Semi-automated reproducible target transfer for cardiac radioablation - A multi-center cross-validation study within the RAVENTA trial.

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) is a therapeutic option for ventricular tachycardia (VT) where catheter-based ablation is not feasible or has previously failed. Target definition and its transfer from electro-anatomic maps (EAM) to radiotherapy treatment planning systems (TPS) is challenging and operator-dependent. Software solutions have been developed to register EAM with cardiac CT and semi-automatically transfer 2D target surface data into 3D CT volume coordinates. Results of a cross-validation study of two conceptually different software solutions using data from the RAVENTA trial (NCT03867747) are reported. METHODS: Clinical Target Volumes (CTVs) were created from target regions delineated on EAM using two conceptually different approaches by separate investigators on data of 10 patients, blinded to each other's results. Targets were transferred using 3D-3D registration and 2D-3D registration, respectively. The resulting CTVs were compared in a core-lab using two complementary analysis software packages for structure similarity and geometric characteristics. RESULTS: Volumes and surface areas of the CTVs created by both methods were comparable: 14.88 ± 11.72 ml versus 15.15 ± 11.35 ml and 44.29 ± 33.63 cm2 versus 46.43 ± 35.13 cm2. The Dice-coefficient was 0.84 ± 0.04; median surface-distance and Hausdorff-distance were 0.53 ± 0.37 mm and 6.91 ± 2.26 mm, respectively. The 3D-center-of-mass difference was 3.62 ± 0.99 mm. Geometrical volume similarity was 0.94 ± 0.05 %. CONCLUSION: The STAR targets transferred from EAM to TPS using both software solutions resulted in nearly identical 3D structures. Both solutions can be used for QA (quality assurance) and EAM-to-TPS transfer of STAR-targets. Semi-automated methods could potentially help to avoid mistargeting in STAR and offer standardized workflows for methodically harmonized treatments.

Refining Treatment Planning in STereotactic Arrhythmia Radioablation: Benchmark Results and Consensus Statement From the STOPSTORM.eu Consortium.

PURPOSE: STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia. However, clinical data are scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS AND MATERIALS: Planning target volumes (PTVs) overlapping extracardiac organs-at-risk and/or cardiac substructures were generated for 3 STAR cases. Participating centers were asked to create single-fraction treatment plans with 25 Gy dose prescriptions based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for International Commission on Radiation Units and Measurements report 91 relevant parameters and crowd dose-volume histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS: Twenty centers submitted 67 treatment plans for this study. In most plans (75%) intensity modulated arc therapy with 6 MV flattening filter free beams was used. Dose prescription was mainly based on PTV D95% (49%) or D96%-100% (19%). Many participants preferred to spare close extracardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D0.035cm3 ranged from 25.5 to 34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged from 2 to 80 minutes. For the consensus statements, a strong agreement was reached for beam technique planning, dose calculation, prescription methods, and trade-offs between target and extracardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSIONS: This STOPSTORM multicenter treatment planning benchmark study not only showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established; however, clinical data are urgently needed for actionable guidelines for treatment planning.

Dose prescription for stereotactic body radiotherapy: general and organ-specific consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery.

PURPOSE AND OBJECTIVE: To develop expert consensus statements on multiparametric dose prescriptions for stereotactic body radiotherapy (SBRT) aligning with ICRU report 91. These statements serve as a foundational step towards harmonizing current SBRT practices and refining dose prescription and documentation requirements for clinical trial designs. MATERIALS AND METHODS: Based on the results of a literature review by the working group, a two-tier Delphi consensus process was conducted among 24 physicians and physics experts from three European countries. The degree of consensus was predefined for overarching (OA) and organ-specific (OS) statements (≥ 80%, 60-79%, < 60% for high, intermediate, and poor consensus, respectively). Post-first round statements were refined in a live discussion for the second round of the Delphi process. RESULTS: Experts consented on a total of 14 OA and 17 OS statements regarding SBRT of primary and secondary lung, liver, pancreatic, adrenal, and kidney tumors regarding dose prescription, target coverage, and organ at risk dose limitations. Degree of consent was ≥ 80% in 79% and 41% of OA and OS statements, respectively, with higher consensus for lung compared to the upper abdomen. In round 2, the degree of consent was ≥ 80 to 100% for OA and 88% in OS statements. No consensus was reached for dose escalation to liver metastases after chemotherapy (47%) or single-fraction SBRT for kidney primaries (13%). In round 2, no statement had 60-79% consensus. CONCLUSION: In 29 of 31 statements a high consensus was achieved after a two-tier Delphi process and one statement (kidney) was clearly refused. The Delphi process was able to achieve a high degree of consensus for SBRT dose prescription. In summary, clear recommendations for both OA and OS could be defined. This contributes significantly to harmonization of SBRT practice and facilitates dose prescription and reporting in clinical trials investigating SBRT.

Pituitary metastasis arising from hepatocellular carcinoma: a case report and update of the literature.

Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the third leading cause of cancer-associated deaths worldwide. Most cases arise in patients with cirrhosis, and early detection through periodic screening can make it potentially curable. The presence of extrahepatic metastases (EHM) affects treatment decisions and curability. The lungs are the most common site for EHM, followed by lymph nodes, bones, and the adrenal glands. Interestingly, approximately only 15 cases of HCC metastasizing to the pituitary gland have been reported so far.The most common symptoms of pituitary metastasis (PM) arising from HCC are nerve palsies affecting the third, fourth, and sixth cranial nerves. Other symptoms, such as diabetes insipidus or pituitary insufficiencies, are present in a minority of cases. Detecting PM is difficult given its rarity. Gold-standard treatments for these patients have not yet been established, but the prognosis is dismal, with a median overall survival of only 4.5 months. In this paper, we present an interesting case of PM as the first symptom of an HCC in a 75-year-old female. We also present an overview of all cases reported to date with emphasis on symptom presentation and survival after diagnosis.Given the improvement of systemic therapy, more cases are diagnosed in both oligometastatic and palliative conditions. Therefore, better approaches and treatment modalities for extrahepatic metastases due to HCC should be defined.

Refining critical structure contouring in STereotactic Arrhythmia Radioablation (STAR): Benchmark results and consensus guidelines from the STOPSTORM.eu consortium.

BACKGROUND AND PURPOSE: In patients with recurrent ventricular tachycardia (VT), STereotactic Arrhythmia Radioablation (STAR) shows promising results. The STOPSTORM.eu consortium was established to investigate and harmonise STAR treatment in Europe. The primary goals of this benchmark study were to standardise contouring of organs at risk (OAR) for STAR, including detailed substructures of the heart, and accredit each participating centre. MATERIALS AND METHODS: Centres within the STOPSTORM.eu consortium were asked to delineate 31 OAR in three STAR cases. Delineation was reviewed by the consortium expert panel and after a dedicated workshop feedback and accreditation was provided to all participants. Further quantitative analysis was performed by calculating DICE similarity coefficients (DSC), median distance to agreement (MDA), and 95th percentile distance to agreement (HD95). RESULTS: Twenty centres participated in this study. Based on DSC, MDA and HD95, the delineations of well-known OAR in radiotherapy were similar, such as lungs (median DSC = 0.96, median MDA = 0.1 mm and median HD95 = 1.1 mm) and aorta (median DSC = 0.90, median MDA = 0.1 mm and median HD95 = 1.5 mm). Some centres did not include the gastro-oesophageal junction, leading to differences in stomach and oesophagus delineations. For cardiac substructures, such as chambers (median DSC = 0.83, median MDA = 0.2 mm and median HD95 = 0.5 mm), valves (median DSC = 0.16, median MDA = 4.6 mm and median HD95 = 16.0 mm), coronary arteries (median DSC = 0.4, median MDA = 0.7 mm and median HD95 = 8.3 mm) and the sinoatrial and atrioventricular nodes (median DSC = 0.29, median MDA = 4.4 mm and median HD95 = 11.4 mm), deviations between centres occurred more frequently. After the dedicated workshop all centres were accredited and contouring consensus guidelines for STAR were established. CONCLUSION: This STOPSTORM multi-centre critical structure contouring benchmark study showed high agreement for standard radiotherapy OAR. However, for cardiac substructures larger disagreement in contouring occurred, which may have significant impact on STAR treatment planning and dosimetry evaluation. To standardize OAR contouring, consensus guidelines for critical structure contouring in STAR were established.

Electroanatomical mapping after cardiac radioablation for treatment of incessant electrical storm: a case report from the RAVENTA trial.

BACKGROUND: Electroanatomical mapping (EAM)-guided stereotactic arrhythmia radioablation (STAR) is a novel noninvasive therapy option for patients with monomorphic ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or urgent catheter ablation (CA). Data on success rates in an emergency situation such as electrical storm (ES) are rare. We present a case of a patient with an initially very poor life expectancy after extensive myocardial infarction with therapy-resistant ES, not amendable for further antiarrhythmic drug therapy, implantable cardioverter-defibrillator implantation, or repeated CA who was introduced to the radiation oncology department for emergency STAR as a bail-out therapy. METHODS: Target volume definition and transfer from EAM to CT were validated and quality assured with a semi-automatic, dedicated visualization tool (CARDIO-RT). Emergency STAR was performed with 25 Gy in the framework of the RAVENTA study. The VT burden gradually decreased after STAR; however, a second VT morphology occurred, which was successfully treated with EAM-guided CA 12 days after STAR. RESULTS: The second EAM-guided CA showed areas of low voltage in the irradiated segments, indicating a precise targeting and early functional response to STAR. The patient remained free of any VT recurrence or any radiation-related toxicities and in good general condition during the recent follow-up of 18 months. CONCLUSION: The case highlights the possible approach, caveats, difficulties, and prognosis of a patient severely affected by therapy-resistant VT in whom CA could not lead to VT suppression. Further studies of putative mechanisms of STAR in the acute and chronic phase of this novel therapy are warranted.

Stereotactic arrhythmia radioablation: A multicenter pre-post intervention safety evaluation of the implantable cardioverter-defibrillator function.

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) appears to be beneficial in selected patients with therapy-refractory ventricular tachycardia (VT). However, high-dose radiotherapy used for STAR-treatment may affect functioning of the patients' implantable cardioverter defibrillator (ICD) by direct effects of radiation on ICD components or cardiac tissue. Currently, the effect of STAR on ICD functioning remains unknown. METHODS: A retrospective pre-post multicenter study evaluating ICD functioning in the 12-month before and after STAR was performed. Patients with (non)ischemic cardiomyopathies with therapy-refractory VT and ICD who underwent STAR were included and the occurrence of ICD-related adverse events was collected. Evaluated ICD parameters included sensing, capture threshold and impedance. A linear mixed-effects model was used to investigate the association between STAR, radiotherapy dose and changes in lead parameters over time. RESULTS: In total, 43 patients (88% male) were included in this study. All patients had an ICD with an additional right atrial lead in 34 (79%) and a ventricular lead in 17 (40%) patients. Median ICD-generator dose was 0.1 Gy and lead tip dose ranged from 0-32 Gy. In one patient (2%), a reset occurred during treatment, but otherwise, STAR and radiotherapy dose were not associated with clinically relevant alterations in ICD leads parameters. CONCLUSIONS: STAR treatment did not result in major ICD malfunction. Only one radiotherapy related adverse event occurred during the study follow-up without patient harm. No clinically relevant alterations in ICD functioning were observed after STAR in any of the leads. With the reported doses STAR appears to be safe.

Surface guidance compared with ultrasound-based monitoring and diaphragm position in cone-beam computed tomography during abdominal stereotactic radiotherapy in breath-hold.

Background and purpose: Spirometry induced deep-inspiration-breath-hold (DIBH) reduces intrafractional motion during upper abdominal stereotactic body radiotherapy (SBRT). The aim of this prospective study was to evaluate whether surface scanning (SGRT) is an adequate surrogate for monitoring residual internal motion during DIBH. Residual motion detected by SGRT was compared with experimental 4D-ultrasound (US) and an internal motion detection benchmark (diaphragm-dome-position in kV cone-beam computed tomography (CBCT) projections). Materials and methods: Intrafractional monitoring was performed with SGRT and US in 460 DIBHs of 12 patients. Residual motion detected by all modalities (SGRT (anterior-posterior (AP)), US (AP, craniocaudal (CC)) and CBCT (CC)) was analyzed. Agreement analysis included Wilcoxon signed rank test, Maloney and Rastogi's test, Pearson's correlation coefficient (PCC) and interclass correlation coefficient (ICC). Results: Interquartile range was 0.7 mm (US(AP)), 0.8 mm (US(CC)), 0.9 mm (SGRT) and 0.8 mm (CBCT). SGRT(AP) vs. CBCT(CC) and US(CC) vs. CBCT(CC) showed comparable agreement (PCCs 0.53 and 0.52, ICCs 0.51 and 0.49) with slightly higher precision of CBCT(CC). Most agreement was observed for SGRT(AP) vs. US(AP) with largest PCC (0.61) and ICC (0.60), least agreement for SGRT(AP) vs. US(CC) with smallest PCC (0.44) and ICC (0.42). Conclusions: Residual motion detected during spirometry induced DIBH is small. SGRT alone is no sufficient surrogate for residual internal motion in all patients as some high velocity motion could not be detected. Observed patient-specific residual errors may require individualized PTV-margins.

Radiosurgery for ventricular tachycardia (RAVENTA): interim analysis of a multicenter multiplatform feasibility trial.

BACKGROUND: Single-session cardiac stereotactic radiation therapy (SBRT) has demonstrated promising results for patients with refractory ventricular tachycardia (VT). However, the full safety profile of this novel treatment remains unknown and very limited data from prospective clinical multicenter trials are available. METHODS: The prospective multicenter multiplatform RAVENTA (radiosurgery for ventricular tachycardia) study assesses high-precision image-guided cardiac SBRT with 25 Gy delivered to the VT substrate determined by high-definition endocardial and/or epicardial electrophysiological mapping in patients with refractory VT ineligible for catheter ablation and an implanted cardioverter defibrillator (ICD). Primary endpoint is the feasibility of full-dose application and procedural safety (defined as an incidence of serious [grade ≥ 3] treatment-related complications ≤ 5% within 30 days after therapy). Secondary endpoints comprise VT burden, ICD interventions, treatment-related toxicity, and quality of life. We present the results of a protocol-defined interim analysis. RESULTS: Between 10/2019 and 12/2021, a total of five patients were included at three university medical centers. In all cases, the treatment was carried out without complications. There were no serious potentially treatment-related adverse events and no deterioration of left ventricular ejection fraction upon echocardiography. Three patients had a decrease in VT episodes during follow-up. One patient underwent subsequent catheter ablation for a new VT with different morphology. One patient with local VT recurrence died 6 weeks after treatment in cardiogenic shock. CONCLUSION: The interim analysis of the RAVENTA trial demonstrates early initial feasibility of this new treatment without serious complications within 30 days after treatment in five patients. Recruitment will continue as planned and the study has been expanded to further university medical centers. TRIAL REGISTRATION NUMBER: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. Study start: October 1, 2019.

Long-term characterization of MRI-morphologic alterations after active motion-compensated liver SBRT: a multi-institutional pooled analysis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an effective therapeutic approach in patients with liver metastases. However, long-term changes in hepatic normal tissue have to be taken into account in multimodal treatment regimes. Magnetic-resonance-imaging (MRI) based morphologic liver alterations (MMA) after liver SBRT have been analyzed longitudinally. MATERIAL AND METHODS: 57 patients treated with gantry-based or robotic-based SBRT of 69 treatment volumes of liver metastases, who had long-term follow-up (FU) ≥6 months were included in this retrospective analysis. Post-SBRT MMAs were contoured on each contrast-enhanced-T1-weighted (T1w) MRI-sequence. Morphologic/volumetric data of the liver and MMAs were evaluated longitudinally, including the dependency on treatment-related factors of the planning target volume (PTV) and liver. RESULTS: The median FU time was 1 year [6-48 months]. 66 of 69 treatment volumes developed MMAs (mean 143.8 ± 135.1 ccm at first appearance). 31.8% of MMAs resolved completely during FU. Of the persisting MMAs 82.2%/13.3% decreased/increased in size until last available FU. Morphological characterization of the MMAs at first appearance included 75% hypointense and 25% hyperintense T1w-MRI-based appearances. Hypointense as compared to hyperintense appearance was significantly associated with a higher mean liver dose EQD2α/ß=3 Gy (p = 0.0212) and non-significantly greater MMA size. Variance analysis demonstrated a significant reduction of MMA and total liver volume after SBRT (p < 0.0001). The volume reduction decelerated longitudinally for both MMA (p < 0.0001) and liver size (p = 0.0033). Radiation doses (PTV-BEDα/ß=3 Gy and 10 Gy) were not significantly associated with MMA volume reduction. SBRT of liver metastases with mean liver dose EQD2α/ß=3 Gy > 18 Gy were characterized by greater MMA volumes (p = 0.0826) and steeper MMA reduction gradients during FU than those with EQD2α/ß=3 Gy ≤ 18 Gy (p < 0.0001). CONCLUSION: Radiogenic MMAs either completely resolve or usually decrease in volume with pronounced reduction during short-term FU. This course was independent of the MMA's morphological appearance. Further, increased mean liver dose was associated with greater MMA size and a greater gradient of MMA size reduction during FU.

STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe.

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs.

Dosimetric benefits of adaptive radiation therapy for patients with stage III non-small cell lung cancer.

BACKGROUND: Daily adaptive radiation therapy (ART) of patients with non-small cell lung cancer (NSCLC) lowers organs at risk exposure while maintaining the planning target volume (PTV) coverage. Thus, ART allows an isotoxic approach with increased doses to the PTV that could improve local tumor control. Herein we evaluate daily online ART strategies regarding their impact on relevant dose-volume metrics. METHODS: Daily cone-beam CTs (1 × n = 28, 1 × n = 29, 11 × n = 30) of 13 stage III NSCLC patients were converted into synthetic CTs (sCTs). Treatment plans (TPs) were created retrospectively on the first-fraction sCTs (sCT1) and subsequently transferred unaltered to the sCTs of the remaining fractions of each patient (sCT2-n) (IGRT scenario). Two additional TPs were generated on sCT2-n: one minimizing the lung-dose while preserving the D95%(PTV) (isoeffective scenario), the other escalating the D95%(PTV) with a constant V20Gy(lungipsilateral) (isotoxic scenario). RESULTS: Compared to the original TPs predicted dose, the median D95%(PTV) in the IGRT scenario decreased by 1.6 Gy ± 4.2 Gy while the V20Gy(lungipsilateral) increased in median by 1.1% ± 4.4%. The isoeffective scenario preserved the PTV coverage and reduced the median V20Gy(lungipsilateral) by 3.1% ± 3.6%. Furthermore, the median V5%(heart) decreased by 2.9% ± 6.4%. With an isotoxic prescription, a median dose-escalation to the gross target volume of 10.0 Gy ± 8.1 Gy without increasing the V20Gy(lungipsilateral) and V5%(heart) was feasible. CONCLUSIONS: We demonstrated that even without reducing safety margins, ART can reduce lung-doses, while still reaching adequate target coverage or escalate target doses without increasing ipsilateral lung exposure. Clinical benefits by means of toxicity and local control of both strategies should be evaluated in prospective clinical trials.