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IntroductionA decentralized and multi-platform-compatible molecular diagnostic tool for kidney transplant biopsies could improve the dissemination and exploitation of this technology, increasing its clinical impact. As a first step towards this molecular diagnostic tool, we developed and validated a classifier using the genes of the Banff-Human Organ Transplant (B-HOT) panel extracted from a historical Molecular Microscope® Diagnostic system microarray dataset. Furthermore, we evaluated the discriminative power of the B-HOT panel in a clinical scenario.Materials and MethodsGene expression data from 1,181 kidney transplant biopsies were used as training data for three random forest models to predict kidney transplant biopsy Banff categories, including non-rejection (NR), antibody-mediated rejection (ABMR), and T-cell-mediated rejection (TCMR). Performance was evaluated using nested cross-validation. The three models used different sets of input features: the first model (B-HOT Model) was trained on only the genes included in the B-HOT panel, the second model (Feature Selection Model) was based on sequential forward feature selection from all available genes, and the third model (B-HOT+ Model) was based on the combination of the two models, i.e. B-HOT panel genes plus highly predictive genes from the sequential forward feature selection. After performance assessment on cross-validation, the best-performing model was validated on an external independent dataset based on a different microarray version.ResultsThe best performances were achieved by the B-HOT+ Model, a multilabel random forest model trained on B-HOT panel genes with the addition of the 6 most predictive genes of the Feature Selection Model (ST7, KLRC4-KLRK1, TRBC1, TRBV6-5, TRBV19, and ZFX), with a mean accuracy of 92.1% during cross-validation. On the validation set, the same model achieved Area Under the ROC Curve (AUC) of 0.965 and 0.982 for NR and ABMR respectively.DiscussionThis kidney transplant biopsy classifier is one step closer to the development of a decentralized kidney transplant biopsy classifier that is effective on data derived from different gene expression platforms. The B-HOT panel proved to be a reliable highly-predictive panel for kidney transplant rejection classification. Furthermore, we propose to include the aforementioned 6 genes in the B-HOT panel for further optimization of this commercially available panel.

Summary Background BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. Methods The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov , NCT00470236 . Findings Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05–0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06–0·20; p=0·00021), persisting at 24 months (0·13 [0·06–0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03–0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [–0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference –1·10 [95% CI –1·79 to –0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. Interpretation Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. Funding National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.

BackgroundAlthough 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 studyThe 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 MethodsA 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.ResultsTwenty 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.ConclusionsStudies 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.

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. (C) 2019 Elsevier B.V. All rights reserved.

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. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Contains fulltext : 225317.pdf (Publisher’s version ) (Open Access) 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.

PurposeThe 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.MethodsWe 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.ResultsA 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.ConclusionsWe 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.

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. (C) 2018 Elsevier B.V. All rights reserved.

18F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I–II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22–1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I–III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27–1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I–III NSCLC, for squamous cell carcinoma and for adenocarcinoma.

Background: To assess the impact of training and interprofessional collaboration on the interobserver variation in the delineation of the lung gross tumor volume (GTVp) and lymph node (GTVln). Material and methods: Eight target volume delineations courses were organized between 2008 and 2013. Specialists and trainees in radiation oncology were asked to delineate the GTVp and GTVln on four representative CT images of a patient diagnosed with lung cancer individually prior each course (baseline), together as group (interprofessional collaboration) and post-training. The mean delineated volume and local standard deviation (local SD) between the contours for each course group were calculated and compared with the expert delineations. Results: A total 410 delineations were evaluated. The average local SD was lowest for the interprofessional collaboration (GTVp = 0.194 cm, GTVln = 0.371 cm) followed by the post-training (GTVp = 0.244 cm, GTVln = 0.607 cm) and baseline delineations (GTVp = 0.274 cm, GTVln: 0.718 cm). The mean delineated volume was smallest for the interprofessional (GTVp = 4.93 cm3, GTVln = 4.34 cm3) followed by the post-training (GTVp = 5.68 cm3, GTVln = 5.47 cm3) and baseline delineations (GTVp = 6.65 cm3, GTVln = 6.93 cm3). All delineations were larger than the expert for both GTVp and GTVln (p Conclusion: Our findings indicate that image interpretational differences can lead to large interobserver variation particularly when delineating the GTVln. Interprofessional collaboration was found to have the greatest impact on reducing interobserver variation in the delineation of the GTVln. This highlights the need to develop a clinical workflow so as to ensure that difficult cases are reviewed routinely by a second radiation oncologist or radiologist so as to minimize the risk of geographical tumor miss and unnecessary irradiation to normal tissue.

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. (C) 2017 Elsevier Ltd. All rights reserved.

Objective The aim of this review is to investigate the effect of timing of the reconstruction and radiotherapy, with respect to complication rate and cosmetic outcome, with a special focus on the timing of the placement of the definite implant. Methods PubMed was searched for publications between January 2000 and December 2012. Of 37 eligible studies, timing of reconstruction, type, and incidence of complications were recorded. First, we calculated the weighted mean including confidence intervals for complications and cosmetic outcome overall, and for the following subgroups: (1) Autologous reconstruction after radiotherapy; (2) Definite implant reconstruction after radiotherapy; (3) Autologous reconstruction before radiotherapy; (4) Definite implant reconstruction before radiotherapy. A second analysis was performed using only studies that directly compared group 1 versus 3 and 2 versus 4. Results A large variation in complication rates (8.7–70.0%) and in acceptable cosmetic outcome (41.4–93.3%) was reported. The first analysis showed more complications and a higher revision rate if an implant reconstruction was performed after radiotherapy; for autologous reconstruction fibrosis occurred more often if reconstruction was applied first. The second analysis showed no significant differences in total complication rate. Only implant failure occurred more often if applied after radiotherapy (odds ratio (OR) 3.03 [1.59–5.77]). No differences were found in both patient and physician satisfaction. Conclusions A definite implant reconstruction placed before radiotherapy limits the rate of complications. For autologous reconstruction, less fibrosis is seen if reconstruction is performed after radiotherapy, but timing had no significant impact on total complication rate.

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 time-points: (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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background: In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated. Methods: Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m(2) d1, 8; 40 mg/m(2) d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m(2) d1, 8 and 8 mg/m(2) d22, 29; (2) 20 mg/m(2) d1, 8 and 8 mg/m(2) d22, 29; (3) 20 mg/m(2) d1, 8; 15 mg/m(2) d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography. Results: Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 +/- 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients. Conclusion: C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m(2) d7 and 250 mg/m(2) weekly, cisplatin 50 mg/m(2) d1, 8; 40 mg/m(2) d22 and vinorelbine 20 mg/m(2) d1, 8; 15 mg/m(2) d22, 29 for 5 weeks together with RT.

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.

This study explored international radiation oncology trainee decision making in the management of radiotherapy-induced nausea and vomiting (RINV). 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. 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. 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 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.

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.

Background Sequential chemotherapy and individualised accelerated radiotherapy (INDAR) has been shown to be effective in non-small cell lung cancer (NSCLC), allowing delivering of high biological doses. We therefore performed a phase II trial (clinicaltrials.gov; NCT00572325 ) investigating the same strategy in concurrent chemo-radiation in stage III NSCLC. Methods 137 stage III patients fit for concurrent chemo-radiation (PS 0-2; FEV 1 and DLCO ⩾30%) were included from April 2006 till December 2009. An individualised prescribed dose based on normal tissue dose constraints was applied: mean lung dose (MLD) 19 Gy, spinal cord 54 Gy, brachial plexus 66 Gy, central structures 74 Gy. A total dose between 51 and 69 Gy was delivered in 1.5 Gy BID up to 45 Gy, followed by 2 Gy QD. Radiotherapy was started at the 2nd or 3rd course of chemotherapy. Primary end-point was overall survival (OS) and secondary end-point toxicity common terminology criteria for adverse events v3.0 (CTCAEv3.0). Findings The median tumour volume was 76.4 ± 94.1 cc; 49.6% of patients had N2 and 32.1% N3 disease. The median dose was 65.0 ± 6.0 Gy delivered in 35 ± 5.7 days. Six patients (4.4%) did not complete radiotherapy. With a median follow-up of 30.9 months, the median OS was 25.0 months (2-year OS 52.4%). Severe acute toxicity (⩾G3, 35.8%) consisted mainly of G3 dysphagia during radiotherapy (25.5%). Severe late toxicity (⩾G3) was observed in 10 patients (7.3%). Interpretation INDAR in concurrent chemo-radiation based on normal tissue constraints is feasible, even in patients with large tumour volumes and multi-level N2–3 disease, with acceptable severe late toxicity and promising 2-year survival.

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. 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. 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

Background There is little data on the survival of elderly patients with stage III non-small cell lung cancer (NSCLC). Methods Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. Findings One thousand and two patients with stage III were diagnosed, of which 237 were 75 years or older. From 228 patients, co-morbidity scores were available. Only 33/237 patients (14.5%) had no co-morbidities, 195 (85.5%) had one or more important co-morbidities, 60 (26.3%) two or more co-morbidities, 18 (7.9%) three or more co-morbidities and 2 patients (0.9%) suffered from four co-morbidities. Forty-eight percent were treated with curative intent. No significant difference in Charlson co-morbidity, age or gender was found between patients receiving curative or palliative intent treatment. Treatment with curative intent was associated with increased overall survival (OS) compared to palliative treatment: median OS 14.2 months (9.6–18.7) versus 5.2 months (4.3–6.0), 2-year OS 35.5% versus 12.1%, for curative versus palliative treatment. Patients who received only radiotherapy with curative intent had a median OS of 11.1 months (95% confidence interval [95% CI] 6.4–15.8) and a 5-year OS of 20.3%; for sequential chemotherapy and radiotherapy, the median OS was 18.0 months (95% CI 12.2–23.7), with a 5-year OS of 14.9%. Only four patients received concurrent chemo-radiation. Interpretation In this prospective series treating elderly patients with stage III NSCLC with curative intent was associated with significant 5-year survival rates.

International audience; 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.

Background and purpose: Surgery is considered the treatment of choice for early-stage non-small cell lung cancer (NSCLC). Patients with poor pulmonary function or other comorbidities are treated with radiotherapy. The objective of this investigation is to compare the 3-year survival of two early-stage NSCLC populations treated in two different hospitals, either by surgical resection (lobectomy) or by individualized high-dose accelerated radiotherapy, after matching patients by propensity scoring analysis. Methods: A retrospective comparative study has been performed on two series of consecutive patients with cytohistological diagnosis of NSCLC, clinically staged IA by means of PET-scan (radiotherapy group) and pathologically staged IA (surgery group). Results: A total of 157 cases were initially selected for the analysis (110 operated and 47 treated by radiotherapy). Patients in the radiotherapy group were older, with higher comorbidity and lower FEV1% with 3-years probability of survival for operated patients higher than that found for patients treated by radiotherapy. After matching by propensity scoring (using age and FEV1%), differences disappear and 3-years probability of survival had no statistical differences. Conclusions: Although this is a non-randomized retrospective analysis, we have not found 3-years survival differences after matching cases between surgery and radiotherapy. Nevertheless, data presented here support the continuous investigation for non-surgical alternatives in this disease.

Purpose We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. Patients and Methods In total, 166 patients with stage III or medically inoperable stage I to II non–small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide ≥ 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. Results The median prescribed TTD was 64.8 Gy (standard deviation, ± 11.4 Gy) delivered in 25 ± 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. Conclusion Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

Introduction: The prognostic value of quantitative 18F-fluoro-2-deoxy-d-glucose (FDG) uptake on positron emission tomography (PET) is controversial in unselected patients with non-small cell lung cancer (NSCLC). We assessed the in vivo FDG uptake, measured as maximum pixel standardized uptake value (SUV max ), in stages I and II NSCLC for its prognostic value and association with in vitro quantitative morphology of tumor vitality. Methods: Prospective FDG-PET data were available in 91 consecutive patients operated for pathologic stages I and II NSCLC. Quantitative morphology was performed of tumor architecture, tumor cell density and immunohistochemical biomarkers for apoptosis (caspase-3), cell proliferation (Ki-67), hypoxia (HIF-1α), cellular pH regulation (carbonic anhydrase IX [CAIX]), and microvessel density (CD31). Results: SUV max ≥ median and SUV max partial volume corrected for lesion size (PVC SUV max ) ≥ median were associated with an increased risk of death in univariable analysis. After correcting for stage, tumor size and age in multivariable analysis, only PVC SUV max ≥ median remained significant. The strong significant association between tumor size and SUV max weakened after PVC, suggesting that an important amount of SUV max can be simply explained by tumor size, which is less in case for PVC SUV max that associates more to the tumor cell density. In multivariable logistic regression analysis, a PVC SUV max ≥ median could be explained by high Ki-67 and high-CAIX length density. Conclusion: PVC SUV max has a prognostic value in completely resected stages I and II NSCLC. A high-quantitative FDG uptake is associated with characteristics of tumor vitality such as high tumor cell density, high cell proliferation, and extracellular acidosis.

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 13.5Gy (SD 4.5Gy), 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.

Purpose Knowledge of changes in gross tumor volume (GTV) and of GTV motion during a course of radiotherapy is necessary for accurate treatment delivery. This study describes the time trends in nodal computed tomography (CT) volume and motion for patients with locally advanced non-small-cell lung cancer (NSCLC). Patients and Methods In a prospective clinical trial, 12 patients with a total of 22 positive nodes underwent a CT-positron emission tomography scan before treatment, as well as in the first and second week following start of radiotherapy. Volume changes could be measured for all nodes. For 21 nodes, the motion was measured on the basis of a respiration correlated CT (RCCT) scan. Repeated RCCT scans were available for 11 nodes to evaluate the change in motion. Results In 6 of 22 (27%) patients, the nodal volume increased >30%, whereas in 3 of 22 (14%) the volume decreased >30%. On average, the nodal volume did not change significantly (from 4.9 to 5.1 to 4.6 cm 3 ). The average motion of the nodal areas was initially 5.6 ± 2.8 mm. This motion decreased slightly during therapy but not statistically significant. However, large interpatient and internodal motion differences were observed. Conclusion A large variability of changes in nodal volume between patients was observed. However, this had limited clinical impact because volumes and hence volume changes were small. The nodal motion did not change significantly during therapy. However, because of the large interpatient variability of nodal motion before treatment, internal margins for nodal areas should be calculated before radiotherapy using RCCT, such that the margins can be applied for individual patients. Repeated imaging of the nodes seems however to be of limited use because the observed individual changes in nodal volume and motion tend to fall within the commonly applied margins.

Purpose To integrate PET-CT scans from different hospitals into radiotherapy treatment planning. Methods and materials A cylindrical phantom with spheres of different diameters was scanned on three different Siemens Biograph PET-CT scanners in three hospitals. The spheres and cylinder were filled with 18F-FDG such that different sphere-to-background (S/B) ratios were obtained. Scans were analyzed using dedicated software for automated delineation based on standardized uptake value (SUV) and using different reconstruction parameters. Results SUV thresholding curves for different S/B ratios were obtained for the different scanners. Differences in SUV auto-contouring thresholds were found to be significant for PET-CT simulators from different radiotherapy and nuclear medicine departments. A change in PET reconstruction parameters showed a significant effect on the results. Conclusion Synchronization of PET-CT imaging protocols between cooperating hospitals is important for reliable determination of SUV auto-contouring thresholds. Whenever this goal has been achieved automated SUV delineation based on a S/B ratio using PET-CT images from different institutions can reliably be performed using individually determined threshold curves.

We evaluated the feasibility to correlate intra-tumour heterogeneity as visualized on 18F-FDG PET with histology for NSCLC. For this purpose we used an ex-vivo model. The procedure was feasible in all operated patients. We have shown that this method is suitable for correlating intra-tumour heterogeneity in tracer uptake with histology.

Purpose To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. Methods and Materials High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non–small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sections were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. Results In 4 of 5 patients, the GTV CT was, on average, 4 cm 3 (∼53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV CT was 16 cm 3 (∼40%) too small. The GTV PET was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. Conclusions Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.

To compare source-to-background ratio (SBR)-based PET-CT auto-delineation with pathology in non-small-cell lung cancer (NSCLC) and to investigate whether auto-delineation reduces the interobserver variability compared with manual PET-CT-based gross tumor volume (GTV) delineation.Source-to-background ratio-based auto-delineation was compared with macroscopic tumor dimensions to assess its validity in 23 tumors. Thereafter, GTVs were delineated manually on 33 PET-CT scans by five observers for the primary tumor (GTV-1) and the involved lymph nodes (GTV-2). The delineation was repeated after 6 months with the auto-contour provided. This contour was edited by the observers. For comparison, the concordance index (CI) was calculated, defined as the ratio of intersection and the union of two volumes (A intersection B)/(A union or logical sum B).The maximal tumor diameter of the SBR-based auto-contour correlated strongly with the macroscopic diameter of primary tumors (correlation coefficient = 0.90) and was shown to be accurate for involved lymph nodes (sensitivity 67%, specificity 95%). The median auto-contour-based target volumes were smaller than those defined by manual delineation for GTV-1 (31.8 and 34.6 cm(3), respectively; p = 0.001) and GTV-2 (16.3 and 21.8 cm(3), respectively; p = 0.02). The auto-contour-based method showed higher CIs than the manual method for GTV-1 (0.74 and 0.70 cm(3), respectively; p0.001) and GTV-2 (0.60 and 0.51 cm(3), respectively; p = 0.11).Source-to-background ratio-based auto-delineation showed a good correlation with pathology, decreased the delineated volumes of the GTVs, and reduced the interobserver variability. Auto-contouring may further improve the quality of target delineation in NSCLC patients.

The purpose of this study was to investigate the relation between the standardised uptake value (SUV) on 18F-fluoro-2-deoxy-glucose-positron emission tomography scan and hypoxia related markers (HIF-1α and CAIX), a proliferation-related marker (Ki-67) and glucose transporters (GLUT-1 and GLUT-3) in non-small cell lung cancer (NSCLC). One hundred and two patients, scheduled for complete resection, received a PET scan in Leuven or Maastricht/Aachen. The maximal SUV (SUVmax) was correlated with survival and immunohistochemical staining patterns. The actuarial survival was worse for patients showing a high SUVmax, the best discriminative value being 8.0 (Leuven, p = 0.032) and 11.0 (Maastricht, p = 0.007). Tumours with a high SUVmax expressed in a higher proportion HIF-1α (63.1% versus 37.9%, p = 0.024) and GLUT-1 (82.9% versus 62.5%, p = 0.025), than tumours with a low SUVmax. No significant difference was found in the expression of CAIX, Ki-67 and GLUT-3. This study supports preclinical data that hypoxia is associated with a higher uptake of FDG.

The aim of this study was to investigate the change in tumor volume, motion, and breathing frequency during a course of radiotherapy, for locally advanced non-small-cell lung cancer.A total of 23 patients underwent computed tomography-positron emission tomography (CT-PET) and respiration correlated CT scans before treatment, which was repeated in the first and second weeks after the start of radiotherapy. Patients were treated with an accelerated fractionation schedule, 1.8 Gy twice a day, with a total tumor dose depending on preset dose constraints for the lungs and spinal cord.A striking heterogeneity of tumor volume changes was observed at all time points. In some patients the volume decreased30% (3/23), whereas in others the volume increased30% (4/24); but for the majority of patients (16/23), the tumor volume changed only slightly (30%). No significant changes in average tumor motion or breathing frequencies were observed during treatment. Although a number of changes in individual tumor motion were seen, only in 1 patient would this have led to an increase of the internal margin1 mm in 1 direction, 1 week after the start of treatment, and in 3 patients for 1 direction, 2 weeks after the start of the treatment.In this patients in this study, a large variability in changes in tumor volume was observed. This underscores the need for repeated imaging during the course of radiotherapy. However, the changes in tumor motion are small, which indicates that repeated respiration correlated CT does not appear to be necessary.

Background and purpose To investigate the effect of radiotherapy planning with a dedicated combined PET-CT simulator of patients with locally advanced non-small cell lung cancer. Patients and methods Twenty-one patients underwent a pre-treatment simulation on a dedicated hybrid PET-CT-simulator. For each patient, two 3D conformal treatment plans were made: one with a CT based PTV and one with a PET-CT based PTV, both to deliver 60 Gy in 30 fractions. The maximum tolerable prescribed radiation dose for CT versus PET-CT PTV was calculated based on constraints for the lung, the oesophagus, and the spinal cord, and the Tumour Control Probability (TCP) was estimated. Results For the same toxicity levels of the lung, oesophagus and spinal cord, the dose could be increased from 55.2±2.0 Gy with CT planning to 68.9±3.3 Gy with the use of PET-CT (P=0.002), with corresponding TCP's of 6.3±1.5% for CT and 24.0±5.6% for PET-CT planning (P=0.01). Conclusions The use of a combined dedicated PET-CT-simulator reduced radiation exposure of the oesophagus and the lung, and thus allowed significant radiation dose escalation whilst respecting all relevant normal tissue constraints.

Purpose: To evaluate the patterns of recurrence when selective mediastinal node irradiation based on FDG-PET scan data is used in patients with non-small-cell lung cancer (NSCLC). Methods and Materials: A prospective Phase I/II study was undertaken on 44 patients with NSCLC without detectable distant metastases on CT and FDG-PET scan, delivering either 61.2 Gy in 34 fractions over 23 days or 64.8 Gy in 36 fractions over 24 days (1.8 Gy b.i.d. with 8-h interval). Only the primary tumor and the positive mediastinal areas on the pretreatment FDG-PET scan were irradiated. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. Results: The CT and FDG-PET stage distribution was as follows: Stage I: 8 patients (18%) and 13 patients (29%); Stage II: 6 patients (14%) and 10 patients (23%); Stage IIIA: 15 patients (34%) and 7 patients (16%); Stage IIIB: 15 patients (34%) and 14 patients (32%), respectively. After a median follow-up time of 16 months (95% confidence interval [CI], 11–21 months) postradiotherapy, 11 patients (25%) developed a local recurrence. Only 1 patient (crude rate, 2.3%; upper bound of 95% CI, 10.3%), with a Stage II tumor on both CT and PET, developed an isolated nodal failure. The median actuarial overall survival was 21 months (95% CI, 14–28 months), and the median actuarial progression-free survival was 18 months (95% CI, 12–24 months). Conclusions: Selective mediastinal node irradiation based on FDG-PET scan data in patients with NSCLC results in low isolated nodal failure rates. In the Phase I component of this trial, radiation dose escalation up to 64.8 Gy in 36 fractions over 24 days is feasible.

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 ?? 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 (|??| > 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 |??| > 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.

Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the "gold standard". The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95% CI, 0.81-0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck.

Background Non-small cell lung cancer (NSCLC) stage T4N0-1 or single nodal station IIIA-N2 are two stage III sub-groups for which the outcome of non-surgical therapy is not well known. We investigated the results of individualised isotoxic accelerated radiotherapy (INDAR) and chemotherapy in this setting. Methods Analysis of NSCLC patients included in 2 prospective trials ( NCT00573040 and NCT00572325 ) stage T4N0-1 or IIIA-N2 with 1 pathologic nodal station, treated with chemo-radiotherapy (CRT) using INDAR with concurrent or sequential platinum-based chemotherapy. Overall survival (OS) was updated and calculated from date of diagnosis (Kaplan–Meier). Toxicity was scored following CTCAEv3.0. To allow comparison with other articles the subgroups were also analysed separately for toxicity, progression free and overall survival. Results 83 patients (42 T4N0-1 and 41 IIIA-N2) were identified: the median radiotherapy dose was 65 Gy. Thirty-seven percent of patients received sequential CRT and 63% received concurrent CRT. At a median follow-up of 48 months the median OS for T4N0-1 patients was 34 months with 55% 2-year survival and 25% 5-year survival. For stage IIIA-N2 at a median follow-up of 50 months the median OS was 26 months with 2- and 5-year survival rates of 53% and 24%, respectively. Conclusion Chemo-radiation using INDAR yields promising survival results in patients with single-station stage IIIA-N2 or T4N0-1 NSCLC.

[(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.[(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.Considerable uptake (TBR1.4) 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.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.

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

Background and purpose: For stereotactic body radiotherapy (SBRT), typically a scheme of 60 Gy in 3-8 fractions is applied, producing local tumour control rates around 90%. The dose specification is in one point only and ignores possible underdosages at the edge of the planning target volume (PTV). We investigated the doses at the edge of the PTV and correlated this with local tumour control with the aim to shed light on the radiation dose needed to eradicate stage I NSCLC. Materials and methods: Published data on the freedom from local progression (FFLP) data from SBRT and accelerated high-dose conventional radiotherapy series for stage I NSCLC with a follow up of at least 30 months were included. The EQD(2,T) was calculated from the dose at the periphery of the PTV. Results; Fifteen studies for SBRT (1076 patients) showed a median FFLP of 88.0 +/- 10.4% with a median EQD(2,T) of 76.9 +/- 17.4 Gy. The median FFLP was 87.6 +/- 6.0% for the accelerated schedules with an EQD(2,T) of 86.9 +/- 39.1 Gy, respectively. No significant relation was found between FFLP and the EQD(2,T) (p = 0.23). Conclusions: Several fractionated and accelerated schedules with equal biological doses achieve the same tumour control rates as SBRT. Lower, but more uniform doses to the whole PTV may be sufficient to achieve similar control rates, with the possibility to deliver SBRT in adapted schedules, beneficial to centrally located tumours in the vicinity of critical structures like the oesophagus and great vessels.

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.

The prognosis of patients with lung cancer has improved over the past years. Patient selection, optimal sequencing of systemic and local treatments, and better surgical techniques, together with unprecedented improvements in imaging and computer technology and technical advances in radiation therapy planning and delivery has revolutionized radiation therapy in a short period of time. Among the most significant evolutions that have direct implications for daily practice are the more widespread use of stereotactic body radiation for stage I non-small-cell lung cancer (NSCLC), concurrent chemoradiation for stage III NSCLC, the implementation of 4-dimensional computed tomography and positron emission tomography, adaptive radiation therapy strategies, optimizing the timing of chest radiation therapy for limited disease small-cell lung cancer (SCLC) and prophylactic cranial irradiation for extensive disease SCLC. Molecular-based individualized radiation therapy dose prescription, which goes hand in hand with the realization of decision-support systems and the introduction of proton therapy centers give only a glimpse of what the future will bring. Clinical Lung Cancer, Vol. 14, No. 2, 89-95

Background: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. Methods: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. Results: Patients (1002) with stage HI NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p

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.Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)(95%) of99%; V(107%) of1.8 cc; heart V(5 Gy) of10% and V(10 Gy) of5%; and mean lung dose of7 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.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.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 of23.6 cm, additional beams were always required.

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.

Purpose To indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. Methods and materials On the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. Results The presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. Conclusions MDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.

Molecular imaging with PET, and certainly integrated PET-CT, combining functional and anatomical imaging, has many potential advantages over anatomical imaging alone in the combined modality treatment of lung cancer. The aim of the current article is to review the available evidence regarding PET with FDG and other tracers in the combined modality treatment of locally advanced lung cancer. The following topics are addressed: tumor volume definition, outcome prediction and the added value of PET after therapy, and finally its clinical implications and future perspectives. The additional value of FDG-PET in defining the primary tumor volume has been established, mainly in regions with atelectasis or post-treatment effects. Selective nodal irradiation (SNI) of FDG-PET positive nodal stations is the preferred treatment in NSCLC, being safe and leading to decreased normal tissue exposure, providing opportunities for dose escalation. First results in SCLC show similar results. FDG-uptake on the pre-treatment PET scan is of prognostic value. Data on the value of pre-treatment FDG-uptake to predict response to combined modality treatment are conflicting, but the limited data regarding early metabolic response during treatment do show predictive value. The FDG response after radical treatment is of prognostic significance. FDG-PET in the follow-up has potential benefit in NSCLC, while data in SCLC are lacking. Radiotherapy boosting of radioresistant areas identified with FDG-PET is subject of current research. Tracers other than (18)FDG are promising for treatment response assessment and the visualization of intra-tumor heterogeneity, but more research is needed before they can be clinically implemented.

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of (11)C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin's disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET's major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.

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.