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Background: Cognitive decline is an arising concern in patients who need cranial irradiation. We used the pooled longitudinal individual patient data of two phase III trials: NCT01780675 and PREMER to investigate whether hippocampal avoidance (HA)-PCI is associated with improved self-reported cognitive functioning (SRCF) compared with PCI without increasing brain metastases (BM) development within the HA area., Methods: Patients with stage I-IV small cell lung cancer (SCLC) were randomized to PCI or HA-PCI. SRCF was assessed and contrast enhanced brain magnetic resonance imaging (MRI) was performed at baseline and up to 24 months follow-up. SRCF and BM incidence after (HA)-PCI were compared between arms. Self reported cognitive impairment was defined as SCRF < 75., Results: In total, 318 patients were randomized. Longitudinal generalized estimating equation (GEE) analysis showed that HA-PCI neither had a significant impact on SRCF (β = 1.41, p = 0.52) nor on cognitive impairment (OR 0.81, 95 %CI 0.53-1.25, p = 0.34). The median follow up was 41.7 (95 %CI 35.7-47.6) months, during which 61 patients developed BM (PCI arm: 30, HA-PCI arm: 31, p = 0.9). BM site was solitary in 15 patients (PCI arm: 7, HA-PCI arm: 8, p = 0.8). Nine of the 61 patients had BM within the HA area (PCI arm: 4, HA-PCI arm: 5, p = 1.0). The BM incidence was not significantly different between arms (subdistribution hazard ratio [sHR] 1.03, 95 %CI 0.62-1.70, p = 0.91)., Conclusion: HA-PCI did not preserve longitudinal SRCF but did also not increase the risk of BM. Additional strategies should be investigated to further improve the therapeutic ratio of PCI., Trials Registration: ClinicalTrials.gov (NCT01780675) ClinicalTrials.gov (NCT02397733)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N Rodríguez de Dios: Consulting or Advisory Role: AstraZeneca Spain. Speakers' Bureau: AstraZeneca Spain, Siemens Healthineers. F Couñago: Honoraria: AstraZeneca, Astellas Pharma. L Hendriks: No related COI. Outside of this manuscript personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, BMS, Boehringer Ingelheim, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and Merck Sharp & Dohme (MSD); fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Merck and Pfizer (Novartis under negotiation); institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for EORTC (European Organisation for Research and Treatment of Cancer) and as the secretary of the studies foundation for NVALT (Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose). The other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy., Materials and Methods: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes., Results: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months., Conclusion: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue., 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.)

Purpose: To externally validate Johnson-Hart et al. findings: the association of tumor baseline shifts towards the heart with overall survival (OS) in SBRT for NSCLC. Further analysis included investigating the presence of interfractional heart baseline shifts and the association of OS with heart dose change during treatment., Methods: Data from 416 SBRT early-stage NSCLC patients was collected. Pearson's correlations (PCCs) between clinical variables and treatment-averaged tumor shifts towards/away from the heart were explored. Validation of published multivariable Cox model was performed. PCCs between heart and tumor baseline shifts were analyzed. Dose accumulation was performed following daily CBCT-to-pCT deformable registration. Maximum heart dose (D 0 ) was computed for planned and accumulated doses. Differences in OS according to shifts towards/away from the heart or D 0 increase/decrease were analyzed. Significant D 0 differences between patients with D 0 increase/decrease and different tumor locations were explored., Results: Tumor shifts towards/away from the heart showed no significant association with OS (p = 0.91). Distance between PTV and heart correlated significantly (PCC = 0.18) with shifts to the heart. Cox model did not validate in our cohort. Heart presented baseline shifts positively correlated with tumor baseline shifts in all three directions (PCC ≥ 0.38; p < 0.001). Counterintuitively, patients experiencing increased D 0 during treatment showed significantly better OS (p = 0.0077). Upper-lobe tumor patients with increased D 0 had lower D 0 than those with decreased D 0 (right-upper-lobe p ≤ 0.018)., Conclusions: In our SBRT cohort, the shifts towards the heart were not associated with worse OS. Moderate correlations were found between tumor and heart baseline shifts in each direction. Moreover, the distance between the PTV and the heart showed a significant correlation with shifts to the heart., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This workwas sponsored in part byresearch grantsfrom Elekta Oncology Systems Ltd., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To identify risk factors for self-reported cognitive impairment in radically treated stage III non-small cell lung cancer (NSCLC)., Methods: Cognitive functioning was assessed using the EORTC-QLQ-C30 at seven pre-specified time points in the phase III NVALT-11 trial (observation versus prophylactic cranial irradiation [PCI] in stage III NSCLC treated with chemo-radiotherapy ± surgery). Cognition was analyzed as binary (impairment or not) and continuous outcome, respectively, using generalized estimating equation (GEE) before and after multiple imputation. A score < 75 was defined as cognitive impairment. A mean difference by < 10, 10-<20, ≥ 20 points was regarded as of no, moderate, and large clinical effect, respectively. We categorized the cognitive impairment into four types based on changes over time: sustained, reversible, recurring, and alternating., Results: In the no-PCI arm, 43/84 [51.2%] reported cognitive impairment at least once, of which 31.4% were sustained, 25.7% reversible, 28.6% recurring, and 14.3% alternating. Results were similar in the PCI arm. Cognitive functioning at baseline was comparable in two arms and a score < 75 was a significant risk factor with large effect for subsequent cognitive impairment (no-PCI: β = -23.30, p < 0.001; PCI arm: β = -22.34, p < 0.001; All: β = -23.47, p < 0.001). Younger age (≤60y), squamous histology, and PCI were risk factors without clinical relevance (β > -10, p < 0.05). Cognitive functioning declined over time (β = -0.26, p = 0.001) except for patients with cognitive impairment at baseline (β = 0.141, p = 0.33)., Conclusion: Cognitive impairment is dynamic over time with four types. Baseline cognitive impairment (score < 75) is the most important risk factor for subsequent cognitive impairment in stage III NSCLC. Note: This work has been partly reported as an oral presentation at the ESTRO 2021 meeting (OC-0176)., 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 © 2023 Elsevier B.V. All rights reserved.)

Background and Purpose: We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18 F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer., Materials and Methods: Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II 'pick-the-winner' design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year., Clinicaltrials: gov:NCT01024829., Results: 150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group., Conclusion: Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies., 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 © 2023 Elsevier B.V. All rights reserved.)

Small cell lung cancer (SCLC) is an aggressive form of lung cancer associated with an increased risk of develping brain metastases (BM), which are a significant cause of morbidity and mortality. Prophylactic cranial irradiation (PCI) was first introduced in the 1970s with the aim of reducing BM incidence and improving survival and quality of life (QoL). Prospective clinical trials and meta-analyses have demonstrated its effectiveness in reducing BM incidence and improving survival, across all stages of the disease following response to induction chemotherapy. Despite its long history, "unknowns" surrounding PCI use still exist and there are particular subgroups of patients for which its use remains controversial. PCI is known to cause neurocognitive toxicity which can have a significant impact on a patient's QoL. Strategies to minimise this, including the use of hippocampal avoidance radiotherapy techniques, neuroprotective drugs and stereotactic radiosurgery in place of whole brain radiotherapy for the treatment of BM, are under evaluation. This review offers a summary of the key PCI trials published to date and the current treatment recommendations based on available evidence. It also discusses the key questions being addressed in ongoing clinical trials and highlights others where there is currently a knowledge gap and therefore where further data are urgently required., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Anatomical changes during the stereotactic body radiation therapy (SBRT) of early stage non-small cell lung cancer (NSCLC) may cause the delivered dose to deviate from the planned dose. We investigate if normal tissue complication probability (NTCP) models based on the delivered dose predict radiation-induced rib fractures better than models based on the planned dose., Material and Methods: 437 NSCLC patients treated to a median dose of 3x18 Gy were included. Delivered dose was estimated by accumulating EQD2-corrected fraction doses after being deformed with daily CBCT-to-planning CT deformable image registration. Dosimetric parameters D x (dose to a relative volume x) were extracted for each rib included in the CBCTs field-of-view. An NTCP model was constructed for both planned and delivered dose, optimizing the parameters TD 50 (dose with 50% toxicity risk), m (steepness of the curve) and x, using maximum likelihood estimation. Best NTCP model was determined using Akaike weights (Aw). Differences between the models were tested for significance using the Vuong's test., Results: Median time to fracture of 110 fractured ribs was 22.5 months. The maximum rib dose, D 0 , best predicted fractures for both planned and delivered dose. The average delivered D 0 was significantly lower than planned (p < 0.001). NTCP model based on the delivered D 0 was the best, with Aw = 0.95. The models were not significantly different., Conclusion: Delivered maximum dose to the ribs was significantly lower than planned. The NTCP model based on delivered dose improved predictions of radiation-induced rib fractures but did not reach statistical significance., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Whole brain radiotherapy (WBRT) is a common treatment option for brain metastases secondary to non-small cell lung cancer (NSCLC). Data from the QUARTZ trial suggest that WBRT can be omitted in selected patients and treated with optimal supportive care alone. Nevertheless, WBRT is still widely used to treat brain metastases secondary to NSCLC. We analysed decision criteria influencing the selection for WBRT among European radiation oncology experts., Methods: Twenty-two European radiation oncology experts in lung cancer as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) for previous projects and by the Advisory Committee on Radiation Oncology Practice (ACROP) for lung cancer were asked to describe their strategies in the management of brain metastases of NSCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies., Results: Eight decision criteria (suitability for SRS, performance status, symptoms, eligibility for targeted therapy, extra-cranial tumour control, age, prognostic scores and "Zugzwang" (the compulsion to treat)) were identified. WBRT was recommended by a majority of the European experts for symptomatic patients not suitable for radiosurgery or fractionated stereotactic radiotherapy. There was also a tendency to use WBRT in the ALK/EGFR/ROS1 negative NSCLC setting., Conclusion: Despite the results of the QUARTZ trial WBRT is still widely used among European radiation oncology experts., 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 © 2020 Elsevier B.V. All rights reserved.)

Radiotherapy (RT) plays a major role in the treatment of small cell lung cancer (SCLC). Therefore, the ACROP committee was asked by ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)-radiotherapy (CRT), adjuvant RT for stages I-III SCLC and consolidation thoracic RT for stage IV disease. The aim of these guidelines is to standardise and optimise the process of RT treatment planning for clinical practice and prospective studies. The process for the development of the guidelines included the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing process within the committee. Firstly, we provide recommendations for both the imaging to be performed as part of the diagnostic work-up and for the RT planning process. Secondly, recommendations are made for target volume delineation including delineation of the primary gross tumour volume (GTV) and lymph node GTV and clinical tumour volume (CTV) expansion in the context of definitive and adjuvant RT. With regard to internal target volume (ITV) and planning target volume (PTV) definitions, we make recommendations about the management of geometric uncertainties and target motion. Finally, we provide our opinions on organ at risk (OAR) delineation and organisational issues to be considered., (Copyright © 2020. Published by Elsevier B.V.)

Background: In limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens., Methods: Thirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies., Results: Logistic reasons, patients' performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site., Conclusion: BID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation., 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 © 2020 Elsevier B.V. All rights reserved.)

Introduction: The aim of this study was to identify subgroups of locally advanced NSCLC patients with a distinct treatment response during concurrent chemoradiotherapy (CCRT). Subsequently, we investigated the association of subgroup membership with treatment outcomes., Methods: 394 NSCLC-patients treated with CCRT between 2007 and 2013 were included. Gross Tumor Volume (GTV) during treatment was determined and relative GTV-volume change from the planning-CT was subsequently calculated. Latent Class Mixed Modeling (LCMM) was used to identify subgroups with distinct volume changes during CCRT. The association of subgroup membership with overall survival (OS), progression free survival (PFS) and local regional control (LRC) was assessed using cox regression analyses., Results: Three subgroups of GTV-volume change during treatment were identified, with each subsequent subgroup showing a more profound reduction of GTV during treatment. No associations between subgroup membership and OS, PFS nor LRC were observed. Nonetheless, baseline GTV (HR1.42; 95%CI 1.06-1.91) was significantly associated with OS., Conclusions: Three different subgroups of GTV-volume change during treatment were identified. Surprisingly, these subgroups did not differ in their risk of treatment outcomes. Only patients with a larger GTV at baseline had a significantly worse OS. Therefore, risk stratification at baseline might already be accurate in identifying the best treatment strategy for most patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: The aim of this work is to assess the validity of real world data (RWD) derived from an electronic toxicity registration (ETR). As a showcase, the NTCP-models of acute esophageal toxicity (AET) for concurrent chemoradiation (CCRT) for NSCLC patients were used to validate the ETR of AET before/after dose de-escalation to the mediastinal lymph nodes., Material and Methods: One hundred and one patients received 24 × 2.75 Gy and 116 patients received de-escalated dose of 24 × 2.42 Gy to the mediastinal lymph nodes. The validity and completeness of the ETR was analyzed. The grade ≥2 AET probability was defined according the V50 Gy and V60 Gy NTCP-models from literature. Validity of the models was assessed by calibration and discrimination. Furthermore, sensitivity and specificity for different cut-off points were determined., Results: The compliance of ETR was 73-80%, with sensitivity and specificity rates of 83% and 86% for grade ≥2 AET, respectively. Discrimination of both NTCP-models demonstrated a moderate accuracy (V50 model, AUC 0.71; V60-model, AUC 0.69). Dose de-escalation did not influence the accuracy of the V50-model; AUC before: 0.69, and AUC after: 0.71. For the V60-model the model-accuracy decreased after dose de-escalation; AUC before: 0.72 and AUC after: 0.62, respectively., Conclusion: RWD is a useful method to audit NTCP models in clinical practice. The NTCP models to predict AET in NSCLC patients showed moderate predictive accuracy. For clinical practice, the V50Gy seems to be most stable for dose de-escalation without compromising safety and efficacy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The role of prophylactic cranial irradiation (PCI) and thoracic radiotherapy (TRT) is unclear in resected small cell lung cancer (SCLC)., Methods: Thirteen European radiotherapy experts on SCLC were asked to describe their strategies on PCI and TRT for patients with resected SCLC. The treatment strategies were converted into decision trees and analyzed for consensus and discrepancies., Results: For patients with resected SCLC and positive lymph nodes most experts recommend prophylactic cranial irradiation and thoracic radiotherapy. For elderly patients with resected node negative SCLC, most experts do not recommend thoracic radiotherapy or prophylactic cranial irradiation., Conclusion: PCI and TRT are considered in patients with resected SCLC and these treatments should be discussed with the patient in the context of shared decision-making., 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 © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: To investigate associations of early post-treatment 18 Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy., Materials and Methods: Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/- Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6-10.1). SUV max , SUV mean , metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metric pre -metric post )/metric pre . Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes., Results: Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUV max /SUV mean ) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome., Conclusion: Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes., 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 © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: (Chemo)Radiotherapy for locally advanced non-small lung cancer (LA-NSCLC) causes severe dysphagia due to the radiation dose to the mediastinal lymphadenopathy. Reducing the dose to the mediastinum and the margins to the planning target volume (PTV) might reduce severe toxicity rates. The results of both adaptations in LA-NSCLC patients receiving (chemo)radiotherapy were analysed., Materials and Methods: 308 LA-NSCLC patients were included in an observational study. Both cohorts received hypofractionated RT (24 × 2.75 Gy) of 70 Gy (EQD2 10 ) to the primary tumour. The reference-cohort (N = 170) received the same dose of 70 Gy (EQD2 10 ) to the involved lymph nodes, while the reduction-cohort (N = 138) received 24 × 2.42 Gy, biologically equivalent to 60 Gy (EQD2 10 ). Furthermore, the patient-specific PTV-margins for both the primary tumour and lymph nodes were reduced by 2-3 mm in the reduction-cohort after implementing a carina based correction strategy. The effects on toxicity, regional failure and overall survival (OS) were assessed., Results: The acute grade 3 (G3) dysphagia and G3 pulmonary toxicity decreased significantly from 12.9% to 3.6% and 4.1% versus 0%, respectively. The regional failures were comparable: 5.9% versus 4.3% (p = 0.546). The median OS was significantly different: 26 months (reference-cohort) versus 35 months (reduction-cohort). After correction for confounders, the association between the reduction-cohort and OS remained significant (HR 0.63 versus HR 0.70)., Conclusion: A reduction in PTV-margins and dose from 70 Gy to 60 Gy to the involved lymph nodes in LA-NSCLC patients receiving (chemo)radiotherapy did not result in an increase in regional failures. Moreover, significantly lower acute toxicities and an improved OS were observed in the reduction-cohort., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 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.)

Background: High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data., Materials and Methods: We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size., Results: A total of 109 local progressions were observed after a median of 17.7 months (range 0.6-76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12-16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy., Conclusions: Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12-16 Gy are more probable, consistent with recent meta-regression analyses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The role of consolidative thoracic radiotherapy (TRT) in stage IV small cell lung cancer (SCLC) is not uniformly accepted., Methods: We obtained a list of 13 European medical oncologists from the International Association for the Study of Lung Cancer (IASLC) and 13 European radiation oncologists from the European Society for Therapeutic Radiation Oncology (ESTRO). The strategies in decision making for TRT in stage IV SCLC were collected. Decision trees were created representing these strategies. Frequencies of recommending TRT were analysed for various parameter combinations based on the objective consensus methodology., Results: The factors associated with the recommendation for TRT included fitness of the patient, limited extrathoracic tumour burden, initial bulky thoracic disease and response to chemotherapy. The highest consensus for TRT was in fit patients with limited extrathoracic tumour burden and initial bulky disease with either a complete extrathoracic response or partial thoracic response (92% recommend TRT). For these patients the recommendations were the same for medical and radiation oncologists. In the setting of partial response (intra- and extra-thoracically) without initial bulky thoracic disease radiation oncologists were more likely to recommend TRT than medical oncologists. For unfit patients or for patients with poor overall response to chemotherapy, the majority did not recommend TRT., Conclusion: European radiation and medical oncologists specializing in lung cancer recommend TRT in selected patients with stage IV SCLC and restrict its use primarily to fit patients who responded to chemotherapy with limited extrathoracic tumour burden., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Due to conflicting results between major trials the role of prophylactic cranial irradiation (PCI) in stage IV small cell lung cancer (SCLC) is controversial., Methods: We obtained a list of 13 European experts from both the European Society for Therapeutic Radiation Oncology (ESTRO) and the International Association for the Study of Lung Cancer (IASLC). The strategies in decision making for PCI in stage IV SCLC were collected. Decision trees were created representing these strategies. Analysis of consensus was performed with the objective consensus methodology., Results: The factors associated with the recommendation for the use of PCI included the fitness of the patient, young age and good response to chemotherapy. PCI was recommended by the majority of experts for non-elderly fit patients who had at least a partial response (PR) to chemotherapy (for complete remission (CR) 85% of radiation oncologists and 69% of medical oncologists, for PR: 85% of radiation oncologists and 54% of medical oncologists). For patients with stable disease after chemotherapy, PCI was recommended by 6 out of 13 (46%) radiation oncologists and only 3 out of 13 medical oncologists (23%). For elderly fit patients with CR, a majority recommended PCI (62%) and no consensus was reached for patients with PR., Conclusion: European radiation and medical oncologists specializing in lung cancer recommend PCI in selected patients and restrict its use primarily to fit, non-elderly patients who responded to chemotherapy., (Copyright © 2018 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 and Purpose: The aim was to investigate the incidence of isolated regional failure following stereotactic ablative radiotherapy (SABR) and risk factors for recurrence., Materials and Methods: Early stage non-small cell lung cancer (NSCLC) patients treated with SABR were included in this retrospective cohort study, with isolated regional recurrence (IRR) as primary endpoint, distant recurrence (DR) and overall survival (OS) as secondary endpoints. Survival analyses were performed using the cumulative incidence function (IRR and DR) or the Kaplan-Meier method (OS) and Cox proportional hazards modelling for univariate and multivariate analyses. The prognostic effect of contact between the tumour and the pleura was investigated using the CT scans used for SABR planning., Results: A total of 554 patients were included, of whom 494 could be analysed for IRR. The median follow-up for surviving patients was 48.1 months. Twenty-one patients developed an IRR (4%). The cumulative incidence of IRR and DR after 1-, 2-, and 5 years was 2%, 3%, 7% and 8%, 15% and 21%, respectively. Two year OS was 71%. The presence and type of pleural contact was not associated with any of the studied outcomes., Conclusion: The presence, type and length of pleural contact as surrogate for visceral pleural invasion were not predictive for outcome. Further studies focussing on risk factors for occult nodal involvement, (I)RR, distant metastases and mortality in early stage NSCLC are warranted for the development of risk adapted diagnostic, treatment and follow-up strategies as more younger, operable and fitter patients receive SABR., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: The PET-boost randomized phase II trial (NCT01024829) investigated dose-escalation to the entire primary tumour or redistributed to regions of high pre-treatment FDG-uptake in inoperable non-small cell lung cancer (NSCLC) patients. We present a toxicity analysis of the 107 patients randomized in the study., Materials and Methods: Patients with stage II-III NSCLC were treated with an isotoxic integrated boost of ≥72 Gy in 24 fractions, with/without chemotherapy and strict dose limits. Toxicity was scored until death according to the CTCAEv3.0., Results: 77 (72%) patients were treated with concurrent chemoradiotherapy. Acute and late ≥G3 occurred in 41% and 25%. For concurrent (C) and sequential or radiotherapy alone (S), the most common acute ≥G3 toxicities were: dysphagia in 14.3% (C) and 3.3% (S), dyspnoea in 2.6% (C) and 6.7% (S), pneumonitis in 0% (C) and 6.7% (S), cardiac toxicity in 6.5% (C) and 3.3% (S). Seventeen patients died of which in 13 patients a possible relation to treatment could not be excluded. In 10 of these 13 patients progressive disease was scored. Fatal pulmonary haemorrhages and oesophageal fistulae were observed in 9 patients., Conclusion: Personalized dose-escalation in inoperable NSCLC patients results in higher acute and late toxicity compared to conventional chemoradiotherapy. The toxicity, however, was within the boundaries of the pre-defined stopping rules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The aim of the study was to compare simple SUVmax and SUVpeak based segmentation methods for calculating the lung tumour volume, compared to a pathology ground truth., Methods: Thirty patients diagnosed with early stage Non-Small Cell lung cancer (NSCLC) underwent surgical resection in the Netherlands between 2006 and 2008. FDG PET-CT scans for these patients were acquired within a median of 20 days before surgery. The tumour volume for each percentage SUVmax and SUVpeak threshold, with and without background correction, was calculated for each patient. The percentage threshold that provided the tumour volume that corresponded best with the pathology volume was considered to be the optimal threshold. The optimal thresholds were plotted as a function of tumour volume using a power law function and cross validated using the leave-one-out technique., Results: The mean optimal percentage threshold was 50% ± 10% and 62% ± 15% for the SUVmax and SUVpeak without background correction respectively and 47% ± 10% and 60 ± 15% for the SUVmax and SUVpeak with background correction respectively. The optimal threshold curves could be fitted well with power law function. After cross validation the correlation between the effective tumour diameter in pathology and autosegmentation was 0.900 and 0.905 for the SUVmax and SUVpeak without background correction respectively and 0.913 and 0.908 for the SUVmax and SUVpeak with background correction respectively., Conclusion: No benefit was shown on clinical data for the SUVpeak based segmentation method over a SUVmax based one. Both methods can be used to determine the tumour volumes in resected NSCLC tumours., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: We externally validated a previously established multivariable normal-tissue complication probability (NTCP) model for Grade ≥2 acute esophageal toxicity (AET) after intensity-modulated (chemo-)radiotherapy or volumetric-modulated arc therapy for locally advanced non-small cell lung cancer., Materials and Methods: A total of 603 patients from five cohorts (A-E) within four different Dutch institutes were included. Using the NTCP model, containing predictors concurrent chemoradiotherapy, mean esophageal dose, gender and clinical tumor stage, the risk of Grade ≥2 AET was estimated per patient and model discrimination and (re)calibration performance were evaluated., Results: Four validation cohorts (A, B, D, E) experienced higher incidence of Grade ≥2 AET compared to the training cohort (49.3-70.2% vs 35.6%; borderline significant for one cohort, highly significant for three cohorts). Cohort C experienced lower Grade ≥2 AET incidence (21.7%, p < 0.001). For three cohorts (A-C), discriminative performance was similar to the training cohort (area under the curve (AUC) 0.81-0.89 vs 0.84). In the two remaining cohorts (D-E) the model showed poor discriminative power (AUC 0.64 and 0.63). Reasonable calibration performance was observed in two cohorts (A-B), and recalibration further improved performance in all three cohorts with good discrimination (A-C). Recalibration for the two poorly discriminating cohorts (D-E) did not improve performance., Conclusions: The NTCP model for AET prediction was successfully validated in three out of five patient cohorts (AUC ≥0.80). The model did not perform well in two cohorts, which included patients receiving substantially different treatment. Before applying the model in clinical practice, validation of discrimination and (re)calibration performance in a local cohort is recommended., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: FDG-PET scans have shown spatial consistency in NSCLC patients before and following chemoradiotherapy, implying radioresistance. We hypothesized that patients, who received FDG-PET redistributed dose painting, would demonstrate reduced spatial consistency when compared to registered patients or to escalated dose treatment., Methods: Stage II-IIIB, inoperable NSCLC patients were randomized in a phase II trial (NCT01024829) to (chemo)radiotherapy of either homogeneous boosting to the primary tumor, or redistributed inhomogeneous boosting to the GTV subvolume (FDG-SUV > 50% SUV max ). Patients who could not be boosted (≥72 Gy) received 66 Gy in 24 fractions. Spatial consistency of pre-treatment and post-treatment (3 months) FDG-PET scans was measured by various overlap fraction thresholds., Results: 66/82 patients analyzed received randomized treatment in the trial. Thresholds of 50% SUV max pre-treatment and 70% SUV max post-treatment yielded a median overlap fraction of 0.63 [interquartile range: 0.15-0.93], with similar results for other thresholds. No significant differences were found among overlap fractions of the treatment groups. A high incidence of FDG-uptake in normal lung (grade-1 pneumonitis: 73%) was found post-treatment., Conclusion: FDG redistributed boosting did not reduce FDG spatial consistency from pre-treatment to post-treatment, which was highly variable among patients. The study found high numbers of patients with lung inflammation after treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The study compared interobserver variation in the delineation of the primary tumour (GTVp) and lymph nodes (GTVln) between three different 4DCT reconstruction types; Maximum Intensity Projection (MIP), Mid-Ventilation (Mid-V) and Mid-Position (Mid-P)., Material and Methods: Seven radiation oncologists delineated the GTVp and GTVln on the MIP, Mid-V and Mid-P 4DCT image reconstructions of 10 lung cancer patients. The volumes, the mean standard deviation (SD) and distribution of SD (SD/area) over the median surface contour were compared for different tumour regions., Results: The overall mean delineated volume on the MIP was significantly larger (p < 0.001) than the Mid-V and Mid-P. For the GTVp the Mid-P had the lowest interobserver variation (SD = 0.261 cm), followed by Mid-V (SD = 0.314 cm) and MIP (SD = 0.330 cm) For GTVln the Mid-V had the lowest interobserver variation (SD = 0.425 cm) followed by the MIP (SD = 0.477 cm) and Mid-P (SD = 0.543 cm). The SD/area distribution showed a statistically significant difference between the MIP versus Mid-P and Mid-P versus Mid-V for both GTVp and GTVln (p < 0.001), with outliers indicating interpretation differences for GTVp located close to the mediastinum and GTVln., Conclusion: The Mid-P reduced the interobserver variation for the GTVp. Delineation protocols must be improved to benefit from the improved image quality of Mid-P for the GTVln., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: We aimed to identify tumour subregions with characteristic phenotypes based on pre-treatment multi-parametric functional imaging and correlate these subregions to treatment outcome. The subregions were created using imaging of metabolic activity (FDG-PET/CT), hypoxia (HX4-PET/CT) and tumour vasculature (DCE-CT)., Materials and Methods: 36 non-small cell lung cancer (NSCLC) patients underwent functional imaging prior to radical radiotherapy. Kinetic analysis was performed on DCE-CT scans to acquire blood flow (BF) and volume (BV) maps. HX4-PET/CT and DCE-CT scans were non-rigidly co-registered to the planning FDG-PET/CT. Two clustering steps were performed on multi-parametric images: first to segment each tumour into homogeneous subregions (i.e. supervoxels) and second to group the supervoxels of all tumours into phenotypic clusters. Patients were split based on the absolute or relative volume of supervoxels in each cluster; overall survival was compared using a log-rank test., Results: Unsupervised clustering of supervoxels yielded four independent clusters. One cluster (high hypoxia, high FDG, intermediate BF/BV) related to a high-risk tumour type: patients assigned to this cluster had significantly worse survival compared to patients not in this cluster (p = 0.035)., Conclusions: We designed a subregional analysis for multi-parametric imaging in NSCLC, and showed the potential of subregion classification as a biomarker for prognosis. This methodology allows for a comprehensive data-driven analysis of multi-parametric functional images., (Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Patients with stage IV non-small cell lung cancer (NSCLC) are considered incurable and are mainly treated with palliative intent. This patient group has a poor overall survival (OS) and progression free survival (PFS). The purpose of this study was to investigate PFS and OS of NSCLC patients diagnosed with synchronous oligometastatic disease who underwent radical treatment of both intrathoracic disease and metastases., Materials and Methods: Patients with NSCLC and oligometastatic disease at diagnosis, who were treated with radical intent between 2008 and 2016, were included in this observational study. Treatment consisted of systemic treatment and radical radiotherapy or resection of the intrathoracic disease. Treatment of the metastases consisted of radical or stereotactic radiotherapy, surgical resection or radiofrequency ablation., Results and Conclusions: Ninety-one patients (52% men, mean age 60 years) in good performance status were included. Thirty-eight patients (42%) died during follow-up (median follow-up 35 months). The cause of dead was lung cancer in all patients, except one. Sixty-three (69%) patients developed recurrent disease. Eleven recurrences (17%) occurred within the irradiated area. For the whole group, the median PFS was 14 months (range 2-89, 95%CI 12-16) and the median OS was 32 months (range 3-89, 95%CI 25-39). The 1- and 2-year OS rates were 85% and 58% and the 1- and 2-year PFS rates were 55% and 27%, respectively. Radical local treatment of a selected group of NSCLC patients with good performance status presenting with synchronous oligometastatic disease resulted in favorable long-term PFS and OS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart&#95;V 2Gy :HR=1.007% -1 (95% CI:1.002-1.013; p=0.006), age:HR=1.026year -1 (1.011-1.042; p=0.001) and GTV volume:HR=1.001cc -1 (1.000-1.002; p=0.006) with overall survival., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To update literature-based recommendations for techniques used in high-precision thoracic radiotherapy for lung cancer, in both routine practice and clinical trials., Methods: A literature search was performed to identify published articles that were considered clinically relevant and practical to use. Recommendations were categorised under the following headings: patient positioning and immobilisation, Tumour and nodal changes, CT and FDG-PET imaging, target volumes definition, radiotherapy treatment planning and treatment delivery. An adapted grading of evidence from the Infectious Disease Society of America, and for models the TRIPOD criteria, were used., Results: Recommendations were identified for each of the above categories., Conclusion: Recommendations for the clinical implementation of high-precision conformal radiotherapy and stereotactic body radiotherapy for lung tumours were identified from the literature. Techniques that were considered investigational at present are highlighted., (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.)

Objectives: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development., Materials and Methods: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients., Results: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60))., Conclusion: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Daily anatomical variations can cause considerable differences between delivered and planned dose. This study simulates and evaluates these effects in spot-scanning proton therapy for lung cancer patients., Materials and Methods: Robust intensity modulated treatment plans were designed on the mid-position CT scan for sixteen locally advanced lung cancer patients. To estimate dosimetric uncertainty, deformable registration was performed on their daily CBCTs to generate 4DCT equivalent scans for each fraction and to map recomputed dose to a common frame., Results: Without adaptive planning, eight patients had an undercoverage of the targets of more than 2GyE (maximum of 14.1GyE) on the recalculated treatment dose from the daily anatomy variations including respiration. In organs at risk, a maximum increase of 4.7GyE in the D1 was found in the mediastinal structures. The effect of respiratory motion alone is smaller: 1.4GyE undercoverage for targets and less than 1GyE for organs at risk., Conclusions: Daily anatomical variations over the course of treatment can cause considerable dose differences in the robust planned dose distribution. An advanced planning strategy including knowledge of anatomical uncertainties would be recommended to improve plan robustness against interfractional variations. For large anatomical changes, adaptive therapy is mandatory., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

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.)

Background and Purpose: The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome., Material and Methods: A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS)., Results: No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p=0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p=0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p=0.02 and 0.03)., Conclusions: Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Concurrent chemoradiotherapy (CCRT) is the standard treatment in locally advanced non-small cell lung cancer (NSCLC) patients. In clinical practice, the primary tumor (PT) and involved lymph nodes (LNs) receive the same radiotherapy dose. This study investigates differences between local failure (LF) and regional failure (RF)., Material and Methods: Patients were irradiated with 66 Gy in 24 fractions (using IMRT) combined with daily low dose cisplatin. The PT and LNs were contoured on the planning CT-scan registered with a (18)FDG-PET-scan. Log10(Volume) and SUVmax of PT and LNs, location (LNs versus PT), performance status, age and gender were tested as prognostic factors for lesion failure using cox regression analysis., Results: In total, 226 patients were analyzed. LF or RF as first event was seen in 37 PT (16%) and 14 LNs (6%). Log10(Volume), location and SUVmax were significantly associated with failure in univariate analysis. In multivariate analysis, only log10(Volume) remained as a significant factor., Conclusions: A LF and RF as first event of respectively 16% and 6% were observed in locally advanced NSCLC patients treated with CCRT. This difference was primarily associated with the difference in log10(Volume) of the primary tumor and lymph nodes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This document describes best practice and evidence based recommendations for the use of FDG-PET/CT for the purposes of radiotherapy target volume delineation (TVD) for curative intent treatment of non-small cell lung cancer (NSCLC). These recommendations have been written by an expert advisory group, convened by the International Atomic Energy Agency (IAEA) to facilitate a Coordinated Research Project (CRP) aiming to improve the applications of PET based radiation treatment planning (RTP) in low and middle income countries. These guidelines can be applied in routine clinical practice of radiotherapy TVD, for NSCLC patients treated with concurrent chemoradiation or radiotherapy alone, where FDG is used, and where a calibrated PET camera system equipped for RTP patient positioning is available. Recommendations are provided for PET and CT image visualization and interpretation, and for tumor delineation using planning CT with and without breathing motion compensation., (Copyright © 2015 The Authors. Published by 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.)

Background: Modest benefits from concurrent chemoradiotherapy in patients with locally advanced NSCLC warrant further clinical investigations to identify more effective treatment regimens. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. We report on the safety and efficacy of the combination of daily dose Cisplatin and concurrent radiotherapy with or without weekly Cetuximab., Patients and Methods: Patients received high dose accelerated radiotherapy (66 Gy in 24 fractions) and concurrent daily Cisplatin (6 mg/m(2)) without (Arm A) or with (Arm B) weekly Cetuximab (400 mg/m(2) loading dose one week prior to radiotherapy followed by weekly 250 mg/m(2)). The primary endpoint of the trial was objective local control rate (OLCR) determined at 6-8 weeks after treatment. Toxicity was reported as well., Results: Between February 2009 and May 2011, 102 patients were randomized. Median follow up was 29 months. The OLCR was 84% in Arm A and 92% in Arm B (p=0.36). The one-year local progression free interval (LPFI) and overall survival (OS) were 69% and 82% for Arm A and 73% and 71% for Arm B, respectively (LPFI p=0.39; OS p=0.99). Toxicity compared equally between both groups., Conclusion: The addition of Cetuximab to radiotherapy and concurrent Cisplatin did not improve disease control in patients with locally advanced NSCLC but increased treatment related toxicity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: We reported the incidence of severe late esophagus toxicity (LET) in locally advanced NSCLC patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. Acute esophagus toxicity (AET) and the dose to the esophagus were analyzed for their associations with severe LET., Material and Methods: Two hundred and thirty-one patients treated from 2008 to 2011 with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin were included. The association between AET and severe LET (grade ≥ 3 RTOG/EORTC) was tested through Cox-proportional-hazards model. Equivalent uniform dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were applied by Lyman-Kutcher-Burman (LKB) model., Results: A total of 171 patients were eligible for this study. Severe LET was observed in 6% patients. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In the EUDn-LKB model, the fitted values and 95% confidence intervals (CIs) were TD50=76.1 Gy (73.2-78.6), m=0.03 (0.02-0.06) and n=0.03 (0-0.08). In the Vx-LKB model, the fitted values and 95% CIs were Tx50=23.5% (16.4-46.6), m=0.44 (0.32-0.60) and x=76.7 Gy (74.7-77.5)., Conclusions: Severe AET, EUD (n=0.03) and V76.7 to the esophagus were significantly associated with severe LET. An independent validation study is required., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To model the local dose-effect relation for lung perfusion reduction in lung cancer patients treated with stereotactic body radiotherapy (SBRT)., Materials and Methods: Forty-two patients having upper-lobe peripheral tumours <5 cm treated with SBRT (3×18 Gy) underwent single-photon emission computed-tomography (SPECT) scans to measure the lung perfusion 2 weeks pre-SBRT, 4-months post-SBRT, and for 8 patients 15-months post-SBRT. The relation between the calculated relative local perfusion reduction and the normalised total dose (α/β=3 Gy) at 4-months post-SBRT was modeled by 3-parameter logistic model and 2-parameter linear-maximum model., Results: The relation between local dose and perfusion reduction at 4-months post-SBRT showed a maximum effect of 42.6% at doses >100 Gy and was best described by the logistic model with parameters (95% CI): M=42.6% (40.7-44.6), D50=28.7 Gy (26.3-31.1) and k=2.2 (1.8-2.5). A significant increase of this maximum effect to 65.2% was found at 15-months post-SBRT., Conclusions: The relation between local dose and perfusion reduction in patients treated with SBRT can be modeled by a 3-parameter logistic model. This demonstrated relationship 4-months post-SBRT approaches a plateau for doses >100 Gy, where 90% of the maximum lung-perfusion reduction is observed at NTD=78 Gy. A further perfusion reduction compared to 4-months post-SBRT was observed fifteen months post-SBRT., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Detailed knowledge on mediastinal lymph nodes position variability is lacking. In this study we quantified the variability over the irradiation course in non-small cell lung cancer (NSCLC) patients., Methods: A 0.35×5 mm gold fiducial marker was inserted in mediastinal lymph nodes of 14 stage III NSCLC patients. A respiration correlated 4D-planning-CT (pCT) and daily 4D-Cone Beam (CB)CT-scans were acquired. To calculate the systematic and random baseline variations, and respiratory motion variability of the lymph nodes, all CBCT scans were registered to both the bony anatomy and marker in the pCT. Patient population statistics of the peak-to-peak amplitude and time averaged mean position relative to the bony anatomy were calculated., Results: The average peak-to-peak amplitude was 0.21 cm, 0.52 cm and 0.20 cm in the Left-Right, Cranial-Caudal and Anterior-Posterior direction respectively, while the amplitude variability was ≤0.1 cm in each direction. Inter-fraction lymph node baseline variation was 0.21/0.2 cm, 0.34/0.23 cm, and 0.17/0.15 cm systematic/random. PTV margins for these variations were 0.92 cm, 1.24 cm, 0.82 cm for an online bone match and could be reduced to 0.77 cm, 0.82 cm and 0.86 cm for an online carina match., Conclusions: Substantial and anisotropic, systematic and random mediastinal lymph node baseline variations were found in NSCLC patients indicating that non-uniform margins could be beneficial., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The local site of relapse in non-small cell lung cancer (NSCLC) is primarily located in the high FDG uptake region of the primary tumour prior to treatment. A phase II PET-boost trial (NCT01024829) randomises patients between dose-escalation of the entire primary tumour (arm A) or to the high FDG uptake region inside the primary tumour (>50% SUV(max)) (arm B), whilst giving 66 Gy in 24 fractions to involved lymph nodes. We analysed the planning results of the first 20 patients for which both arms A and B were planned., Methods: Boost dose levels were escalated up to predefined normal tissue constraints with an equal mean lung dose in both arms. This also forces an equal mean PTV dose in both arms, hence testing pure dose-redistribution. Actual delivered treatment plans from the ongoing clinical trial were analysed. Patients were randomised between arms A and B if dose-escalation to the primary tumour in arm A of at least 72 Gy in 24 fractions could be safely planned., Results: 15/20 patients could be escalated to at least 72 Gy. Average prescribed fraction dose was 3.27±0.31 Gy [3.01-4.28 Gy] and 3.63±0.54 Gy [3.20-5.40 Gy] for arms A and B, respectively. Average mean total dose inside the PTV of the primary tumour was comparable: 77.3±7.9 Gy vs. 77.5±10.1 Gy. For the boost region dose levels of on average 86.9±14.9 Gy were reached. No significant dose differences between both arms were observed for the organs at risk. Most frequent observed dose-limiting constraints were the mediastinal structures (13/15 and 14/15 for arms A and B, respectively), and the brachial plexus (3/15 for both arms)., Conclusion: Dose-escalation using an integrated boost could be achieved to the primary tumour or high FDG uptake regions whilst keeping the pre-defined dose constraints., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

A practical technique is presented to deliver hippocampus avoiding prophylactic cranial irradiation for lung cancer patients, using two lateral fields. For a prescribed dose of 12×2.5 Gy, sparing of the hippocampi to 6.1 Gy was achieved with a V95% of the brain of 81.7%., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)