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Purpose: Substantiating data guiding clinical decision making in locally recurrent rectal cancer (LRRC) is lacking, specifically in target volume (TV) definition for chemoradiotherapy (CRT). A case-by-case review of local re-recurrences (re-LRRC) after multimodal treatment for LRRC was performed, to determine location of re-LRRC and assess whether treatment could have been improved., Methods: All patients treated with curative intent for LRRC at the Catharina Hospital Eindhoven from October 2016 onwards, in whom complete imaging of (re-)LRRC and radiotherapy was available, were retrieved. Patients were discussed in plenary meetings with expert colorectal surgeons, radiation oncologists and radiologists. Each case was classified based on re-LRRC location, whether it was in accordance with the (current) radiotherapy protocol, and whether multimodal management would have been different in retrospect., Results: Thirty-three cases were discussed. LRRC treatment was deemed suboptimal in 17/33 patients, due to different target volumes (13/17) and/or different surgery (9/17). 15/33 (46 %) of re-LRRC developed in-field of the prior radiotherapy TV, possibly showing RT-resistant disease. Other re-LRRCs developed out-field (n = 5, 15 %), marginally (n = 6, 18 %), or in a combined fashion (n = 7, 21 %). In retrospect, 48 % of cases were irradiated in line with current TV recommendations. TVs of 13/33 cases would have been altered if irradiated today., Conclusion: This study highlights room for improvement within current standard-ofcare treatment for LRRC. Different surgical management or TVs may have improved outcome in up to half of discussed cases. Further delineation guideline development, incorporating the results from this study, may improve oncological outcome, specifically local control, for LRRC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To evaluate acute toxicity at 6 months after stereotactic body radiotherapy (SBRT) in patients with oligometastatic cancer within the OligoCare cohort., Material and Methods: OligoCare is a prospective, registry-based, single-arm, observational study that aims to report prospective real-world data of patients with oligometastases from solid cancer treated with SBRT (NCT03818503). Primary tumor included non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC), and prostate cancer (PC). This analysis addresses a secondary endpoint of the trial, acute toxicity within 6 months after SBRT., Results: Out of 1,597registered patients, 1'468 patients were evaluated for acute toxicity. Globally, 290 (20 %) had NSCLC primary disease, 227 (16 %) had BC, 293 (20 %) had CRC, and 658 (45 %) had PC. Concomitant systemic treatment was administered in 527 (35.9 %) patients. According to the EORTC/ESTRO oligometastatic disease (OMD) classification, 828 (56 %) patients had de novo OMD, 464 (32 %) repeat OMD, and 176 (12 %) induced OMD. Acute grade ≥ 3 SBRT related adverse events were reported in 8 (0.5 %) patients, including 2 (0.1 %) fatal AEs. In particular, 6 (0.4 %) grade 3 events were: 1 empyema, 1 pneumonia, 1 radiation pneumonitis, 1 radiation skin injury, 1 decreased appetite, and 1 bone pain. Among those 2 occurred in NSCLC patients, 2 in BC patients, and 1 in CRC and PC patients each. The two (0.1 %) grade 5 toxicity were represented by: pneumonitis and cerebral hemorrhage., Conclusion: OligoCare is the largest prospective registry cohort on oligometastatic disease. Acute toxicity within 6 months was low, confirming the safety of SBRT in the treatment of oligometastases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Introduction: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation., Materials and Methods: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC)., Results: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions., Conclusion: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: BAJF received grants from Accuray, AIRC, IBA and Fondazione IEO-CCM, lecture payments/honoraria from Bayer, Accuray, Astellas, IBA, IPSEN, Astra Zeneca, Tecnologie Avanzate, Recordati, and Novartis, and has board appointments at Astra Zeneca, Bayer, and Seagen. MG and PO are PIs of the ESTRO-EORTC 1811-E²-RADIatE OligoCare trial. MG is president-elect of ESTRO., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the technical and clinical feasibility of the phase I Hybrid trial (NCT01933568), combining SBRT of the primary tumor (PT) and fractionated radiotherapy (FRT) to the lymph nodes (LN)., Materials and Methods: Ten patients with stage III NSCLC with a peripheral PT < 5 cm were prospectively selected. The EQD 2 corrected normal tissue dose parameters of the FRT plan of 24×2.75 Gy to PT and 24×2.42 Gy to LN (IMRT) was compared with 3×18 Gy on the PT and 24×2.42 Gy on the LN (VMAT) using a Wilcoxon signed-rank test. To anticipate differential motion between PT and LN, worst-case scenarios for OAR were calculated. Electronic portal imaging device (EPID) dosimetry analysis was performed to rule out dosimetric errors during delivery., Results: The Hybrid plans revealed a significant decrease of esophagus EUD n = 0.13, lung V5 and V20 and a significant increase in D max of the PRV of the mediastinal envelope. Plans were robust against differential motion of 5 mm between PT and LN in 8 patients and failed in 2 patients due to spinal cord constraints. Average pass rates were ≥87% for EPID dosimetry., Conclusions: SBRT and FRT could be combined within the given OAR constraints. Safety will be assessed in the Hybrid trial., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: The EORTC 22113-08113 LungTech trial assesses the safety and efficacy of SBRT for centrally located NSCLC. To insure protocol compliance an extensive RTQA procedure was implemented., Methods: Twelve centres were audited using a CIRS008A phantom. The phantom was scanned using target inserts of 7.5 mm and 12.5 mm radius in static condition. For the 7.5 mm insert a 4DCT was acquired while moving according to a cos 6 function. Treatment plans were measured using film and an ionization chamber. Wilcoxon's signed-rank tests were performed to compare the three plans across institutions. A Spearman correlation was calculated to evaluate the influence of factors such as PTV, slice thickness and total number of monitor units on the dosimetric results., Results: The reference output dose median [min, max] variation was 0.5% [-1.1, +1.5]. The median deviations between chamber doses and point-planned doses were 1.8% [-0.1; 6.7] for the 7.5 mm and 1.1% [-2.8; 5.0] for the 12.5 mm sphere in static situation and 3.2% [-3.2; 15.7] for the dynamic situation. Film gamma median pass rates were 92.0% [68.0, 99.0] for 7.5 mm static, 96.2% [73.0, 99.0] for 12.5 mm static and 71.0% [40.0, 99.0] for 7.5 mm dynamic. Wilcoxon's signed-rank tests showed that the dynamic irradiations resulted in significantly lower gamma pass rates compared to the 12.5 mm static plan (p = 0.001). The total number of MUs per plan was correlated to both film and IC results., Conclusion: An end-to-end audit was successfully performed, revealing important variations between institutions especially in dynamic irradiations. This shows the importance of dosimetry audits and the potentials for further technique and methodology improvements., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To investigate if a local dose-effect (LDE) relationship for perfusion loss improves the NTCP model fit for SBRT induced radiation pneumonitis (RP) compared to conventional LDEs., Methods and Materials: Multi-institutional data of 1015 patients treated with SBRT were analyzed. Dose distributions were converted to NTD with α/β = 3 Gy. The Lyman-Kutcher-Burman NTCP model was fitted to the incidence grade ≥2 RP by maximum likelihood estimation with mean lung dose (MLD), equivalent uniform doses (EUD) using three LDE functions (power-law (EUD power ), logistic with 2 free parameters (EUD log-free ) and logistic with fixed parameters describing local perfusion loss (EUD Perfusion )) and volume above a threshold dose (V x ). Models were compared with the Akaike weights (Aw) derived from the Akaike information criteria (AIC)., Results: The median time to grade ≥2 RP was 4.2 months and plateaued after 17 months at 5.4%. A strong dose-effect relationship for RP incidence was observed. The EUD Perfusion based NTCP model had the lowest AIC. The Aw were 0.53, 0.19, 0.11, 0.11, 0.05 for the EUD Perfusion , V x , MLD, EUD log-free and EUD power LDEs respectively., Conclusion: A LDE for perfusion loss provided modest improvement in NTCP model fit for SBRT induced radiation pneumonitis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: PARP inhibitors are currently evaluated in combination with radiotherapy and/or chemotherapy. As sensitizers, PARP inhibitors are active at very low concentrations therefore requiring highly sensitive pharmacodynamic (PD) assays. Current clinical PD-assays partly fail to provide such sensitivities. The aim of our study was to enable sensitive PD evaluation of PARP inhibitors for clinical sensitizer development., Material and Methods: PBMCs of healthy individuals and of olaparib and radiotherapy treated lung cancer patients were collected for ELISA-based PD-assays., Results: PAR-signal amplification by ex vivo irradiation enabled an extended quantification range for PARP inhibitory activities after ex vivo treatment with inhibitors. This "radiation-enhanced-PAR" (REP) assay provided accurate IC50 values thereby also revealing differences among healthy individuals. Implemented in clinical radiotherapy combination Phase I trials, the REP-assay showed sensitive detection of PARP inhibition in patients treated with olaparib and establishes strong PARP inhibitory activities at low daily doses., Conclusions: Combination trials of radiotherapy and novel targeted agent(s) often require different and more sensitive PD assessments than in the monotherapy setting. This study shows the benefit and relevance of sensitive and adapted PD-assays for such combination purposes and provides proof of clinically relevant cellular PARP inhibitory activities at low daily olaparib doses., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT)., Methods: 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively., Results: Median follow-up was 34.8months. Two year Kaplan-Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009-197, HR=1.005, p-value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003-70, HR=1.025, p-value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death., Conclusions: Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: To determine a dose-effect relation for radiation induced rib fractures after stereotactic body radiation therapy (SBRT) in early stage non-small cell lung cancer (NSCLC). Automatic rib delineation has enabled the analysis of a large patient group., Material and Methods: Four-hundred and sixty-six patients with stage I/II NSCLC received SBRT with a median of 54Gy in 3 fractions. The optimal EQD2-corrected dose parameter to predict (a)symptomatic fractures was found using Cox regression. Three normal tissue complication probability (NTCP) models based on this optimal parameter were constructed: (1) at a median follow up (FU) of 26months, (2) for all data, with time to toxicity taken into account and (3) at a FU of 26months, excluding low dose ribs., Results: The median time to fracture was 22 (range 5-51) months. Maximum rib dose best predicted fractures. The TD 50 (dose with 50% complication) of the second NTCP model was 375Gy. The TD 50 was significantly higher for the other models indicating an under-estimation of the dose effect at the median follow-up time and/or when excluding low dose ribs., Conclusions: The risk of symptomatic rib fractures after SBRT was significantly correlated to dose, and was <5% at 26months when D max <225Gy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP)., Materials and Methods: Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared., Results: Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar., Conclusions: Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To quantify the target delineation variability in peripheral early stage lung cancer treated with SBRT and derive corresponding margins., Methods and Materials: Sixteen early stage NSCLC GTV's were delineated by 11 radiation oncologists from 4 institutes. A median surface was computed and the delineation variation perpendicular to this surface was measured (local standard deviation=SD). The overall target delineation variability was quantified by the root-mean-square (rms) of the local SD. The required margin was determined by expanding all delineations to encompass the median surface, where after the underlying probability distribution was modeled by a number of uncorrelated 'pimples-and-dimples'., Results: The overall target delineation variability was 2.1mm (rms). Institute I-III delineated significantly smaller volumes than institute IV, yielding target delineation variabilities of 1.2mm and 1.8mm respectively. The margin required to obtain 90% coverage of the delineated contours was 3.4mm and 5.9mm respectively. The factor α in M=αΣ required to calculate adequate margins was 2.8-3.2, which is larger than the 2.5 found for 3D rigid target displacement., Conclusion: A relatively small target delineation uncertainty of 1.2mm-1.8mm (1SD) was observed for early stage NSCLC. A 3.4-5.9mm GTV-to-PTV margin was required to account for this uncertainty alone, ignoring other sources of geometric uncertainties., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Large tumor motion leads to large treatment volumes with an Internal Target Volume (ITV) based approach, whereas mid-ventilation (MidV) based Planning Target Volumes (PTV) margins typically lead to smaller treatment volumes. The purpose of this study was to evaluate the MidV approach on clinical outcome data of Stereotactic Body Radiotherapy (SBRT) in NSCLC., Methods and Materials: 297 patients with 314 peripheral tumors treated from 2006 to 2012 were retrospectively analyzed. In all patients a 4D-CT was acquired and the MidV-CT-scan was selected. Tumor amplitudes were determined in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction, to calculate patient specific PTV margins., Results: The median LR, CC and AP tumor amplitudes were 2mm (0-16 mm), 4mm (0-39 mm) and 3mm (0-18 mm), respectively, yielding a median CTV-to-PTV margin of 8mm. An ITV+5mm based PTV margin would have been bigger in 47% of the patients. After a median follow up of 22 months, local recurrence occurred in six patients (2%). Two year LC and OS were 98% and 67%, respectively., Conclusions: Using the MidV approach combined with online image guidance an excellent LC of 98% was established with SBRT. This provides clinical support that incorporating respiratory motion into the PTV margin is a safe approach., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To assess toxicity and feasibility of reirradiation with stereotactic body radiotherapy (SBRT) after prior lung SBRT for primary lung cancer or lung metastases., Patients and Materials: Twenty-nine patients reirradiated with SBRT on 32 lung lesions (11 central, 21 peripheral) were retrospectively reviewed. Median follow-up time was 12 months (range 1-97). The primary endpoint was toxicity, secondary endpoints were local control and overall survival time. Toxicity was scored according to the NCI-CTCAE version 3., Results: Grade 3-4 toxicity was scored 14 times in eight patients. Three patients died because of massive bleeding (grade 5). Larger clinical target volumes (CTV) and central tumour localization were associated with more severe toxicity. There was no correlation between mean lung dose (MLD) and lung toxicity. Local control at 5 months after reirradiation was 52%, as assessed by CT-scan (n=12) or X-thorax (n=3). A larger CTV was associated with poorer local control. Kaplan-Meier estimated 1- and 2-year survival rates were 59% and 43%, respectively., Conclusions: Reirradiation with SBRT is feasible although increased risk of toxicity was reported in centrally located tumours. Further research is warranted for more accurate selection of patients suitable for reirradiation with SBRT., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Dose painting by numbers lacks the conventional margin approach for geometric uncertainties. Moreover, the DVH is unable to assess the geometric accuracy of a non-uniform dose distribution because spatial information is lost. In this work we present tools for planning and evaluation of non-uniform treatment dose which take geometric uncertainties into account., Methods and Materials: The IMRT optimization functions in the Pinnacle treatment planning software were extended to allow non-uniform prescription dose distributions, e.g., derived from a PET image set. Also, explicit handling of systematic and random geometric uncertainties was incorporated in the functions, enabling confidence level based probabilistic treatment planning. For plan evaluation the concept of ΔVH was introduced, which is the volume histogram of the difference between planned and prescribed doses. Probability distributions for ΔVH points were estimated using Monte Carlo methods. As a demonstration of these methods, two examples are presented; one plan for a lung cancer patient and one for a tumor in the head-and-neck region., Results: Dose distributions were obtained using the PET SUV, while allowing for geometric uncertainties. Optimization was performed such that the ΔVH evaluation indicated a 90% confidence of having under-dosage less than 5% of prescription dose maximum in 99% of the tumor volume. This corresponds to the clinical target constraint for margin based planning with uniform dose prescription., Conclusions: Clinical treatment planning tools were extended to allow non-uniform prescription. For planning we introduced confidence level based probabilistic optimization with non-uniform target dose, while confidence levels of ΔVH points summarize the probability of proper target coverage., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)