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Using fiducial-marker-based robotic respiratory tumor tracking, we treated perihilar cholangiocarcinoma patients in the STRONG trial with 15 daily fractions of 4 Gy. For each of the included patients, in-room diagnostic-quality repeat CTs (rCT) were acquired pre- and post-dose delivery in 6 treatment fractions to analyze inter- and intrafraction dose variations. Planning CTs (pCTs) and rCTs were acquired in expiration breath-hold. Analogous to treatment, spine and fiducials were used to register rCTs with pCTs. In each rCT, all OARs were contoured, and the target was rigidly copied from the pCT based on grey values. The rCTs acquired were used to calculate the doses to be delivered through the treatment-unit settings. On average, target doses in rCTs and pCTs were similar. However, due to target displacements relative to the fiducials in rCTs, 10% of the rCTs showed PTV coverage losses of >10%. Although target coverages had been planned below desired values in order to protect OARs, many pre-rCTs contained OAR constraint violations: 44.4% for the 6 major constraints. Most OAR dose differences between pre- and post-rCTs were not statistically significant. The dose deviations observed in repeat CTs represent opportunities for more advanced adaptive approaches to enhancing SBRT treatment quality.

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.

Background and purpose: Scenario-based robust optimization and evaluation are commonly used in proton therapy (PT) with pencil beam scanning (PBS) to ensure adequate dose to the clinical target volume (CTV). However, a statistically accurate assessment of the clinical application of this approach is lacking. In this study, we assess target dose in a clinical cohort of neuro-oncological patients, planned according to the DUPROTON robustness evaluation consensus, using polynomial chaos expansion (PCE). Materials and methods: A cohort of the first 27 neuro-oncological patients treated at HollandPTC was used, including realistic error distributions derived from geometrical and stopping-power prediction (SPP) errors. After validating the model, PCE-based robustness evaluations were performed by simulating 100.000 complete fractionated treatments per patient to obtain accurate statistics on clinically relevant dosimetric parameters and population-dose histograms. Results: Treatment plans that were robust according to clinical protocol and treatment plansin which robustness was sacrificed are easily identified. For robust treatment plans on average, a CTV dose of 3 percentage points (p.p.) more than prescribed was realized (range +2.7 p.p. to +3.5 p.p.) for 98% of the sampled fractionated treatments. For the entire patient cohort on average, a CTV dose of 0.1 p.p. less than prescribed was achieved (range −2.4 p.p. to +0.5 p.p.). For the 6 treatment plans in which robustness was clinically sacrificed, normalized CTV doses of 0.98, 0.94(7)1, 0.94, 0.91, 0.90 and 0.89 were realized. The first of these was clinically borderline non-robust. Conclusion: The clinical robustness evaluation protocol is safe in terms of CTV dose as all plans that fulfilled the clinical robustness criteria were also robust in the PCE evaluation. Moreover, for plans that were non-robust in the PCE-based evaluation, CTV dose was also lower than prescribed in the clinical evaluation.

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org. ispartof: RADIOTHERAPY AND ONCOLOGY vol:160 pages:259-265 ispartof: location:Ireland status: published

Stereotactic body radiation therapy (SBRT) has emerged as an effective, noninvasive treatment option for primary liver cancer and metastatic disease occurring in the liver. Although SBRT can be highly effective for establishing local control in hepatic malignancies, a tradeoff exists between tumor control and normal tissue complications. The objective of the present study was to review the normal tissue dose-volume effects for SBRT-induced liver and gastrointestinal toxicities and derive normal tissue complication probability models.

Oligometastatic disease has been proposed as an intermediate state between localised and systemically metastasised disease. In the absence of randomised phase 3 trials, early clinical studies show improved survival when radical local therapy is added to standard systemic therapy for oligometastatic disease. However, since no biomarker for the identification of patients with true oligometastatic disease is clinically available, the diagnosis of oligometastatic disease is based solely on imaging findings. A small number of metastases on imaging could represent different clinical scenarios, which are associated with different prognoses and might require different treatment strategies. 20 international experts including 19 members of the European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer OligoCare project developed a comprehensive system for characterisation and classification of oligometastatic disease. We first did a systematic review of the literature to identify inclusion and exclusion criteria of prospective interventional oligometastatic disease clinical trials. Next, we used a Delphi consensus process to select a total of 17 oligometastatic disease characterisation factors that should be assessed in all patients treated with radical local therapy for oligometastatic disease, both within and outside of clinical trials. Using a second round of the Delphi method, we established a decision tree for oligometastatic disease classification together with a nomenclature. We agreed oligometastatic disease as the overall umbrella term. A history of polymetastatic disease before diagnosis of oligometastatic disease was used as the criterion to differentiate between induced oligometastatic disease (previous history of polymetastatic disease) and genuine oligometastatic disease (no history of polymetastatic disease). We further subclassified genuine oligometastatic disease into repeat oligometastatic disease (previous history of oligometastatic disease) and de-novo oligometastatic disease (first time diagnosis of oligometastatic disease). In de-novo oligometastatic disease, we differentiated between synchronous and metachronous oligometastatic disease. We did a final subclassification into oligorecurrence, oligoprogression, and oligopersistence, considering whether oligometastatic disease is diagnosed during a treatment-free interval or during active systemic therapy and whether or not an oligometastatic lesion is progressing on current imaging. This oligometastatic disease classification and nomenclature needs to be prospectively evaluated by the OligoCare study.

Simple Summary The role of radiotherapy in the treatment of perihilar cholangiocarcinoma has not yet been properly defined. In this prospective study, we therefore explored the addition to first-line chemotherapy of stereotactic body radiation therapy (SBRT) delivered in 15 fractions. Patients eligible for the study had been diagnosed with unresectable perihilar cholangiocarcinoma, and then had no progressive disease after completing treatment with 6–8 cycles of cisplatin-gemcitabine. Primary endpoints were feasibility and safety. Secondary endpoints were local control, progression-free survival, overall survival, and quality of life. As each patient completed the SBRT successfully and no dose-limiting toxicity was found, we consider this treatment to be both feasible and safe. The local control rate and overall survival were promising. However, due to the small sample size of this study, we urge the analysis of this treatment in a larger series of patients. Abstract Background: In unresectable pCCA, the standard of care is palliative chemotherapy. We investigated the feasibility and safety of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Methods: Patients with unresectable pCCA, stage T1-T4N0-N1M0, ECOG 0-1, having finished 6–8 cycles of cisplatin and gemcitabine without disease progression were eligible. SBRT was planned in 15 fractions of 3.0–4.5 Gy. The primary endpoints were feasibility (defined as completing SBRT as planned) and toxicity, evaluated within 3 months after SBRT (CTCAE v4.03). A conventional “3 + 3” design was used, corresponding to a sample size of 6 patients. Dose-limiting toxicity (DLT) was defined as grade ≥ 4 hepatobiliary or grade ≥ 3 gastrointestinal toxicity. The secondary endpoints, measured from the start of radiotherapy, were local control, progression-free survival, overall survival, and quality of life (QoL). ClinicalTrials.gov identifier: NCT03307538. Results: Six patients were enrolled between November 2017 and March 2020. SBRT was delivered as planned. All patients were treated with 60Gy (15 × 4.0Gy). No SBRT-related DLT was observed. The most common grade ≥ 3 toxicity was cholangitis (n = 5). The median follow-up was 14 months. The 12-month local control rate was 80%. We observed no substantial changes in QoL. Conclusion: In patients with unresectable pCCA with stable disease after palliative chemotherapy, adding SBRT is feasible and safe. The observed local control merits an additional evaluation of effectiveness.

Contains fulltext : 232797.pdf (Publisher’s version ) (Open Access) PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Proton beam therapy (PBT) delivers less dose to nearby normal organs compared to X-ray therapy (XRT), which is particularly relevant for treating liver cancers given that both mean and low liver dose are among the most significant predictors of radiation induced liver disease (RILD). High-dose PBT has been shown to achieve excellent long-term tumor control with minimal toxicity in hepatocellular carcinoma (HCC) patients. Increasing data support ablative PBT for patients with unresectable cholangiocarcinoma or liver metastases, especially those with larger tumors not suitable for XRT.

PURPOSE: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. METHODS: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. RESULTS: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). CONCLUSION: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required. ispartof: RADIOTHERAPY AND ONCOLOGY vol:128 issue:1 pages:37-43 ispartof: location:Ireland status: published

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 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. (c) 2017 Elsevier B.V. All rights reserved.

Background and purposeFractionated stereotactic radiotherapy (FSRT) is an alternative treatment for large vestibular schwannomas (VS), if patients are not fit for or refuse surgery. In this study, we compared long-term clinical and radiological outcome in both small–medium sized and larger tumours.Material and methodsA retrospective study was performed of patients with sporadic VS who underwent primarily conventional FSRT. In total, 50 consecutive patients were divided into two groups by volume. Clinical and volumetric parameters were analysed.ResultsIn all, 41 patients (82%) had large tumours affecting the 4thventricle (modified Koos stage 4). Definitive expansion of VS occurred in eight out of 50 patients (16%). After 7·2 years (median) the overall freedom from clinical failure was 100% in smaller and 92% in larger schwannomas (arbitrarily sized >7·4 cc). Useful hearing was preserved in only 35% of the patients. The facial nerve remained intact in all cases, while new deficit of the trigeminal nerve occurred in 20% of the cases. Of the larger tumours 20% needed a cerebrospinal fluid (CSF) shunt.ConclusionsFSRT is a treatment in its own right as it is highly effective in both smaller and larger VS without causing permanent disabling complications. The outcome is beneficial also in larger tumours that affect the 4thventricle.

Purpose: To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients.Methods: LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (+/- 4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome.Results: A total of 29 patients met inclusion criteria. Mean dose in EQD2Gy to the bilateral hippocampus was 39.8Gy (95% CI 34.3-44.4Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score.Conclusions: In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.

textabstractObject To explore the use of automated planning in robotic radiosurgery of benign vestibular schwannoma (VS) tumors for dose reduction outside the planning target volume (PTV) to potentially reduce risk of secondary tumor induction. Methods A system for automated planning (AUTOplans) for VS patients was set up. The goal of AUTO- planning was to reduce the dose bath, including the occurrence of high dose spikes leaking from the PTV into normal tissues, without worsening PTV coverage, OAR doses, or treatment time. For 20 VS patients treated with 1x12 Gy, the AUTOplan was compared with the plan generated with conventional, manual trial-and-error planning (MANplan). Results With equal PTV coverage, AUTOplans showed clinically negligible differences with MANplans in OAR sparing (largest mean difference for all OARs: ΔD2% = 0.2 Gy). AUTOplan dose distributions were more compact: mean/maximum reductions of 23.6/53.8% and 9.6/ 28.5% in patient volumes receiving more than 1 or 6 Gy, respectively (p

Technical developments allowed stereotactic body radiation therapy (SBRT) to deliver effective doses of irradiation with high precision in a small number of fractions. This paper reviews the role of SBRT for liver metastases, hepatocellular carcinoma and cholangiocarcinoma, paying special attention to patient eligibility and treatment outcomes regarding local control, toxicity and quality of life. As well as discussing specific issues of these different tumors, such as the presence of underlying liver cirrhosis and the impact on toxicity, it outlines the limitations of SBRT and future areas of development and research. (C) 2016 Elsevier Ltd. All rights reserved.

IntroductionFor patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12–15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33–35 months.Methods and analysisThis study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3–4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures.Ethics and disseminationEthics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences.Trial registration numberNCT03307538; Pre-results.

PURPOSE: To quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and to examine whether outcomes are affected by SBRT dosing regimen. METHODS AND MATERIALS: We identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (100 Gy(10)). Comparisons were made using logerank testing. RESULTS: Thirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, logerank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy(10) (3-year local control 93%) than for those treated with BEDs of 100 Gy(10) (3-year local control 65%, P < .001). CONCLUSIONS: Stereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a doseeresponse relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy(10) are utilized.

Purpose: To validate a novel deformable image registration (DIR) method for online adaptation of planning organ-at-risk (OAR) delineations to match daily anatomy during hypo-fractionated RT of abdominal tumors. Materials and methods: For 20 liver cancer patients, planning OAR delineations were adapted to daily anatomy using the DIR on corresponding repeat CTs. The DIRs accuracy was evaluated for the entire cohort by comparing adapted and expert-drawn OAR delineations using geometric (Dice Similarity Coefficient (DSC), Modified Hausdorff Distance (MHD) and Mean Surface Error (MSE)) and dosimetric (D-max and D-mean) measures. Results: For all OARs, DIR achieved average DSC, MHD and MSE of 86%, 2.1 mm, and 1.7 mm, respectively, within 20 s for each repeat CT. Compared to the baseline (translations), the average improvements ranged from 2% (in heart) to 24% (in spinal cord) in DSC, and 25% (in heart) to 44% (in right kidney) in MHD and MSE. Furthermore, differences in dose statistics (D-max, D-mean and D-2%) using delineations from an expert and the proposed DIR were found to be statistically insignificant (p amp;gt; 0.01). Conclusion: The validated DIR showed potential for online-adaptive radiotherapy of abdominal tumors as it achieved considerably high geometric and dosimetric correspondences with the expert-drawn OAR delineations, albeit in a fraction of time required by experts. (C) 2018 The Authors. Published by Elsevier B.V. Funding Agencies|Accuray Incorportated; Erasmus MC Cancer Institute

Background: Stereotactic body radiotherapy (SBRT) has become the standard of care for medically inoperable patients with peripherally located, early stage non-small cell lung cancer (NSCLC), and for those refusing surgical resection. Despite the availability of national and international guidelines, there exists substantial variability in many aspects of SBRT practice. Methods: The ESTRO ACROP guideline is based on a questionnaire covering all aspects of SBRT implementation and practice (n = 114 items). The questionnaire was answered by the 11 faculty members of the ESTRO course "Clinical practice and implementation of image-guided SBRT" and their 8 institutions. Results: Agreement by >50% of the institutions was achieved in 72% of all items. Only 8/57 technologies and techniques were identified as mandatory for SBRT while 32/57 were considered as optional. In contrast, quality-assurance related elements were considered as mandatory in 12/24 items. A consensus of risk-adapted SBRT fractionation was achieved with 3 x 15 Gy for peripherally located lesions and 4 x 12 Gy (PTV D95-D99; D-max

Aim: To investigate whether the impact of dose escalation in our patient population represented an improvement in local control without increasing treatment related toxicity. Materials and methods: A cohort of consecutive patients with colorectal liver metastases treated with stereotactic body radiation therapy (SBRT) between December 2002 and December 2013 were eligible for this study. Inclusion criteria were a Karnofsky performance status ≥80% and, according to the multidisciplinary tumor board, ineligibility for surgery or radiofrequency ablation. Exclusion criteria were a lesion size>6. cm, more than 3 metastases, and treatment delivered with other fractionation scheme than 3 times 12.5. Gy or 16.75. Gy prescribed at the 65-67% isodose. To analyze local control, CT or MRI scans were acquired during follow-up. Toxicity was scored using the Common Toxicity Criteria Adverse Events v4.0. Results: A total of 40 patients with 55 colorectal liver metastases were included in this study. We delivered 37.5. Gy to 32 lesions, and 50.25. Gy to 23 lesions. Median follow-up was 26 and 25 months for these two groups. Local control at 2 and 3 years was 74 and 66% in the low dose group while 90 and 81% was reached in the high dose group. No significant difference in local control between the two dose fractionation schemes could be found. Grade 3 toxicity was limited and was not increased in the high dose group. Conclusions: SBRT for colorectal liver metastases offers a high chance of local control at long term. High irradiation doses may contribute to enhance this effect without increasing toxicity.

To investigate how dose distributions for liver stereotactic body radiation therapy (SBRT) can be improved by using automated, daily plan reoptimization to account for anatomy deformations, compared with setup corrections only.For 12 tumors, 3 strategies for dose delivery were simulated. In the first strategy, computed tomography scans made before each treatment fraction were used only for patient repositioning before dose delivery for correction of detected tumor setup errors. In adaptive second and third strategies, in addition to the isocenter shift, intensity modulated radiation therapy beam profiles were reoptimized or both intensity profiles and beam orientations were reoptimized, respectively. All optimizations were performed with a recently published algorithm for automated, multicriteria optimization of both beam profiles and beam angles.In 6 of 12 cases, violations of organs at risk (ie, heart, stomach, kidney) constraints of 1 to 6 Gy in single fractions occurred in cases of tumor repositioning only. By using the adaptive strategies, these could be avoided (1 Gy). For 1 case, this needed adaptation by slightly underdosing the planning target volume. For 2 cases with restricted tumor dose in the planning phase to avoid organ-at-risk constraint violations, fraction doses could be increased by 1 and 2 Gy because of more favorable anatomy. Daily reoptimization of both beam profiles and beam angles (third strategy) performed slightly better than reoptimization of profiles only, but the latter required only a few minutes of computation time, whereas full reoptimization took several hours.This simulation study demonstrated that replanning based on daily acquired computed tomography scans can improve liver stereotactic body radiation therapy dose delivery.

To propose a novel treatment approach, designated VMAT+, involving addition of5 IMRT beams with computer-optimized non-coplanar orientations to VMAT, and evaluate it for liver Stereotactic Body Radiation Therapy (SBRT). VMAT+ is investigated as an alternative for (1) coplanar VMAT and (2) multi-beam non-coplanar treatment.For fifteen patients with liver metastases, VMAT+ plans were compared with (1) dual-arc VMAT and (2) 25-beam, non-coplanar treatment with computer-optimized beam orientations (25-NCP). All plans were generated fully automatically for delivery of the highest feasible tumor Biologically Effective Dose (BED). OAR doses, intermediate-dose-spillage, dose-compactness, and measured delivery times were evaluated.With VMAT+ the maximum achievable tumor BED was equal to that of 25-NCP. Conversely, VMAT resulted in a lower tumor BED in 5 patients. Compared to VMAT, VMAT+ yielded significant dose reductions in OARs. Intermediate-dose-spillage and dose-compactness were significantly improved by 9.8% and 17.3% (p≤0.002), respectively. Treatment times with VMAT+ were only enhanced by 4.1min on average, compared to VMAT (8.4min). Improvements in OAR sparing with 25-NCP, compared to VMAT+, were generally modest and/or statistically insignificant, while delivery times were on average 20.5min longer.For liver SBRT, VMAT+ is equivalent to time-consuming treatment with 25 non-coplanar beams in terms of achievable tumor BED. Compared to VMAT, OAR sparing and intermediate-dose-spillage are significantly improved, with minor increase in delivery time.

Purpose: To compare pathology macroscopic tumor dimensions with magnetic resonance imaging (MRI) measurements and to establish the microscopic tumor extension of colorectal liver metastases. Methods and Materials: In a prospective pilot study we included patients with colorectal liver metastases planned for surgery and eligible for MRI. A liver MRI was performed within 48 hours before surgery. Directly after surgery, an MRI of the specimen was acquired to measure the degree of tumor shrinkage. The specimen was fixed in formalin for 48 hours, and another MRI was performed to assess the specimen/tumor shrinkage. All MRI sequences were imported into our radiotherapy treatment planning system, where the tumor and the specimen were delineated. For the macroscopic pathology analyses, photographs of the sliced specimens were used to delineate and reconstruct the tumor and the specimen volumes. Microscopic pathology analyses were conducted to assess the infiltration depth of tumor cell nests. Results: Between February 2009 and January 2010 we included 13 patients for analysis with 21 colorectal liver metastases. Specimen and tumor shrinkage after resection and fixation was negligible. The best tumor volume correlations between MRI and pathology were found for T1-weighted (w) echo gradient sequence (r s = 0.99, slope = 1.06), and the T2-w fast spin echo (FSE) single-shot sequence (r s = 0.99, slope = 1.08), followed by the T2-w FSE fat saturation sequence (r s = 0.99, slope = 1.23), and the T1-w gadolinium-enhanced sequence (r s = 0.98, slope = 1.24). We observed 39 tumor cell nests beyond the tumor border in 12 metastases. Microscopic extension was found between 0.2 and 10 mm from the main tumor, with 90% of the cases within 6 mm. Conclusions: MRI tumor dimensions showed a good agreement with the macroscopic pathology suggesting that MRI can be used for accurate tumor delineation. However, microscopic extensions found beyond the tumor border indicate that caution is needed in selecting appropriate tumor margins.

Purpose: We investigated the potentials and limitations of guiding liver stereotactic body radiation therapy (SBRT) set-up on liver-implanted fiducial markers. Methods and Materials: Twelve patients undergoing compression-supported SBRT in a stereotactic body frame received fluoroscopy at treatment preparation and before each treatment fraction. In fluoroscopic videos we localized the markers and diaphragm tip at expiration and the spine (measurements on free-breathing and abdominal compression). Day-to-day displacements, rotations (markers only), and deformations were determined. Marker guidance was compared to conventional set-up strategies in treatment set-up simulations. Results: For compression, day-to-day motion of markers with respect to their centers of mass (COM) was sigma = 0.9 mm (random error SD), Sigma = 0.4 mm (systematic error SD), and

Purpose: Stereotactic body radiation therapy (SBRT) provides a high local control rate for primary and metastatic liver tumors. The aim of this study is to assess the impact of this treatment on the patient's quality of life. This is the first report of quality of life associated with liver SBRT. Methods and Materials: From October 2002 to March 2007, a total of 28 patients not suitable for other local treatments and with Karnofsky performance status of at least 80% were entered in a Phase I-II study of SBRT for liver tumors. Quality of life was a secondary end point. Two generic quality of life instruments were investigated, EuroQol-5D (EQ-5D) and EuroQoL-Visual Analogue Scale (EQ-5D VAS), in addition to a disease-specific questionnaire, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C-30). Points of measurement were directly before and 1, 3, and 6 months after treatment. Mean scores and SDs were calculated. Statistical analysis was performed using paired-samples t-test and Student t-test. Results: The calculated EQ-5D index, EQ-51) VAS and QLQ C-30 global health status showed that mean quality of life of the patient group was not significantly influenced by treatment with SBRT; if anything, a tendency toward improvement was found. Conclusions: Stereotactic body radiation therapy combines a high local control rate, by delivering a high dose per fraction, with no significant change in quality of life. Multicenter studies including larger numbers of patients are recommended and under development. (c) 2008 Elsevier Inc.

Purpose: To investigate whether automatically optimized coplanar, or non-coplanar beam setups improve intensity modulated radiotherapy (IMRT) treatment plans for stereotactic body radiotherapy (SBRT) of liver tumors, compared to a reference equi-angular IMRT plan. Methods: For a group of 13 liver patients, an in-house developed beam selection algorithm (Cycle) was used for generation of 3D-CRT plans with either optimized coplanar-, or non-coplanar beam setups. These 10 field, coplanar and non-coplanar setups, and an 11 field, equi-angular coplanar reference setup were then used as input for generation of IMRT plans. For all plans, the PTV dose was maximized in an iterative procedure by increasing the prescribed PTV dose in small steps until further increase was prevented by constraint violation(s). Results: For optimized non-coplanar setups, D-PTV,D- (max) increased by on average 30% (range 8-64%) compared to the corresponding reference IMRT plan. Similar increases were observed for D-PTV, 99% and gEUD(a). For optimized coplanar setups, mean PTV dose increases were only similar to 4%. After re-scaling all plans to the clinically applied dose, optimized non-coplanar configurations resulted in the best sparing of organs at risk (healthy liver, spinal cord, bowel). Conclusion: Compared to an equi-angular beam setup, computer optimized non-coplanar setups do result in substantial improvements in IMIRT plans for SBRT of liver tumors. (C) 2008 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 88 (2008) 376-381.

Purpose: To investigate in a three-dimensional framework the effectiveness and reproducibility of reducing the respiratory motion of liver tumors using abdominal compression in a stereotactic body frame. Methods and Materials: A total of 12 patients with liver tumors, who were treated with stereotactic body radiotherapy, were included in this study. These patients had three gold fiducial markers implanted in the healthy liver tissue surrounding the tumor. Fluoroscopic videos were acquired on the planning day and before each treatment fraction to visualize the motion of the fiducial markers during free breathing and varying levels of abdominal compression. Software was developed to track the fiducial markers and measure their excursions. Results: Abdominal compression reduced the patient group median excursion by 62% in the craniocaudal and 38% in the anteroposterior direction with respect to the median free-breathing excursions. In the left-right direction, the median excursion increased 15% (maximal increase 1.6 mm). The median residual excursion was 4.1 mm in the craniocaudal, 2.4 mm in the anteroposterior, and 1.8 mm in the left-right direction. The mean excursions were reduced by compression to

Purpose Recently we have demonstrated that our in-house developed algorithm for automated plan generation for fully non-coplanar SBRT of liver patients (designated Cycle) yields plans that are superior to conventionally generated plans of experienced dosimetrists. Here we use Cycle in the comparison of plans with prescription isodoses of 65% or 80% of the isocentre dose. Methods Plans were generated using CT-data of 15 previously treated patients. For each patient, both for the 65%- and the 80% strategy, Cycle was used to generate a plan with the maximum isocentre dose, D isoc , while strictly obeying a set of hard constraints for the organs at risk (OAR). Plans for the two strategies were compared using D isoc , D PTV,99% (the minimum dose delivered to 99% of the PTV), and the generalised equivalent uniform dose, gEUD PTV ( a ), for several values of the parameter a . Moreover, for the OARs, the distance to the constraint values was analysed. Results The 65% strategy resulted in treatment plans with a higher D isoc (average 17.6%, range 7.6–31.1%) than the 80% strategy, at the cost of a somewhat lower D PTV,99% (average −2.0%, range −9.6% to 9.3%). On average, voxels with a dose in the 65% strategy, lower than the minimum PTV dose in the 80% strategy, were within 0.2cm from the PTV surface. For a ⩾−10, the 65% strategy yielded on average a significantly ( P PTV ( a ) than the 80% strategy, whereas for highly negative a -values the 80% approach was slightly better, although not significantly. Large variations between patients were observed. Generally, for the OAR the approach to the constraint levels was similar for the two strategies. Conclusion On average, PTV dose delivery is superior with the 65% strategy. However, apart from the isocentre dose, for each applied PTV dose parameter at least one patient would have been better off with the 80% dose prescription strategy.

Purpose: To investigate whether computer-optimized fully noncoplanar beam setups may improve treatment plans for the stereotactic treatment of liver tumors. Methods: An algorithm for automated beam orientation and weight selection (Cycle) was extended for noncoplanar stereotactic treatments. For 8 liver patients previously treated in our clinic using a prescription isodose of 65%, Cycle was used to generate noncoplanar and coplanar plans with the highest achievable minimum planning target volume (PTV) dose for the clinically delivered isocenter and mean liver doses, while not violating the clinically applied hard planning constraints. The clinical and the optimized coplanar and noncoplanar plans were compared, with respect to D PTV,99% , the dose received by 99% of the PTV, the PTV generalized equivalent uniform dose (gEUD), and the compliance with the clinical constraints. Results: For each patient, the ratio between D PTV,99% and D isoc , and the gEUD −5 and gEUD −20 values of the optimized noncoplanar plan were higher than for the clinical plan with an average increase of respectively 18.8% (range, 7.8–24.0%), 6.4 Gy (range, 3.4–11.8 Gy), and 10.3 Gy (range, 6.7–12.5). D PTV,99% /D isoc , gEUD −5 , and gEUD −20 of the optimized noncoplanar plan was always higher than for the optimized coplanar plan with an average increase of, respectively, 4.5% (range, 0.2–9.7%), 2.7 Gy (range, 0.6–9.7 Gy), and 3.4 Gy (range, 0.6–9.9 Gy). All plans were within the imposed hard constraints. On average, the organs at risk were better spared with the optimized noncoplanar plan than with the optimized coplanar plan and the clinical plan. Conclusions: The use of automatically generated, fully noncoplanar beam setups results in plans that are favorable compared with coplanar techniques. Because of the automation, we found that the planning workload can be decreased from 1 to 2 days to 1 to 2 h.

The feasibility, toxicity and tumor response of stereotactic body radiation therapy (SBRT) for treatment of primary and metastastic liver tumors was investigated. From October 2002 until June 2006, 25 patients not suitable for other local treatments were entered in the study. In total 45 lesions were treated, 34 metastases and 11 hepatocellular carcinoma (HCC). Median follow-up was 12.9 months (range 0.5-31). Median lesion size was 3.2 cm (range 0.5-7.2) and median volume 22.2 cm3 (range 1.1-322). Patients with metastases, HCC without cirrhosis, and HCC4 cm with cirrhosis were mostly treated with 3 x 12.5 Gy. Patients with HCCor =4 cm and cirrhosis received 5 x 5 Gy or 3 x 10 Gy. The prescription isodose was 65%. Acute toxicity was scored following the Common Toxicity Criteria and late toxicity with the SOMA/LENT classification. Local failures were observed in two HCC and two metastases. Local control rates at 1 and 2 years for the whole group were 94% and 82%. Acute toxicity gradeor =3 was seen in four patients; one HCC patient with Child B developed a liver failure together with an infection and died (grade 5), two metastases patients presented elevation of gamma glutamyl transferase (grade 3) and another asthenia (grade 3). Late toxicity was observed in one metastases patient who developed a portal hypertension syndrome with melena (grade 3). SBRT was feasible, with acceptable toxicity and encouraging local control. Optimal dose-fractionation schemes for HCC with cirrhosis have to be found. Extreme caution should be used for patients with Child B because of a high toxicity risk.

The liver is a common site of metastatic disease. Systemic therapy is most frequently the preferred therapy for patients with liver metastases, but surgical excision or tumor ablation strategies are often considered for patients with limited disease and favorable histology. Advances in radiation therapy technology made it possible to deliver potent biological doses to limited volumes of the liver with high precision in a few fractions. This method is known as stereotactic body radiation therapy (SBRT). Low-dose radiation therapy administered to the whole-liver radiation therapy (WLRT) is not regularly used for palliation of patients with massive liver metastases. The purpose of this review is to present an update of the most recent literature on SBRT and WLRT.Recently published studies confirm the role of SBRT as a highly effective treatment for ablation of liver metastases. The toxicity related to the therapy is mild or moderate. This treatment is indicated for patients with limited burden of intrahepatic and extrahepatic disease. Low-dose WLRT is a useful treatment for symptom palliation in patients with end-stage cancer and diffuse metastatic infiltration of the liver which became refractory to systemic treatment.SBRT and WLRT are highly efficient in the treatment of patients with liver metastases. However, prospective randomized trials in radiation therapy for liver metastases are warranted.

Purpose: To assess day-to-day differences between planned and delivered target volume (TV) and organ-at-risk (OAR) dose distributions in liver stereotactic body radiation therapy (SBRT), and to investigate the dosimetric impact of setup corrections. Methods and Materials: For 14 patients previously treated with SBRT, the planning CT scan and three treatment scans (one for each fraction) were included in this study. For each treatment scan, two dose distributions were calculated: one using the planned setup for the body frame (no correction), and one using the clinically applied (corrected) setup derived from measured tumor displacements. Per scan, the two dose distributions were mutually compared, and the clinically delivered distribution was compared with planning. Doses were recalculated in equivalent 2-Gy fraction doses. Statistical analysis was performed with the linear mixed model. Results: With setup corrections, the mean loss in TV coverage relative to planning was 1.7%, compared with 6.8% without corrections. For calculated equivalent uniform doses, these figures were 2.3% and 15.5%, respectively. As for the TV, mean deviations of delivered OAR doses from planning were small (between -0.4 and +0.3 Gy), but the spread was much larger for the OARs. In contrast to the TV, the mean impact of setup corrections on realized OAR doses was close to zero, with large positive and negative exceptions. Conclusions: Daily correction of the treatment setup is required to obtain adequate TV coverage. Because of day-to-day patient anatomy changes, large deviations in OAR doses from planning did occur. On average, setup corrections had no impact on these doses. Development of new procedures for image guidance and adaptive protocols is warranted. (C) 2009 Elsevier Inc.

Purpose: To quantify potential benefits of CTV-to-PTV margin reduction for SBRT of liver tumours, as allowed by enhanced treatment precision. Materials and methods: For 14 patients plans were generated for the clinical margin and for 3 tighter margins. An in-house developed algorithm was used to optimise beam directions, shapes, and weights for generation of the plan with the highest isocenter dose (D-iso), while keeping the minimum PTV dose at least 65% x D-iso and strictly adhering to all imposed hard OAR constraints. Each plan contains 10 optimal beam directions, automatically selected from up to 252 coplanar and non-coplanar input directions. Results: Apart from the expected tumour dose escalation (D-iso, EUDPTV, EUDPTV) with decreasing margin, a simultaneous improved sparing of the normal liver (D33%, D50%, D-mean) was also observed. The smaller the margin was, the bigger both effects were. For renormalized plans with Diso equal to the clinical value (3 x 19.2 Gy), and a margin reduction of 50% (2.5 mm laterally, 5 mm longitudinally), normal liver D33% and D50% reduced on average by 22% (maximum 38%). and 26% (maximum 47%), respectively. Conclusions: Using an algorithm for beam direction, shape and weight optimisation, large increases in the therapeutic ratio of liver plans could be obtained for reduced margins. (C) 2007 Elsevier Ireland Ltd. All rights reserved.