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Purpose To compare set-up and 2-dimensional (2D) electronic portal imaging device (EPID) dosimetry data of breast cancer patients treated during voluntary moderately deep inspiration breath hold (vmDIBH) and free breathing (FB). Methods and materials Set-up data were analyzed for 29 and 51 consecutively treated patients, irradiated during FB and vmDIBH, respectively. Of the 51 vmDIBH patients, the first 25 had undergone an extra trained computed tomography (CT) scan and used an additional “breathing stick” (vmDIBH_trained). The last 26 patients did not use the breathing stick and did not undergo a trained CT (vmDIBH_untrained). The delivered 2D transit dose was measured with EPID in 15 FB and 28 vmDIBH patients and compared with a 2D predicted dose by calculating global gamma values γ using 5% and 5 mm as dose difference and distance-to-agreement criteria, respectively. Measurements with a percentage of pixels with an absolute gamma value > 1 (|γ| > 1) greater than 10% were classified as deviating. Results Only small, sub-millimeter differences were seen in the set-up data between the different patient groups. The mean of means, systematic error, and random error ranged from - 0.6 mm to 3.3 mm. The percentage of pixels with |γ| > 1 for all patients was 9.8% (2-25.8). No statistically significant differences were observed between the patient groups. In total, 38% of the gamma images were classified as deviating: 43.6% in vmDIBH_untrained patients compared with 38.0% in vmDIBH_trained patients and 33.3% in FB patients ( P > .05). Conclusion Both set-up and 2D EPID dosimetry data indicate that reproducibility of radiation therapy for patients treated during FB and vmDIBH is similar. Small but not significant differences in 2D EPID dosimetry were observed. Further investigation with 3-dimensional EPID dosimetry is recommended to investigate the clinical relevance of deviant gamma images. [ABSTRACT FROM AUTHOR]

The article offers information on the standards of care in high-dose radiotherapy for treatment of localized non-small cell lung cancer (NSCLC). Topics discussed include the importance of stereotactic body radiotherapy (SBRT) in treatment of early stage NSCLC, the risk associated with the use of this treatment method, and the use of radiotherapy for the treatment of stage III NSCLC.

Background FDG-PET–CT-based selective lymph node (LN) irradiation is standard using 3D-conformal techniques for locally advanced NSCLC. With newer techniques (intensity-modulated/volumetric-arc therapy (IMRT/VMAT)), the dose to non-involved adjacent LN decreases, which raises the question whether FDG-PET–CT-delineation is still safe. We therefore evaluated the impact of adding linear endosonography with needle aspiration (E(B)US-NA) to FDG-PET–CT in selective nodal irradiation. Methods Based on literature data on sensitivity and specificity of E(B)US-NA in FDG-PET–CT-staged NSCLC, false negative (FN) rates for different constellations of CT, PET and E(B)US-NA were calculated. The algorithm was tested on consecutive patients with N2/N3 disease referred for radiotherapy in Leuven and Maastricht. Results An algorithm determining when to include LN in the GTV is proposed, based on data from 5 meta-analyses. Adding E(B)US-NA to FDG-PET–CT decreases the FN-rate, but for PET-positive and E(B)US-negative LN, FN rates are still 14–16%. In Leuven 520 LN were analyzed, in Maastricht 364 LN; with E(B)US-NA a geographical miss was avoided in 2 (2/40 = 5%) and 1 (1/28 = 4%) patients, respectively. Conclusions E(B)US-NA in addition to FDG-PET–CT for mediastinal staging decreases the risk of a geographical miss with 4–5%. The impact of this small decrease on survival is unknown. The proposed algorithm may guide the radiation oncologist when to include LN in the nodal GTV. [ABSTRACT FROM AUTHOR]

Purpose: In non-small cell lung cancer, gross tumor volume (GTV) influences survival more than other risk factors. This could also apply to small cell lung cancer. Methods and Materials: Analysis of our prospective database with stage I to III SCLC patients referred for concurrent chemo radiation therapy. Standard treatment was 45 Gy in 1.5-Gy fractions twice daily concurrently with carboplatin-etoposide, followed by prophylactic cranial irradiation (PCI) in case of non-progression. Only fluorodeoxyglucose (FDG)-positron emission tomography (PET)-positive or pathologically proven nodal sites were included in the target volume. Total GTV consisted of post chemotherapy tumor volume and pre chemotherapy nodal volume. Survival was calculated from diagnosis (Kaplan-Meier ). Results: A total of 119 patients were included between May 2004 and June 2009. Median total GTV was 93 ± 152 cc (7.5-895 cc). Isolated elective nodal failure occurred in 2 patients (1.7%). Median follow-up was 38 months, median overall survival 20 months (95% confidence interval = 17.8-22.1 months), and 2-year survival 38.4%. In multivariate analysis, only total GTV (P=.026) and performance status (P=.016) significantly influenced survival. Conclusions: In this series of stage I to III small cell lung cancer patients treated with FDG-PET-based selective nodal irradiation total GTV is an independent risk factor for survival. [Copyright &y& Elsevier]

Purpose: Because individual tumors are heterogeneous, including for 18F-deoxyglucose (FDG) uptake and, most likely, for radioresistance, selective boosting of high FDG uptake zones within the tumor has been suggested. To do this, it is critical to know whether the location of these high FDG uptake patterns within the tumor remain stable during radiotherapy (RT). Methods and Materials: Twenty-three patients with Stage I-III non–small-cell lung cancer underwent repeated FDG positron emission tomography computed tomography scans before radical RT (Day 0) and at Days 7 and 14 of RT. On all scans, the high and low FDG uptake regions were autodelineated using several standardized uptake value thresholds, varying from 34% to 80% of the maximal standardized uptake value. The volumes and overlap fractions of these delineations were calculated to demonstrate the stability of the high FDG uptake regions during RT. Results: The mean overlap fraction of the 34% uptake zones at Day 0 with Days 7 and 14 was 82.8% ± 8.1% and 84.3% ± 7.6%, respectively. The mean overlap fraction of the high uptake zones (60%) was 72.3% ± 15.0% and 71.3% ± 19.7% at Day 0 with Days 7 and 14, respectively. The volumes of the thresholds varied markedly (e.g., at Day 0, the volume of the 60% zone was 16.8 ± 20.3 cm3). In contrast, although the location of the high FDG uptake patterns within the tumor during RT remained stable, the delineated volumes varied markedly. Conclusion: The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor. [Copyright &y& Elsevier]

Background: Although kidney transplantation improves patient survival and quality of life, long-term results are hampered by both immune- and non-immune-mediated complications. Current biomarkers of post-transplant complications, such as allograft rejection, chronic renal allograft dysfunction, and cutaneous squamous cell carcinoma, have a suboptimal predictive value. DNA methylation is an epigenetic modification that directly affects gene expression and plays an important role in processes such as ischemia/reperfusion injury, fibrosis, and alloreactive immune response. Novel techniques can quickly assess the DNA methylation status of multiple loci in different cell types, allowing a deep and interesting study of cells' activity and function. Therefore, DNA methylation has the potential to become an important biomarker for prediction and monitoring in kidney transplantation. Purpose of the study: The aim of this study was to evaluate the role of DNA methylation as a potential biomarker of graft survival and complications development in kidney transplantation. Material and Methods: A systematic review of several databases has been conducted. The Newcastle–Ottawa scale and the Jadad scale have been used to assess the risk of bias for observational and randomized studies, respectively. Results: Twenty articles reporting on DNA methylation as a biomarker for kidney transplantation were included, all using DNA methylation for prediction and monitoring. DNA methylation pattern alterations in cells isolated from different tissues, such as kidney biopsies, urine, and blood, have been associated with ischemia–reperfusion injury and chronic renal allograft dysfunction. These alterations occurred in different and specific loci. DNA methylation status has also proved to be important for immune response modulation, having a crucial role in regulatory T cell definition and activity. Research also focused on a better understanding of the role of this epigenetic modification assessment for regulatory T cells isolation and expansion for future tolerance induction-oriented therapies. Conclusions: Studies included in this review are heterogeneous in study design, biological samples, and outcome. More coordinated investigations are needed to affirm DNA methylation as a clinically relevant biomarker important for prevention, monitoring, and intervention. [ABSTRACT FROM AUTHOR]

Purpose: After radiation therapy for painful bone metastases, up to 44% of patients report a pain flare (PF). Our study compared 2 dose schedules of dexamethasone versus placebo to prevent PF.Methods and Materials: This double-blind, randomized, placebo-controlled trial allocated patients with painful bone metastases from solid tumors randomly to receive 8 mg dexamethasone before radiation therapy followed by 3 daily doses (group A), 8 mg dexamethasone followed by 3 doses of placebo (group B), or 4 doses of placebo (group C). Patients reported worst pain scores, study medication side effects, and opioid intake before treatment and thereafter daily for 14 days and on day 28. PF was defined as at least a 2-point increase on a 0 to 10 pain scale with no decrease in opioid intake or a 25% or greater increase in opioid intake with no decrease in pain score, followed by a return to baseline or lower. The primary analysis was by intention to treat with patients who had missing data classified as having a PF.Results: From January 2012 to April 2016, 295 patients were randomized. PF incidence was 38% for group A, 27% for group B, and 39% for group C (P = .07). Although patients in group B had the lowest PF incidence, a relatively high percentage did not return to baseline pain levels, indicating pain progression. The mean duration of PF was 2.1 days for group A, 4.5 days for group B, and 3.3 days for group C (P = .0567). Dexamethasone postponed PF occurrence; in group A 52% occurred on days 2 to 5 versus 73% in group B and 99% in group C (P = .02). Patients in group A reported lower mean pain scores on days 2 to 5 than those in group B or C (P < .001). Side effects were similar.Conclusions: There was insufficient evidence that dexamethasone reduced the incidence of radiation-induced PF. However, dexamethasone postponed the occurrence of PF and led to lower mean pain scores on days 2 to 5. [ABSTRACT FROM AUTHOR]

Highlights • The 2-year cumulative incidence of isolated regional recurrence following stereotactic ablative radiotherapy (SABR) for early stage non-small cell lung cancer was 3%. • The 2-year cumulative incidence of distant recurrence following SABR was 15%. • The presence, type and length of pleural contact as surrogate for visceral pleural invasion were not associated with regional or distant recurrence and overall survival. • Of the patients with an IRR, 33% received radical treatment with either radiotherapy alone or sequential or concurrent chemoradiotherapy and 43% received best supportive care. Abstract 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. [ABSTRACT FROM AUTHOR]

Background and purpose Isolated nodal failures (INF) are rare after 3D-conformal radiotherapy (3D-CRT) for stage III non-small cell lung cancer (NSCLC). Since incidental nodal irradiation doses are lower with Intensity Modulated Radiation Therapy (IMRT) than with 3D-CRT, INF may be higher after IMRT. We therefore investigated the incidence of INF after IMRT in stage III NSCLC patients. Materials and methods Stage III NSCLC patients undergoing radical radiotherapy using IMRT in the period January 2010 till March 2012 were included. The primary endpoint was the rate of INF, secondary endpoints included patterns of failure, progression free survival (PFS), overall survival (OS) and toxicity. Results 183 stage III NSCLC patients were enrolled. With a median follow-up of 58.0 months 2.2% of patients had an INF. The median PFS was 15.0 months, the median OS 19.5 months. Patterns of recurrence: 2.2% INF, 11.5% local and 2.7% loco-regional recurrence, 26.8% distant metastases only, 18.0% a combination of local/loco-regional and distant metastases, and 38.3% patients without recurrence. One INF was out of field, in adjacent lymph nodes. Acute toxicity was limited. Discussion Selective nodal irradiation using IMRT in stage III NSCLC patients results in a low in-field incidence of INF (2.2%), similar to 3D-CRT, and may thus be considered safe. [ABSTRACT FROM AUTHOR]

Background and purpose: [18F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [18F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. Materials and methods: [18F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUVmax), tumor-to-blood-ratio (TBRmax), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5min acquisitions. Results: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBRmax increased significantly from 2h (1.6±0.3) to 4h p.i. (2.0±0.6). Uptake patterns at 2h and 4h p.i. showed a strong correlation (R =0.77±0.10) with a DICE similarity coefficient of 0.69±0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUVmax and CNR. TBRmax and HF were only affected for scan-times of 5min. Conclusions: The majority of NSCLC lesions showed considerable [18F]HX4 uptake. The heterogeneous uptake pattern was stable between 2h and 4h p.i. [18F]HX4 PET imaging at 4h p.i. is superior to 2h p.i. to reach highest contrast. Acquisition time may be reduced to 10min without significant effects on TBRmax and HF. [ABSTRACT FROM AUTHOR]

Purpose: One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). Methods and Materials: 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. Results: MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high-risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. Conclusions: CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors. [ABSTRACT FROM AUTHOR]

Purpose: To explore forward planning methods for breast cancer treatment to obtain homogeneous dose distributions (using International Commission on Radiation Units and Measurements criteria) within normal tissue constraints and to determine the feasibility of class solutions. Methods and Materials: Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)95% of >99%; V107% of <1.8 cc; heart V5 Gy of <10% and V10 Gy of <5%; and mean lung dose of <7 Gy. Treatment planning started with classic tangential beams. Optimization was done by adding a maximum of four segments before adding beams, in a second step. A breath-hold technique was used for heart sparing if necessary. Results: Dose constraints were met for all 60 patients. The classic tangential beam setup was not sufficient for any of the patients; in one-third of patients, additional segments were required (<3), and in two-thirds of patients, additional beams (<2) were required. Logistic regression analyses revealed central breast diameter (CD) and central lung distance as independent predictors for transition from additional segments to additional beams, with a CD cut-off point at 23.6 cm. Conclusions: Treatment plans fulfilling strict dose homogeneity criteria and normal tissue constraints could be obtained for all patients by stepwise dose intensity modification using limited numbers of segments and additional beams. In patients with a CD of >23.6 cm, additional beams were always required. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). Material and methods: Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. Results: FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. Conclusions: Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department. [Copyright &y& Elsevier]

Poster: Clinical track: Lung PO-1025: Prognostic factors for PFS and OS in radically treated patients with oligometastatic NSCLC M. LeenderS, R. Robeers, L. Hendriks, J. Van Loon, G. Bootsma, R. Wanders, C. Pitz, B. Reymen, R. Houben, A. Van Baardwijk, K. Verhoeven, S. Peeters, D. De Ruysscher. [Extracted from the article]

Poster: Clinical track: Lung PO-1024: Fractionated RT is equally effective but less toxic than SBRT for central early-stage NSCLC M. Leenders, S. Peeters, J. Van Loon, A. Van Baardwijk, B. Reymen, K. Verhoeven, M. Ã llers, R. Wanders, D. De Ruysscher. [Extracted from the article]

Purpose: To investigate international patterns of practice in the management of radiation therapy-induced nausea and vomiting (RINV). Methods and Materials: Oncologists prescribing radiation therapy in the United States, Canada, The Netherlands, Australia, New Zealand, Spain, Italy, France, Hong Kong, Singapore, Cyprus, and Israel completed a Web-based survey that was based on 6 radiation therapy-only clinical cases modeled after the minimal-, low-, moderate-, and high-emetic risk levels defined in the antiemetic guidelines of the American Society of Clinical Oncology and the Multinational Association of Supportive Care in Cancer. For each case, respondents estimated the risks of nausea and vomiting separately and committed to an initial management approach. Results: In total, 1022 responses were received. Risk estimates and management decisions for the minimal- and high-risk cases varied little and were in line with guideline standards, whereas those for the low- and moderate-risk cases varied greatly. The most common initial management strategies were as follows: rescue therapy for a minimal-risk case (63% of respondents), 2 low-risk cases (56% and 80%), and 1 moderate-risk case (66%); and prophylactic therapy for a second moderate-risk case (75%) and a high-risk case (95%). The serotonin (5-HT)3 receptor antagonists were the most commonly recommended prophylactic agents. On multivariate analysis, factors predictive of a decision for prophylactic or rescue therapy were risk estimates of nausea and vomiting, awareness of the American Society of Clinical Oncology antiemetic guideline, and European Society for Therapeutic Radiology and Oncology membership. Conclusions: Risk estimates and management strategies for RINV varied, especially for low- and moderate-risk radiation therapy cases. Radiation therapy-induced nausea and vomiting are under-studied treatment sequelae. New observational and translational studies are needed to allow for individual patient risk assessment and to refine antiemetic guideline management recommendations. [Copyright &y& Elsevier]

Background: Stage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy., Patients and Methods: Patients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity., Results: From May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ± 12.8 Gy (36-73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3-22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%., Conclusions: INDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: Palliative radiotherapy (RT) is one of the treatment options for bleeding tumours; a frequent symptom in patients with advanced cancer. The optimal RT schedule is however unclear. This study explores the current pattern of practice of palliative RT for bleeding tumours in the Netherlands., Materials and Methods: An internet-based questionnaire, including respondent characteristics, factors influencing the choice of RT schedules and five patient case scenarios, was sent to all members of the Dutch Society for Radiation Oncology. Descriptive statistics were used to evaluate the results., Results: The response rate was 125/374 (34%); representing 20 out of 21 Dutch RT departments. Most reported influencing factors were performance status, prognosis, patients' comfort and patients' choice. Most preferred RT schedules were 1 × 8 Gy for hematemesis, 1 × 8 Gy and 5 × 4 Gy for haemoptysis, 5 × 4 Gy for haematuria, 5 × 5 Gy for rectal bleeding, 1 × 8 Gy, 5 × 4 Gy and 10-13 × 3 Gy for vaginal bleeding., Conclusions: The current patterns of practice in the Netherlands for bleeding tumours varied considerably. Most often a single fraction is chosen (35% of all cases), followed by a five-fraction schedule (30% of all cases). The choice of an RT schedule is mainly influenced by patient related factors.

Introduction: Two randomized studies have shown an increased progression-free survival (PFS) by adding a radical local treatment to systemic therapy in responding patients with oligometastatic NSCLC, but long-term data are lacking. We updated the results of our previous phase II trial with a minimal follow-up exceeding 7 years., Methods: This is a prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was needed., Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44 to 81 years). Twenty-nine (74%) had N2 or N3 disease; 17 (44%) brain, 7 (18%) bone, and 4 (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval: 7.6-19.4 months); 1-, 2-, 3-, 5-, and 6- year OS was 56.4%, 23.3%,12.8%, 10.3%, 7.7%, and 5.1%, respectively. Median PFS was 12.1 months (95% confidence interval: 9.6-14.3 months); 1-, 2-, 3-, 5-, and 6- year OS was 51.3%, 13.6%, %,12.8%, 7.7%, 7.7%, and 2.5%, respectively. Only three patients (7.7%) had a local recurrence., Conclusions: In patients who were not selected according to response to systemic treatment, the PFS at 5 years was 8%. Entering patients in trials combining local therapy with novel systemic agents (e.g., immunotherapy) remains mandatory., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate the use of a probabilistic quad-tree graph (hidden Markov tree, HMT) to provide fast computation, robustness and an interpretational framework for multimodality image processing and to evaluate this framework for single gross tumor target (GTV) delineation from both positron emission tomography (PET) and computed tomography (CT) images., Methods: We exploited joint statistical dependencies between hidden states to handle the data stack using multi-observation, multi-resolution of HMT and Bayesian inference. This framework was applied to segmentation of lung tumors in PET/CT datasets taking into consideration simultaneously the CT and the PET image information. PET and CT images were considered using either the original voxels intensities, or after wavelet/contourlet enhancement. The Dice similarity coefficient (DSC), sensitivity (SE), positive predictive value (PPV) were used to assess the performance of the proposed approach on one simulated and 15 clinical PET/CT datasets of non-small cell lung cancer (NSCLC) cases. The surrogate of truth was a statistical consensus (obtained with the Simultaneous Truth and Performance Level Estimation algorithm) of three manual delineations performed by experts on fused PET/CT images. The proposed framework was applied to PET-only, CT-only and PET/CT datasets, and were compared to standard and improved fuzzy c-means (FCM) multimodal implementations., Results: A high agreement with the consensus of manual delineations was observed when using both PET and CT images. Contourlet-based HMT led to the best results with a DSC of 0.92 ± 0.11 compared to 0.89 ± 0.13 and 0.90 ± 0.12 for Intensity-based HMT and Wavelet-based HMT, respectively. Considering PET or CT only in the HMT led to much lower accuracy. Standard and improved FCM led to comparatively lower accuracy than HMT, even when considering multimodal implementations., Conclusions: We evaluated the accuracy of the proposed HMT-based framework for PET/CT image segmentation. The proposed method reached good accuracy, especially with pre-processing in the contourlet domain., (© 2017 American Association of Physicists in Medicine.)

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for patients with early stage non-small cell lung cancer (NSCLC) who are inoperable due to comorbid disease or who refuse surgery. SBRT results in an excellent local control rate of more than 90%, which is comparable to surgery, while short and long-term overall toxicity is low. Surgically treated patients are often more extensively staged pre-operatively, e.g. with endobronchial ultrasound and/or mediastinoscopy, and typically undergo intra-operative lymph node dissection or sampling. Occult nodal metastases (ONM), detected by lymph node dissection, have been shown to increase the incidence of regional recurrence (RR) after surgery, which is associated with poor outcome. In patients undergoing SBRT, however, definite pathological nodal staging is lacking and so other ways to identify patients at high risk for ONM and RR are desirable. The aim of this systematic review is to summarize the incidence of, and risk factors for, RR after SBRT and compare these to those after surgery. The available evidence shows the incidence of RR after SBRT or surgery to be comparable, despite more elaborate pre- and intra-operative lymph node evaluation in surgical patients. However, the fact that this finding is based on mostly retrospective studies in which the majority of patients treated with SBRT were inoperable, needs to be taken into consideration. For now, there is no evidence that inoperable clinical stage I patients with no indication of pathological lymph nodes on PET/CT will benefit from more invasive lymph node staging prior to SBRT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Decision Support Systems, based on statistical prediction models, have the potential to change the way medicine is being practiced, but their application is currently hampered by the astonishing lack of impact studies. Showing the theoretical benefit of using these models could stimulate conductance of such studies. In addition, it would pave the way for developing more advanced models, based on genomics, proteomics and imaging information, to further improve the performance of the models., Purpose: In this prospective single-center study, previously developed and validated statistical models were used to predict the two-year survival (2yrS), dyspnea (DPN), and dysphagia (DPH) outcomes for lung cancer patients treated with chemo radiation. These predictions were compared to probabilities provided by doctors and guideline-based recommendations currently used. We hypothesized that model predictions would significantly outperform predictions from doctors., Materials and Methods: Experienced radiation oncologists (ROs) predicted all outcomes at two timepoints: (1) after the first consultation of the patient, and (2) after the radiation treatment plan was made. Differences in the performances of doctors and models were assessed using Area Under the Curve (AUC) analysis., Results: A total number of 155 patients were included. At timepoint #1 the differences in AUCs between the ROs and the models were 0.15, 0.17, and 0.20 (for 2yrS, DPN, and DPH, respectively), with p-values of 0.02, 0.07, and 0.03. Comparable differences at timepoint #2 were not statistically significant due to the limited number of patients. Comparison to guideline-based recommendations also favored the models., Conclusion: The models substantially outperformed ROs' predictions and guideline-based recommendations currently used in clinical practice. Identification of risk groups on the basis of the models facilitates individualized treatment, and should be further investigated in clinical impact studies., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients., Materials and Methods: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions., Results: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min., Conclusions: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients., Material and Methods: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ≥2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC)., Results: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set., Conclusion: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV)., Methods: Radiation oncology trainees who were members of the national radiation oncology associations of the USA, Canada, Netherlands, Australia, New Zealand, France, Spain and Singapore completed a Web-based survey. Respondents estimated the risks of nausea and vomiting associated with six standardised radiotherapy-only clinical case vignettes modelled after international anti-emetic guidelines and then committed to prophylactic, rescue or no therapy as an initial management approach for each case., Results: One hundred and seventy-six trainees from 11 countries responded. Only 28 % were aware of any anti-emetic guideline. In general, risk estimates and management approaches for the high-risk and minimal risk cases varied less and were more in line with guideline standards than were estimates and approaches for the moderate- and low-risk cases. Prophylactic therapy was the most common approach for the high-risk and a moderate-risk case (83 and 71 % of respondents respectively), while rescue therapy was the most common approach for a second moderate-risk case (69 %), two low-risk cases (69 and 76 %) and a minimal risk case (68 %). A serotonin receptor antagonist was the most commonly recommended prophylactic agent. On multivariate analysis, a higher estimated risk of nausea predicted for recommending prophylactic therapy, and a lower estimated risk of nausea predicted for recommending rescue therapy., Conclusions: Radiation oncology trainee risk estimates and recommended management approaches for RINV clinical case vignettes varied and matched guideline standards more often for high-risk and minimal risk cases than for moderate- and low-risk cases. Risk estimates of nausea specifically were strong predictors of management decisions.

Background: Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET-based tumour delineation methods to pathology findings., Methods: Retrospective non-respiratory gated whole body [18F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter., Results: 50%, adaptive 41% threshold-based and contrast-oriented delineation methods showed good agreement with pathology after removing two outliers (R2=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R2: 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R2>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R2=0.81). Good correlation between CT delineation and pathology was observed (R2=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05)., Conclusions: PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes.

Background: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking., Methods and Patients: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy., Results: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023)., Conclusion: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted.

Unlabelled: The objectives of this study were to investigate the relationship between CT- and (18)F-FDG PET-based tumor volumes in non-small cell lung cancer (NSCLC) and the impact of tumor size and uptake heterogeneity on various approaches to delineating uptake on PET images., Methods: Twenty-five NSCLC cancer patients with (18)F-FDG PET/CT were considered. Seventeen underwent surgical resection of their tumor, and the maximum diameter was measured. Two observers manually delineated the tumors on the CT images and the tumor uptake on the corresponding PET images, using a fixed threshold at 50% of the maximum (T(50)), an adaptive threshold methodology, and the fuzzy locally adaptive Bayesian (FLAB) algorithm. Maximum diameters of the delineated volumes were compared with the histopathology reference when available. The volumes of the tumors were compared, and correlations between the anatomic volume and PET uptake heterogeneity and the differences between delineations were investigated., Results: All maximum diameters measured on PET and CT images significantly correlated with the histopathology reference (r > 0.89, P < 0.0001). Significant differences were observed among the approaches: CT delineation resulted in large overestimation (+32% ± 37%), whereas all delineations on PET images resulted in underestimation (from -15% ± 17% for T(50) to -4% ± 8% for FLAB) except manual delineation (+8% ± 17%). Overall, CT volumes were significantly larger than PET volumes (55 ± 74 cm(3) for CT vs. from 18 ± 25 to 47 ± 76 cm(3) for PET). A significant correlation was found between anatomic tumor size and heterogeneity (larger lesions were more heterogeneous). Finally, the more heterogeneous the tumor uptake, the larger was the underestimation of PET volumes by threshold-based techniques., Conclusion: Volumes based on CT images were larger than those based on PET images. Tumor size and tracer uptake heterogeneity have an impact on threshold-based methods, which should not be used for the delineation of cases of large heterogeneous NSCLC, as these methods tend to largely underestimate the spatial extent of the functional tumor in such cases. For an accurate delineation of PET volumes in NSCLC, advanced image segmentation algorithms able to deal with tracer uptake heterogeneity should be preferred.

The observation that improved local tumour control also results in increased survival rates, even in a disease such as non-small cell lung cancer (NSCLC), has fuelled the interest in strategies aimed at local tumour eradication. It has been demonstrated that a clear dose-response relationship exists for radiotherapy, i.e. higher doses of radiation lead to increased local tumour control. However, prolongation of the overall treatment time beyond 4-5 weeks renders radiotherapy less effective because of increased proliferation of tumour cells. It is therefore of interest to deliver as high doses as possible in short overall treatment times. An extreme example of this strategy is stereotactic body radiotherapy (SBRT), where a few large radiation doses, equalling very high biological doses, delivered in a short overall treatment time has resulted in at least 90 % tumour control in stage I NSCLC. However, when large volumes or critical normal structures such as the main bronchi are in the high-dose radiation volumes, more extensive fractionation schedules have been used, such as 70 Gy in 35 daily fractions of 2 Gy. As the overall treatment time than exceeds 4-5 weeks, hyperfractionated radiotherapy schedules have been introduced, which all delivered 2-3 relatively small fractions per day to total doses that are similar to the so-called standard regimen. Several randomized phase III trials and a meta-analysis based on individual patient data have demonstrated a superior 5-year survival with this strategy, without increased side effects. Our group has also shown that individualised hyperfractionated accelerated radiotherapy (INDAR) makes treatment with curative intent even in patients with large tumour volumes possible with few important side effects. Early results of INDAR with concurrent chemotherapy or with cetuximab are promising.

We discussed in this article about the role of surgery, in a broad sense, and radiotherapy for the treatment of early stage of non-small cell lung cancer (NSCLC), and we also examined if patients' outcomes after radiation therapy are comparable to the ones after surgery. Radiotherapy is at present a less attractive alternative to surgery in operable patients with early stage of NSCLC. Indeed, radiotherapy is frequently reserved for patients who are deemed unfit for surgery due to poor pulmonary function or other comorbidities. This introduces a large patient selection bias compared to surgery, rendering overall survival less suitable for comparison. When we compare patients who are deemed operable but refuse surgery, the 5-year overall survival rate observed, after a high effective dose, is equivalent to the outcome after surgery. On the other hand, it is difficult to enroll patients in randomized clinical trials for this purpose, propensity matched analysis allows to compares the effectiveness of radiotherapy and surgery using comparable series of patients, using this methodology two studies obtained similar results. This data support the need of continuous investigation for non-surgical alternatives in this disease, radiotherapy can be a good option. Until then, surgery remains the treatment of choice for early stage of NSCLC.

Purpose: Extensive research has led to the identification of numerous dosimetric parameters as well as patient characteristics, associated with lung toxicity, but their clinical usefulness remains largely unknown. We investigated the predictive value of patient characteristics in combination with established dosimetric parameters., Patients and Methods: Data from 438 lung cancer patients treated with (chemo)radiation were used. Lung toxicity was scored using the Common Toxicity Criteria version 3.0. A multivariate model as well as two single parameter models, including either V(20) or MLD, was built. Performance of the models was expressed as the AUC (Area Under the Curve)., Results: The mean MLD was 13.5 Gy (SD 4.5 Gy), while the mean V(20) was 21.0% (SD 7.3%). Univariate models with V(20) or MLD both yielded an AUC of 0.47. The final multivariate model, which included WHO-performance status, smoking status, forced expiratory volume (FEV(1)), age and MLD, yielded an AUC of 0.62 (95% CI: 0.55-0.69)., Conclusions: Within the range of radiation doses used in our clinic, dosimetric parameters play a less important role than patient characteristics for the prediction of lung toxicity. Future research should focus more on patient-related factors, as opposed to dosimetric parameters, in order to identify patients at high risk for developing radiation-induced lung toxicity more accurately.