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Background: Although stereotactic body radiotherapy (SBRT) was progressively adopted in clinical practice in Belgium, a reimbursement request in 2011 was not granted because of remaining clinical and economic uncertainty. A coverage with evidence development (CED) program on SBRT started in 2013, with the aim to assess clinical and technical patterns-of-care in Belgium and monitor survival per indication, in view of supporting inclusion in the reimbursement system., Methods: The Belgian National Institute for Health and Disability Insurance (NIHDI) initiated this prospective observational registry. Participating departments, using SBRT in clinical practice, signed the 'NIHDI convention'. Eligible patients had a primary tumour (PT) or oligometastatic disease (OMD). Patient, tumour, and treatment characteristics were collected through an online module of the Belgian Cancer Registry, prerequisite for financing. Five-year overall survival (5YOS) and 30- and 90-days mortality were primary outcomes, derived from vital status information., Findings: Between 10/2013 and 12/2019, 20 of the 24 accredited radiotherapy departments participated, 6 were academic. Registered cases per department ranged from 21 to 867. Of 5675 registrations analysed, the majority had good performance status and limited number of lesions. Enrolment of PTs remained stable over time, OMDs almost doubled. Peripheral lung lesions dominated in PTs as in OMDs. Other metastases were (para)spinal, 'non-standard' and hepatic. Thirty- and 90-days mortalities remained below 0.5% [95% CI 0.3%-0.8%] respectively 2.1% [95% CI 1.6%-2.7%]. 5YOS varied by indication, primary prostate patients performing best (85%, 95% CI [76%, 96%]), those with liver metastases worst (19%, 95% CI [15%, 24%]). Better OS was observed in academic departments, department size did not significantly impact survival. OMD survival was better in 2018-19., Interpretation: CED can be used to define patterns-of-care and real-life outcome of innovative radiotherapy. As the observed survival for different indications was in line with outcome in emerging literature, SBRT was included in the Belgian reimbursement system as of January 2020., Funding: NIHDI financed participating departments per registered case., Competing Interests: All authors have completed the ICMJE disclosure form and declare: YL is recipient of the HERO-VBHC chair, with payments made to her institution and has unpaid leadership roles in ESTRO (Scientific Committee member and ESTRO-HERO co-chair), the Belgian College of Oncology (Board member) and in the EORTC-ESTRO E2-RADIATE project (PI); DV has research collaboration with RaySearch Laboratories and received speakers fees from BeSTRO and JASTRO and per diem payment as teacher in the ESTRO SBRT course, and reports advisory roles for the Belgian Supreme Health Council and the Medical Jury of the Belgian Federal Agency for Nuclear Control, treasurer of ESTRO and board member of ‘Stand Up Against Cancer’; ML receives a grant of the Foundation Against Cancer for proton radiotherapy in pregnancy (ProPOSE). None of the aforementioned payments or roles are in relation to the submitted work. RW receives fees as president of the College for Physicians of Radiation Oncology Centres, which are paid to her institution; SR is working for the NIHDI, HE was working for the NIHDI during the course of the CED program; SJ and NVD both work for the BCR; but none declare financial or personal interests that could have influenced the submitted work. XG, NJ, LM, VR, KS and CW reported no financial or other relationships that might impact the submitted work., (© 2024 The Authors.)

Purpose: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial., Methods and Materials: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients., Results: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms., Conclusions: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Currently in-vivo dosimetry (IVD) is primarily used to identify individual patient errors in radiotherapy. This study investigated possible correlations of observed trends in transit IVD results, with adaptations to the clinical workflow, aiming to demonstrate the possibility of using the bulk data for continuous quality improvement., Materials and Methods: In total 84,100 transit IVD measurements were analyzed of all patients treated between 2018 and 2022, divided into four yearly periods. Failed measurements (FM) were divided per pathology and into four categories of causes of failure: technical, planning and positioning problems, and anatomic changes., Results: The number of FM due to patient related problems gradually decreased from 9.5% to 6.6%, 6.1% and 5.6% over the study period. FM attributed to positioning problems decreased from 10.0% to 4.9% in boost breast cancer patients after introduction of extra imaging, from 9.1% to 3.9% in Head&Neck patients following education of radiation therapists on positioning of patients' shoulders, from 6.1% to 2.8% in breast cancer patients after introduction of ultrahypofractionated breast radiotherapy with daily online pre-treatment imaging and from 11.2% to 4.3% in extremities following introduction of immobilization with calculated couch parameters and a Surface Guided Radiation Therapy solution. FM related to anatomic changes decreased from 10.2% to 4.0% in rectum patients and from 6.7% to 3.3% in prostate patients following more patient education from dieticians., Conclusions: Our study suggests that IVD can be a powerful tool to assess the impact of adaptations to the clinical workflow and its use for continuous quality improvement., 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., (© 2023 The Authors.)

Background and Purpose: First reports on clinical use of commercially automated systems for Electronic Portal Imaging Device (EPID)-based dosimetry in radiotherapy showed the capability to detect important changes in patient setup, anatomy and external device position. For this study, results for more than 3000 patients, for both pre-treatment verification and in-vivo transit dosimetry were analyzed., Materials and Methods: For all Volumetric Modulated Arc Therapy (VMAT) plans, pre-treatment quality assurance (QA) with EPID images was performed. In-vivo dosimetry using transit EPID images was analyzed, including causes and actions for failed fractions for all patients receiving photon treatment (2018-2019). In total 3136 and 32,632 fractions were analyzed with pre-treatment and transit images respectively. Parameters for gamma analysis were empirically determined, balancing the rate between detection of clinically relevant problems and the number of false positive results., Results: Pre-treatment and in-vivo results depended on machine type. Causes for failed in-vivo analysis included deviations in patient positioning (32%) and anatomy change (28%). In addition, errors in planning, imaging, treatment delivery, simulation, breath hold and with immobilization devices were detected. Actions for failed fractions were mostly to repeat the measurement while taking extra care in positioning (54%) and to intensify imaging procedures (14%). Four percent initiated plan adjustments, showing the potential of the system as a basis for adaptive planning., Conclusions: EPID-based pre-treatment and in-vivo transit dosimetry using a commercially available automated system efficiently revealed a wide variety of deviations and showed potential to serve as a basis for adaptive planning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Iridium Kankernetwerk is a member of the SunCHECK Customer Advisory Board and a Reference center for Sun Nuclear Corporation, but there has been no significant financial support for this work that could have influenced its outcome., (© 2020 The Authors.)

Advantages of using intraoperative radiotherapy with electrons (IOERT) as a boosting modality in breast-conserving therapy include the direct visualization of the tumor bed, a reduced skin dose, and patient convenience. We report oncological outcome, postoperative complication rate, and mammographic changes on follow-up imaging in women treated at our institution with IOERT as a boost modality in breast-conserving therapy for early-stage breast carcinoma. Between January 2007 and June 2018, 763 consecutive patients were enrolled. During breast-conserving surgery, an IOERT boost of 9 Gy was applied, followed by whole breast irradiation (WBI). At a median follow-up of 62.2 months (range: 0.5-135), 13 in-breast recurrences were observed, yielding a local tumor control rate of 98.4% at 5 years. In multivariable analysis, high tumor grading was predictive for local recurrence (HR = 5.6; 95%CI: 1.19-26.2). A total of 27 (3.5%) patients developed any kind of postoperative complication. None of the tumor characteristics nor any of the IOERT technical parameters were predictive for development of a postoperative complication. On follow-up imaging, 145 patients with mammographic changes BIRADS score ≥3 were found of which 50.3% required a biopsy. Only 17 patients had positive biopsies; none of the IOERT parameters were predictive for false-positive imaging. A 9 Gy IOERT boost combined with postoperative WBI provided outstanding local control rates, was well-tolerated, with limited postoperative complications. However, radiologists must be aware of a presumable higher prevalence of mammographic changes after IORT as a boost., (© 2020 Wiley Periodicals, Inc.)

Background and Purpose: The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported., Materials and Methods: Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans., Results: For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R 2  < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001)., Conclusions: Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In a previous national central review project, 74% of the rectal cancer clinical target volumes (CTVs) needed a modification. In a follow-up initiative, we evaluated whether the use of refined international consensus guidelines improves the uniformity of CTV delineation in clinical practice., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To evaluate the reproducibility and diagnostic value of apparent diffusion coefficient (ADC) as an early predictor of response to chemotherapy of liver metastasis in routine clinical practice., Materials and Methods: A prospective study of 20 patients with histologically proven primary tumors with liver metastases was undertaken. Diffusion weighted MRI was performed twice before and 12-14 days after the start of treatment. Absolute and liver normalized ADC values were calculated. Bland Altman statistics were used to assess the reproducibility of ADC change for predicting lesion response as measured by RECIST., Results: Nineteen of 31 metastases responded. Significant increases in absolute and normalized ADC values were found in responding (mean +208.7 × 10(-6) m(2)/s and +18% respectively, both P < 0.001) compared with nonresponding lesions (mean +98.6 × 10(-6) m(2)/s and 2%, respectively, P = 0.09 and 0.519). Reproducibility was better using normalized ADC compared with absolute ADC values (within patient coefficient of variability 8.0% and 10.1%, respectively). Using the repeatability threshold of ±22.3% for normalized ADC, only 8 of 19 responding and all but one nonresponding lesions could be prospectively detected., Conclusion: Increases in ADC values in responding liver metastases occurred within days after the start of chemotherapy but were of smaller magnitude than the variability of ADC measurement. These preliminary data suggest that the presently used technique is not reliable enough to predict final response at such an early time point in individual lesions., (© 2013 Wiley Periodicals, Inc.)

Serum and plasma concentrations of vascular endothelial growth factor (sVEGF and pVEGF), serum concentrations of interleukin 6 (IL-6), and VEGF platelet load (VEGF/pl) in the blood of healthy controls (n = 26), breast cancer patients with locoregional disease (n = 31), and patients with progressive advanced disease (n = 73) have been compared. The 95th percentile values for the control population were 250 pg/mL for sVEGF, 30 pg/mL for pVEGF, and 1.6 pg/mL for IL-6. The 95th percentile value of the calculated VEGF/pl was 1.0 pg/10(6) platelets in the control population. Serum VEGF concentrations correlated with platelet number in all the groups. Patients with thrombocytosis had a median sVEGF concentration of 833 pg/mL, compared to 249 pg/mL in other patients (P = 0.018). Serum IL-6 levels correlated with sVEGF levels and with the calculated VEGF/pl. Serum IL-6 concentration was significantly higher in patients with breast cancer compared to healthy controls (P < 0.0001). Median IL-6 serum levels were nearly 10 times higher in patients with metastatic breast cancer as compared to the those with locoregional disease (6.0 pg/mL versus 0.7 pg/mL, respectively). Plasma VEGF and the VEGF/pl were also significantly different in the 3 groups. The ratio between sVEGF and pVEGF tended to be smaller in the metastatic breast cancer group compared to the patients with locoregional disease (median, 7.5 versus 10.1, respectively; P = 0.066), suggestive of more intravasal platelet degranulation in the former group. Serum IL-6 level is the most discriminative factor separating healthy controls and the locoregional and metastatic breast cancer patient groups. These results suggest a role for tumor-derived IL-6 in regulating VEGF expression in platelets and their precursors and also confirm the role of circulating platelets in the storage of VEGF.

The growth of primary tumours beyond a critical mass is dependent on angiogenesis. The switch to the angiogenic phenotype involves changes in the local equilibrium of cytokines with either pro- or anti-angiogenic properties. Vascular Endothelial Growth Factor (VEGF) is one of the major positive regulators of tumour angiogenesis. Serum VEGF is, in cancer patients, correlated with worse prognosis. Recent evidence suggests that platelets are the main contributors of serum VEGF. We demonstrate, ultrastructurally and with immunofluorescence techniques, the alpha granule and membranous localisation of VEGF and provide further evidence for the role of platelets, both in healthy individuals as in patients with locally and advanced breast cancer, in the storage of circulating VEGF. We also demonstrate that, linear with tumoural progression, platelets accumulate more VEGF. Enhanced production in bone marrow platelet progenitors as well as endocytosis of circulating VEGF by platelets and/or megakaryocytes could explain the higher VEGF load in platelets from advanced cancer patients. This study provides further evidence for a role of platelets in transporting VEGF.