Stereotactic body radiotherapy for centrally located inoperable early-stage NSCLC: EORTC 22113-08113 LungTech phase II trial results.

BACKGROUND: The international EORTC phase II single-arm LungTech trial 22113-08113 assessed safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance (RTQA) for any eligible patient, SBRT (8x7.5 Gy, ICRU 83) was delivered. The primary endpoint was freedom from local progression probability at three years after start of SBRT. RESULTS: The trial was closed earlier due to poor accrual related to repeated safety-related pauses in recruitment. Between 08/2015 and 12/2017, 39 patients from 6 European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range, 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Median follow-up was 3.6 years. The 3-year freedom from local progression and overall survival rates were 81.5% (90% CI: 62.7-91.4%) and 61.1% (90%CI: 44.1-74.4%), respectively. Cumulative incidence rates of local, regional and distant progression at 3 years were 6.7% (90% CI: 1.6-17.1%), 3.3% (90% CI: 0.4 - 12.4%) and 29.8% (90% CI: 16.8 - 44.1%), respectively. SBRT-related acute and late AEs ≥ G3 were reported in 6.5% (n=2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4 % (n=6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively. CONCLUSION: The LungTech trial suggests that SBRT with 8×7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints and post-SBRT interventions is crucial.

Cardiac Function Modifies the Impact of Heart Base Dose on Survival: A Voxel-Wise Analysis of Patients With Lung Cancer From the PET-Plan Trial.

INTRODUCTION: Heart dose has emerged as an independent predictor of overall survival in patients with NSCLC treated with radiotherapy. Several studies have identified the base of the heart as a region of enhanced dose sensitivity and a potential target for cardiac sparing. We present a dosimetric analysis of overall survival in the multicenter, randomized PET-Plan trial (NCT00697333) and for the first time include left ventricular ejection fraction (EF) at baseline as a metric of cardiac function. METHODS: A total of 205 patients with inoperable stage II or III NSCLC treated with 60 to 72 Gy in 2 Gy fractions were included in this study. A voxel-wise image-based data mining methodology was used to identify anatomical regions where higher dose was significantly associated with worse overall survival. Univariable and multivariable Cox proportional hazards models tested the association of survival with dose to the identified region, established prognostic factors, and baseline cardiac function. RESULTS: A total of 172 patients remained after processing and censoring for follow-up. At 2-years posttreatment, a highly significant region was identified within the base of the heart (p < 0.005), centered on the origin of the left coronary artery and the region of the atrioventricular node. In multivariable analysis, the number of positron emission tomography-positive nodes (p = 0.02, hazard ratio = 1.13, 95% confidence interval: 1.02-1.25) and mean dose to the cardiac subregion (p = 0.02, hazard ratio = 1.11 Gy-1, 95% confidence interval: 1.02-1.21) were significantly associated with overall survival. There was a significant interaction between EF and region dose (p = 0.04) for survival, with contrast plots revealing a larger effect of region dose on survival in patients with lower EF values. CONCLUSIONS: This work validates previous image-based data mining studies by revealing a strong association between dose to the base of the heart and overall survival. For the first time, an interaction between baseline cardiac health and heart base dose was identified, potentially suggesting preexisting cardiac dysfunction exacerbates the impact of heart dose on survival.

Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies.

The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1ß, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002-1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056-1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018-1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002-1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061-1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.

Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

INTRODUCTION: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial. METHODS: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed. RESULTS: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities. CONCLUSIONS: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

FDG-PET Radiomics for Response Monitoring in Non-Small-Cell Lung Cancer Treated with Radiation Therapy.

The aim of this study is to identify clinically relevant image feature (IF) changes during chemoradiation and evaluate their efficacy in predicting treatment response. Patients with non-small-cell lung cancer (NSCLC) were enrolled in two prospective trials (STRIPE, PET-Plan). We evaluated 48 patients who underwent static (3D) and retrospectively-respiratory-gated 4D PET/CT scans before treatment and a 3D scan during or after treatment. Our proposed method rejects IF changes due to intrinsic variability. The IF variability observed across 4D PET is employed as a patient individualized normalization factor to emphasize statistically relevant IF changes during treatment. Predictions of overall survival (OS), local recurrence (LR) and distant metastasis (DM) were evaluated. From 135 IFs, only 17 satisfied the required criteria of being normally distributed across 4D PET and robust between 3D and 4D images. Changes during treatment in the area-under-the-curve of the cumulative standard-uptake-value histogram (δAUCCSH) within primary tumor discriminated (AUC = 0.87, Specificity = 0.78) patients with and without LR. The resulted prognostic model was validated with a different segmentation method (AUC = 0.83) and in a different patient cohort (AUC = 0.63). The quantification of tumor FDG heterogeneity by δAUCCSH during chemoradiation correlated with the incidence of local recurrence and might be recommended for monitoring treatment response in patients with NSCLC.

FET-PET radiomics in recurrent glioblastoma: prognostic value for outcome after re-irradiation?

PURPOSE: The value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET)-radiomics in the outcome assessment of patients with recurrent glioblastoma (rGBM) has not been evaluated until now. The aim of this study was to evaluate whether a prognostic model based on FET-PET radiomics features (RF) is feasible and can identify rGBM patients that would most benefit from re-irradiation. METHODS: We prospectively recruited rGBM patients who underwent FET-PET before re-irradiation (GLIAA-Pilot trial, DRKS00000633). Tumor volume was delineated using a semi-automatic method with a threshold of 1.8 times the standardized-uptake-value of the background. 135 FET-RF (histogram parameters, shape and texture features) were extracted. The analysis involved the characterization of tumor and non-tumor tissue with FET-RF and the evaluation of the prognostic value of FET-RF for time-to-progression (TTP), overall survival (OS) and recurrence location (RL). RESULTS: Thirty-two rGBM patients constituted our cohort. FET-RF discriminated significantly between tumor and non-tumor. The texture feature Small-Zone-Low-Gray-Level-Emphasis (SZLGE) showed the best performance for the prediction of TTP (p = 0.001, satisfying Bonferroni-multiple-test significance level). Additionally, two radiomics signatures could predict TTP (TTP-radiomics-signature, p = 0.001) and OS (OS-radiomics-signature, p = 0.038). SZLGE and the TTP-radiomics-signature additionally predicted RL. Specifically, high values for TTP-radiomics-signature and for SZLGE indicated not only earlier progression, but also a RL within the initial FET-PET active volume. CONCLUSION: Our findings suggest that FET-PET radiomics could contribute to the prognostic assessment and selection of rGBM-patients benefiting from re-irradiation. Trial registration DRKS00000633. Registered on 8th of December in 2010. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00000633 .

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.

Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer.

Background: The aim of the study was to evaluate the role of different immunohistochemical and radiomics features in patients with small cell lung cancer (SCLC). Methods: Consecutive patients with histologically proven SCLC with limited (n = 47, 48%) or extensive disease (n = 51, 52%) treated with radiotherapy and chemotherapy at our department were included in the analysis. The expression of different immunohistochemical markers from the initial tissue biopsy, such as CD56, CD44, chromogranin A, synaptophysin, TTF-1, GLUT-1, Hif-1 a, PD-1, and PD-L1, and MIB-1/KI-67 as well as LDH und NSE from the initial blood sample were evaluated. H-scores were additionally generated for CD44, Hif-1a, and GLUT-1. A total of 72 computer tomography (CT) radiomics texture features from a homogenous subgroup (n = 31) of patients were correlated with the immunohistochemistry, the survival (OS), and the progression-free survival (PFS). Results: The median OS, calculated from diagnosis, was 21 months for patients with limited disease and 13 months for patients with extensive disease. The expression of synaptophysin correlated with a better OS (HR 0.546 95% CI 0.308-0.966, p = 0.03). The expression of TTF-1 (HR 0.286, 95% CI: 0.117-0.698, p = 0.006) and a lower GLUT-1 H-score (median = 50, HR: 0.511, 95% CI: 0.260-1.003, p = 0.05) correlated with a better PFS. Patients without chromogranin A expression had a higher risk for developing cerebral metastases (p = 0.02) and patients with PD 1 expression were at risk for developing metastases (p = 0.02). Our radiomics analysis did not reveal a single texture feature that correlated highly with OS or PFS. Correlation coefficients ranged between -0.48 and 0.39 for OS and between -0.46 and 0.38 for PFS. Conclusions: The role of synaptophysin should be further evaluated as synaptophysin-negative patients might profit from treatment intensification. We report an, at most, moderate correlation of radiomics features with overall and progression free survival and no correlation with the expression of different immunohistochemical markers.

Quality of life after pulmonary stereotactic fractionated radiotherapy (SBRT): Results of the phase II STRIPE trial.

BACKGROUND AND PURPOSE: Preserving health related quality of life (HRQOL) plays an important role in considering stereotactic body fractionated radiotherapy (SBRT). The prospective monocenter phase II STRIPE trial investigated long-term HRQOL after SBRT, efficacy and toxicity. MATERIALS AND METHODS: Patients with ≤2 pulmonary lesions ≤5 cm were treated with 4DPET/CT-based SBRT (3 × 12.5 Gy or risk-adapted 5 × 7 Gy, to 60% isodose). Follow up (FU) was performed 2 and 7 weeks after SBRT, then 3-monthly for 2 years with assessment of response (primary endpoint: 2-year cumulative incidence of local progression (LP); secondary endpoints: local progression free survival (LPFS), overall survival (OS) and toxicity (CTCAE)). Impact of predefined patient and treatment related factors on HRQOL (EORTC QLQ-C30 and EORTC QLQ-LC13) was evaluated. RESULTS: Between 02/2011 and 11/2014, 100 patients were given SBRT for 56 NSCLC and 44 pulmonary metastases (M1). Long-term FU overall revealed stable Quality of Life (QoL)/Global health status (GHS), functions-scores and symptoms. For QoL/GHS, patients with low (

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Challenges and caveats of a multi-center retrospective radiomics study: an example of early treatment response assessment for NSCLC patients using FDG-PET/CT radiomics.

BACKGROUND: Prognostic models based on individual patient characteristics can improve treatment decisions and outcome in the future. In many (radiomic) studies, small size and heterogeneity of datasets is a challenge that often limits performance and potential clinical applicability of these models. The current study is example of a retrospective multi-centric study with challenges and caveats. To highlight common issues and emphasize potential pitfalls, we aimed for an extensive analysis of these multi-center pre-treatment datasets, with an additional 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan acquired during treatment. METHODS: The dataset consisted of 138 stage II-IV non-small cell lung cancer (NSCLC) patients from four different cohorts acquired from three different institutes. The differences between the cohorts were compared in terms of clinical characteristics and using the so-called 'cohort differences model' approach. Moreover, the potential prognostic performances for overall survival of radiomic features extracted from CT or FDG-PET, or relative or absolute differences between the scans at the two time points, were assessed using the LASSO regression method. Furthermore, the performances of five different classifiers were evaluated for all image sets. RESULTS: The individual cohorts substantially differed in terms of patient characteristics. Moreover, the cohort differences model indicated statistically significant differences between the cohorts. Neither LASSO nor any of the tested classifiers resulted in a clinical relevant prognostic model that could be validated on the available datasets. CONCLUSION: The results imply that the study might have been influenced by a limited sample size, heterogeneous patient characteristics, and inconsistent imaging parameters. No prognostic performance of FDG-PET or CT based radiomics models can be reported. This study highlights the necessity of extensive evaluations of cohorts and of validation datasets, especially in retrospective multi-centric datasets.

Diffusion-weighted MRI and ADC versus FET-PET and GdT1w-MRI for gross tumor volume (GTV) delineation in re-irradiation of recurrent glioblastoma.

BACKGROUND AND PURPOSE: GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI). MATERIAL AND METHODS: We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7-1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm2) and parametric ADC maps. The localization of recurrence was correlated with initial GdT1w-MRI and PET data. RESULTS: In 30/41 patients, DWI-MRI showed areas with restricted diffusion (mean ADC-value 0.74 ±â€¯0.22 mm2/s). 66% of GTVs-ADClow were located outside the GdT1w-MRI volume and 76% outside increased FET uptake regions. Furthermore, GTVs-ADClow were only partially included in the high dose volume and received in mean 82% of the reference dose. An adjusted volume including GdT1w-MRI, PET-positive and restricted diffusion areas would imply a GTV increase of 48%. GTV-PET and GdT1w-MRI correlated better with the localization of re-recurrence in comparison to GTV-ADClow. CONCLUSION: Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies.

Early Impact of Pulmonary Fractionated Stereotactic Body Radiotherapy on Quality of Life:Benefit for Patients With Low Initial Scores (STRIPE Trial).

INTRODUCTION: Quality of life (QoL) of comorbid patients with pulmonary malignancies is a key issue in considering fractionated stereotactic body radiotherapy (SBRT) indication. This study investigates the early impact of SBRT on QoL. METHODS: One hundred patients with pulmonary lesions were treated with SBRT from February 2011 to December 2014 within the prospective, monocenter, phase II STRIPE trial. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core module (EORTC QLQ-C30) and the QLQ-LC13 lung cancer-specific questionnaire were used to evaluate QoL before, 2 and 7 weeks after SBRT, then every 3 months for 2 years. We report on the analysis of early changes from baseline to 7-week follow-up exam. Impact of patient- and treatment-related factors on the change in QoL was analyzed. RESULTS: QoL was assessed in 97 patients; compliance was 92% and 85% at baseline and 7 weeks after SBRT, respectively. No clinically relevant changes greater than or equal to 10 in the QoL/global health status (GHS), function scores and inquired symptoms were observed. Patients with baseline QoL below the median showed clinically relevant improvement in QoL/GHS (Δ16.7 ± 25.3, p = 0.003), emotional function (Δ14.4 ± 25.4, p = 0.013), and fatigue (Δ -10.1 ± 26.5, p = 0.089) in contrast to patients with high initial scores. No changes were observed in the dichotomized subgroups of initial Karnofsky index, Charlson Comorbidity Index, age, diagnosis, and tumor localization. CONCLUSIONS: In short-term follow-up, QoL is well maintained after pulmonary SBRT. Especially patients with low initial QoL/GHS scores show benefit from SBRT with respect to QoL.

Correction: Is serum level of CC chemokine ligand 18 a biomarker for the prediction of radiation induced lung toxicity (RILT)?

[This corrects the article DOI: 10.1371/journal.pone.0185350.].

Anatomic, functional and molecular imaging in lung cancer precision radiation therapy: treatment response assessment and radiation therapy personalization.

This article reviews key imaging modalities for lung cancer patients treated with radiation therapy (RT) and considers their actual or potential contributions to critical decision-making. An international group of researchers with expertise in imaging in lung cancer patients treated with RT considered the relevant literature on modalities, including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). These perspectives were coordinated to summarize the current status of imaging in lung cancer and flag developments with future implications. Although there are no useful randomized trials of different imaging modalities in lung cancer, multiple prospective studies indicate that management decisions are frequently impacted by the use of complementary imaging modalities, leading both to more appropriate treatments and better outcomes. This is especially true of 18F-fluoro-deoxyglucose (FDG)-PET/CT which is widely accepted to be the standard imaging modality for staging of lung cancer patients, for selection for potentially curative RT and for treatment planning. PET is also more accurate than CT for predicting survival after RT. PET imaging during RT is also correlated with survival and makes response-adapted therapies possible. PET tracers other than FDG have potential for imaging important biological process in tumors, including hypoxia and proliferation. MRI has superior accuracy in soft tissue imaging and the MRI Linac is a rapidly developing technology with great potential for online monitoring and modification of treatment. The role of imaging in RT-treated lung cancer patients is evolving rapidly and will allow increasing personalization of therapy according to the biology of both the tumor and dose limiting normal tissues.

Visualization of 4D multimodal imaging data and its applications in radiotherapy planning.

PURPOSE: To explore the benefit of using 4D multimodal visualization and interaction techniques for defined radiotherapy planning tasks over a treatment planning system used in clinical routine (C-TPS) without dedicated 4D visualization. METHODS: We developed a 4D visualization system (4D-VS) with dedicated rendering and fusion of 4D multimodal imaging data based on a list of requirements developed in collaboration with radiation oncologists. We conducted a user evaluation in which the benefits of our approach were evaluated in comparison to C-TPS for three specific tasks: assessment of internal target volume (ITV) delineation, classification of tumor location in peripheral or central, and assessment of dose distribution. For all three tasks, we presented test cases for which we measured correctness, certainty, consistency followed by an additional survey regarding specific visualization features. RESULTS: Lower quality of the test ITVs (ground truth quality was available) was more likely to be detected using 4D-VS. ITV ratings were more consistent in 4D-VS and the classification of tumor location had a higher accuracy. Overall evaluation of the survey indicates 4D-VS provides better spatial comprehensibility and simplifies the tasks which were performed during testing. CONCLUSIONS: The use of 4D-VS has improved the assessment of ITV delineations and classification of tumor location. The visualization features of 4D-VS have been identified as helpful for the assessment of dose distribution during user testing.

Is serum level of CC chemokine ligand 18 a biomarker for the prediction of radiation induced lung toxicity (RILT)?

The CC chemokine ligand 18 (CCL18) is produced by alveolar macrophages in patients with fibrosing lung disease and its concentration is increased in various fibrotic lung diseases. Furthermore CCL18 is elevated in several malignancies as it is produced by tumor associated macrophages. In this study we aimed to analyze the role of CCL18 as a prognostic biomarker for the development of early radiation induced lung toxicity (RILT), i.e. radiation pneumonitis after thoracic irradiation and its significance in the course of the disease. Sixty seven patients were enrolled prospectively in the study. Patients were treated with irradiation for several thoracic malignancies (lung cancer, esophageal cancer, thymoma), either with conventionally fractionated or hypo-fractionated radiotherapy. The CCL18 serum levels were quantified with ELISA (enzyme-linked immunosorbent assay) at predefined time points: before, during and at the end of treatment as well as in the first and second follow-up. Treatment parameters and functional tests were also correlated with the development of RILT.Fifty three patients were evaluable for this study. Twenty one patients (39%) developed radiologic signs of RILT Grade >1 but only three of them (5.6%) developed clinical symptoms (Grade 2). We could not find any association between the different CCL18 concentrations and a higher incidence of RILT. Statistical significant factors were the planning target volume (odds ratio OR: 1.003, p = 0.010), the volume of the lung receiving > 20 Gy (OR: 1.132 p = 0.004) and age (OR: 0.917, p = 0.008). There was no association between serial CCL18 concentrations with tumor response and overall survival.In our study the dosimetric parameters remained the most potent predictors of RILT. Further studies are needed in order to estimate the role of CCL18 in the development of early RILT.

Using a contextualized sensemaking model for interaction design: A case study of tumor contouring.

Sensemaking theories help designers understand the cognitive processes of a user when he/she performs a complicated task. This paper introduces a two-step approach of incorporating sensemaking support within the design of health information systems by: (1) modeling the sensemaking process of physicians while performing a task, and (2) identifying software interaction design requirements that support sensemaking based on this model. The two-step approach is presented based on a case study of the tumor contouring clinical task for radiotherapy planning. In the first step of the approach, a contextualized sensemaking model was developed to describe the sensemaking process based on the goal, the workflow and the context of the task. In the second step, based on a research software prototype, an experiment was conducted where three contouring tasks were performed by eight physicians respectively. Four types of navigation interactions and five types of interaction sequence patterns were identified by analyzing the gathered interaction log data from those twenty-four cases. Further in-depth study on each of the navigation interactions and interaction sequence patterns in relation to the contextualized sensemaking model revealed five main areas for design improvements to increase sensemaking support. Outcomes of the case study indicate that the proposed two-step approach was beneficial for gaining a deeper understanding of the sensemaking process during the task, as well as for identifying design requirements for better sensemaking support.

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) - protocol of a randomized phase II trial (NOA 10/ARO 2013-1).

BACKGROUND: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. METHODS: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRI- or PET-derived target volumes, rate of long term survivors (>1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. DISCUSSION: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. TRIAL REGISTRATION: The GLIAA trial is registered with ClinicalTrials.gov ( NCT01252459 , registration date 02.12.2010), German Clinical Trials Registry ( DRKS00000634 , registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012).