, 37% of VCF had undergone an intervention (range, 11%-60%). Conclusion VCF is an important adverse effect following SBRT. Risk factors have been identified to guide the selection of high-risk patients. Evidence-based algorithms with respect to patient selection and intervention are needed.

Background and purpose To interrogate inter-observer variability in gross tumour volume (GTV) and clinical target volume (CTV) delineation specific to the treatment of sacral metastases with spinal stereotactic body radiation therapy (SBRT) and develop CTV consensus contouring recommendations. Materials and methods Nine specialists with spinal SBRT expertise representing 9 international centres independently contoured the GTV and CTV for 10 clinical cases of metastatic disease within the sacrum. Agreement between physicians was calculated with an expectation minimisation algorithm using simultaneous truth and performance level estimation (STAPLE) and with kappa statistics. Optimised confidence level consensus contours were obtained using a voxel-wise maximum likelihood approach and the STAPLE contours for GTV and CTV were based on an 80% confidence level. Results Mean GTV STAPLE agreement sensitivity and specificity was 0.70 (range, 0.54–0.87) and 1.00, respectively, and 0.55 (range, 0.44–0.64) and 1.00 for the CTV, respectively. Mean GTV and CTV kappa agreement was 0.73 (range, 0.59–0.83) and 0.59 (range, 0.41–0.70), respectively. Optimised confidence level consensus contours were identified by STAPLE analysis. Consensus recommendations for the CTV include treating the entire segment containing the disease in addition to the immediate adjacent bony anatomic segment at risk of microscopic extension. Conclusion Consensus recommendations for CTV target delineation specific to sacral metastases treated with SBRT were established using expert contours. This is a critical first step to achieving standardisation of target delineation practice in the sacrum and will serve as a baseline for meaningful pattern of failure analyses going forward.

Purpose Limited data exist quantifying the risk of adverse radiation effect (ARE) specific to hypofractionated stereotactic radiosurgery (HSRS). We present our analyses of the risk of ARE after 5 daily fractions of HSRS to surgical cavities and intact metastases. Methods and Materials One hundred and eighty-seven consecutively treated patients with 118 surgical cavities and 132 intact metastases were retrospectively reviewed. All patients were treated with 5 daily fractions with a 2 mm planning target volume applied. Clinical and dosimetric variables were assessed to identify predictors of ARE. Results The median total prescribed dose was 30 Gy (range, 20-35 Gy) and median follow-up was 12 months. One hundred forty-four patients (77%) received treatment to a single target. Median planning target volumes for resection cavity and intact metastases were 24.9 cm3 and 7.7 cm3, respectively. ARE and symptomatic ARE were observed 21.2% and 10.8% of targets, respectively, and the median time to ARE was 8 months. Time to ARE was 12 months for 19% of targets. Multivariable analysis identified intact metastases versus cavities (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.33-10) as a significant predictor of symptomatic ARE. Specific to cavity HSRS, prior whole brain radiation therapy (OR 7.73; 95% CI, 1.67-35.69) and prior stereotactic radiosurgery (OR 8.66; 95% CI, 1.14-65.7) were significant predictors of symptomatic ARE. For intact metastases, the total brain minus gross tumor volume (GTV) receiving 30 Gy (BMC30) was a significant predictor of symptomatic ARE (OR, 1.21; 95% CI, 1.02-1.43), and a volume-based BMC30 threshold of 10.5 cm3 was significant with an OR of 7.21 (95% CI, 1.31-39.45). Conclusions The risk of ARE was greater for intact metastases compared with cavities after HSRS. For intact lesions, the BMC30 was predictive for symptomatic necrosis, and a threshold of 10.5 cm3 may guide treatment planning.

Bony metastases frequently involve the spine and can cause significant morbidity with pain and neurologic compromise. A shift toward hypofractionated radiotherapy delivered over 1 to 5 fractions has taken place to provide increased long-term local control and pain relief. Patients with radioresistant histologies and oligometastatic disease, and/or patients who have had previous radiotherapy to the region, should be considered for spine stereotactic body radiotherapy (SBRT). Evaluation at presentation should include an assessment of spine stability and the extent of epidural disease. Potentially unstable or frankly unstable metastases and high-grade epidural disease should have a spine surgical consult prior to SBRT. If surgery is needed, SBRT can be delivered in the postoperative setting. Spine SBRT is performed with the patient immobilized in a near-rigid body immobilization device, simulation with thin-slice CT and volumetric thin-slice axial T1 and T2 MR images for subsequent image fusion, and delivery with an image-guided linac delivery apparatus. Guidelines for patient selection and contouring are well described, and OAR constraints from both evidence-based toxicity analyses and multicenter randomized controlled trials are available. Patients need to be followed up closely with spine MRI for tumor progression, pseudoprogression, and side effects of radiotherapy which can include vertebral compression fracture.

BACKGROUND The unique anatomy and biomechanical features of the cervical spine and sacrum may impact treatment outcomes following spine stereotactic body radiotherapy (SBRT). Current data for spine metastases are not specific for these locations. OBJECTIVE To report imaging-based SBRT outcomes to cervical and sacral metastases. METHODS We retrospectively reviewed our prospective spine SBRT database for cervical and sacral metastases. Patients were followed at 2- to 3-mo intervals with a clinical visit and full spine magnetic resonance imaging (MRI) and we report overall survival (OS), vertebral compression fracture (VCF), and MR imaging-based local control (LC) rates. RESULTS Fifty-two patients and 93 treated spinal segments were identified. Fifty-six segments were within the cervical spine and 37 within the sacrum, the median follow-up was 14.4 and 19.5 mo, and the median total dose/number of fractions was 24 Gy/2, respectively. Cumulative LC at 1 and 2 yr were 94.5% and 92.7% for the cervical cohort, and 86.5% and 78.7% in the sacral cohort, respectively. Lack of posterior spinal element involvement in the cervical spine (P

Purpose Stereotactic body radiation therapy (SBRT) is a highly effective and potentially ablative treatment for complex spinal metastases. Recent data have suggested radiobiologic effects of SBRT that expand beyond the traditional concept of DNA damage. Antitumor immunity, vascular damage leading to tumor necrosis, and increased rates of tumor apoptosis have been implied; however, in-human evidence remains scarce. The present study reports unique pathologic confirmation of SBRT-induced biological effects within spinal metastases treated with preoperative SBRT. Methods and Materials Ten patients with spinal metastases secondary to various solid tumors were treated with preoperative single-fraction SBRT (18 Gy) to the magnetic resonance imaging–defined macroscopic metastasis, followed by spinal stabilization within 24 hours. Perioperative samples of spinal metastases were obtained, and 6 patients also had a pre-SBRT biopsy specimen available for a matched comparison. The samples were stained for tumor necrosis on routine hematoxylin-eosin–stained slices and, subsequently, immunohistochemical staining for T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), endothelium (CD31+), and apoptotic activity (caspase-3). Results Perioperative biopsy specimens were obtained ∼6 hours (range 4.5-7.5) or 21 hours (range 18.5-22.5) after SBRT. Necrosis was observed in 83% of the 21-hour post-SBRT samples (5 of 6) compared with 0% of pre-SBRT biopsies (0 of 6) and 6-hour post-SBRT biopsies (0 of 4). Tumor cell apoptosis had increased greatly in the 21-hour post-SBRT samples compared with before and 6 hours after SBRT. The CD31+ vessel counts decreased after SBRT, as did mitotic activity. Both of the renal cell metastases displayed major decreases in vessel density. Desmoplastic reaction was visible in 67% (4 of 6) of the pre-SBRT samples compared with 100% (10 of 10) the post-SBRT samples. The T-cell and natural killer cell counts were relatively unaffected. Conclusions High-dose single-fraction SBRT induced tumor necrosis, desmoplasia, and tumor apoptosis and decreased tumor vessel density within 24 hours, even in renal cell metastases. The role of immune cells seems limited in this early phase. These first-in-human results imply direct vascular and DNA damage mechanisms important in the clinical efficacy specific to spinal SBRT.

Radiation-induced parenchymal lung changes after stereotactic body radiotherapy are common, and can obscure the primary tumor site. In this study we propose a structured radiographic reporting tool for characterization of these changes, pilot its feasibility in a group of radiation oncologists, and test the interrater agreement. We could demonstrate the applicability of the scale, with a fair to moderate agreement.The purpose of the study was to design and pilot a synoptic scale for characterization of late radiographic changes after lung stereotactic body radiotherapy (SBRT).A participatory design process involving 6 radiation oncologists and 2 thoracic radiologists was used in the scale's design. Seventy-seven early-stage non-small-cell lung cancer patients who were treated with SBRT were included, and after treatment their serial computed tomography (CT) images were scored by 6 radiation oncologists. Gwet's First-order Agreement Coefficient (AC1) and a leave-one-out (LOO) analysis was used to assess interrater reliability and variability among raters, respectively.The scale reports on 5 independent categories including "tumor in primary site," "tumor in involved lobe," "consolidation," "volume loss," and "ground-glass or interstitial changes." At each time point, each category is reported as "increased," "stable," "decreased," "obscured," or "not present," compared with the previous. The total number of rated images for the pilot ranged from 450 at 6 months to 84 at 48 months. The primary tumor site was scored as obscured in 38% to 40% of ratings from 12 months onward; 3% to 5% of primary tumors were scored as "increased." Consolidation, volume loss, and ground-glass or interstitial changes were increasingly marked as "stable" with time. At 24 months, AC1 was 0.28 (LOO, 0.22-0.42), 0.47 (LOO, 0.39-0.72), 0.45 (LOO, 0.42-0.50), 0.21 (LOO, 0.15-0.26), and 0.25 (LOO, 0.20-0.38) for the 5 categories listed, respectively.In a population of clinicians, this scale could be implemented to characterize evolving lung changes after SBRT, and had fair to moderate interrater agreement. Obscured tumor site is a common challenge of follow-up CT imaging, and new imaging techniques should be explored. This scale provides a tool for communicating changes after SBRT.

Purpose Radiographic changes after lung stereotactic body radiation therapy (SBRT) have been categorized into 4 groups: modified conventional pattern (A), mass-like fibrosis; (B), scar-like fibrosis (C), and no evidence of increased density (D). The purpose of this study was to assess the interrater reliability of this categorization system in patients with early-stage non-small cell lung cancer (NSCLC). Methods and Materials Seventy-seven patients were included in this study, all treated with SBRT for early-stage (T1/2) NSCLC at a single institution, with a minimum follow-up of 6 months. Six experienced clinicians familiar with post-SBRT radiographic changes scored the serial posttreatment CT images independently in a blinded fashion. The proportion of patients categorized as A, B, C, or D at each interval was determined. Krippendorff's alpha (KA), Multirater kappa (M-kappa), and Gwet's AC1 (AC1) scores were used to establish interrater reliability. A leave-one-out analysis was performed to demonstrate the variability among raters. Interrater agreement of the first and last 20 patients scored was calculated to explore whether a training effect existed. Results The number of ratings ranged from 450 at 6 months to 84 at 48 months of follow-up. The proportion of patients in each category was as follows: A, 45%; B, 16%; C, 13%; and D, 26%. KA and M-kappa ranged from 0.17 to 0.34. AC1 measure range was 0.22 to 0.48. KA increased from 0.24 to 0.36 at 12 months with training. The percent agreement for pattern A peaked at 12 month with a 54% chance of having >50% raters in agreement and decreased over time, whereas that for patterns B and C increased over time to a maximum of 20% and 22%, respectively. Conclusion This post-SBRT radiographic change categorization system has modest interrater agreement, and there is a suggestion of a training effect. Patterns of fibrosis evolve after SBRT and alternative categorization systems should be evaluated.