Despite ongoing efforts to develop new treatment options, the prognosis for patients with inoperable esophageal carcinoma is still poor and the reliability of individual therapy outcome prediction based on clinical parameters is not convincing. The aim of this work was to investigate whether PET can provide independent prognostic information in such a patient group and whether the tumor-to-blood standardized uptake ratio (SUR) can improve the prognostic value of tracer uptake values. Methods: ¹⁸F-FDG PET/CT was performed in 130 consecutive patients (mean age ± SD, 63 ± 11 y; 113 men, 17 women) with newly diagnosed esophageal cancer before definitive radiochemotherapy. In the PET images, the metabolically active tumor volume (MTV) of the primary tumor was delineated with an adaptive threshold method. The blood standardized uptake value (SUV) was determined by manually delineating the aorta in the low-dose CT. SUR values were computed as the ratio of tumor SUV and blood SUV. Uptake values were scan-time-corrected to 60 min after injection. Univariate Cox regression and Kaplan–Meier analysis with respect to overall survival (OS), distant metastases-free survival (DM), and locoregional tumor control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. Results: In multivariate Cox regression with respect to OS, including T stage, N stage, and smoking state, MTV- and SUR-based parameters were significant prognostic factors for OS with similar effect size. Multivariate analysis with respect to DM revealed smoking state, MTV, and all SUR-based parameters as significant prognostic factors. The highest hazard ratios (HRs) were found for scan-time-corrected maximum SUR (HR = 3.9) and mean SUR (HR = 4.4). None of the PET parameters was associated with LRC. Univariate Cox regression with respect to LRC revealed a significant effect only for N stage greater than 0 (P = 0.048). Conclusion: PET provides independent prognostic information for OS and DM but not for LRC in patients with locally advanced esophageal carcinoma treated with definitive radiochemotherapy in addition to clinical parameters. Among the investigated uptake-based parameters, only SUR was an independent prognostic factor for OS and DM. These results suggest that the prognostic value of tracer uptake can be improved when characterized by SUR instead of SUV. Further investigations are required to confirm these preliminary results.

The standardized uptake value (SUV) is the nearly exclusive means for quantitative evaluation of clinical [18F-]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) whole body investigations. However, the SUV methodology has well-known shortcomings. In this context, it has been recognized that at least part of the problems can be eliminated if tumor SUV is normalized to the SUV of a reference region in the liver (tumor-to-liver [TLR] ratio). In recent publications, we have systematically investigated the tumor-to-blood SUV ratio (SUR) for normalization of tumor SUVs which in our view offers principal advantages in comparison to TLR. The aim of this study was a comprehensive comparison of TLR and SUR in terms of quantification of tumor lesions. 18F-FDG PET/CT was performed in 424 patients (557 scans) with different tumor entities prior to radio(chemo)therapy. In the PET images, SUVmax of the primary tumor was determined. SUVliver was calculated in the inferior right lobe of the liver. SUVblood was determined by manually delineating the aorta in the low-dose CT. TLR and SUR were computed and scan time corrected to 60 min p.i. (TLRtc and SURtc). Correlation analysis was performed for SUVliver vs. SUVblood, TLR vs. SUR, SUVliver/SUVblood vs. SUVblood,SURtc/TLR vs. SURtc, and SURtc/TLRtc vs. SURtc. Variability of the respective ratios was assessed via histogram analysis. The prognostic value of TLR and TLRtc for distant metastases-free survival (DM) was investigated with univariate Cox regression in a homogeneous subgroup (N = 130) and compared to previously published results for SUV and SURtc. Correlation analysis revealed a linear correlation of SUVliver vs. SUVblood (R 2=0.83) and of TLR vs. SURtc (R 2=0.92). The SUVliver/SUVblood ratio (mean ± s.d.) was 1.47 ± 0.18. For the SURtc/TLR ratio, we obtained 1.14 ± 0.21 and for the SURtc/TLRtc ratio 1.38 ± 0.17. Survival analysis revealed TLR and TLRtc as significant prognostic factors for DM (hazard ratio [HR] = 3.3 and HR = 3, respectively). Both hazard ratios are lower than that of SURtc (HR = 4.1) although this reduction does not reach statistical significance for the given limited group size. HRs of TLR and SURtc are both significantly higher than HR of SUV (HR = 2.2). Suitability of the liver as surrogate of arterial tracer supply for SUV normalization via TLR computation is limited. Further studies in sufficiently large patient groups are required to better characterize the relative performance of SUV, TLR, and SUR in different settings.

Radiomics analyses have been shown to predict clinical outcomes of radiotherapy based on medical imaging-derived biomarkers. However, the biological meaning attached to such image features often remains unclear, thus hindering the clinical translation of radiomics analysis. In this manuscript, we describe a preclinical radiomics trial, which attempts to establish correlations between the expression of histological tumor microenvironment (TME)- and magnetic resonance imaging (MRI)-derived image features. A total of 114 mice were transplanted with the radioresistant and radiosensitive head and neck squamous cell carcinoma cell lines SAS and UT-SCC-14, respectively. The models were irradiated with five fractions of protons or photons using different doses. Post-treatment T1-weighted MRI and histopathological evaluation of the TME was conducted to extract quantitative features pertaining to tissue hypoxia and vascularization. We performed radiomics analysis with leave-one-out cross validation to identify the features most strongly associated with the tumor's phenotype. Performance was assessed using the area under the curve (AUC_Valid) and F1-score. Furthermore, we analyzed correlations between TME- and MRI features using the Spearman correlation coefficient ρ. TME and MRI-derived features showed good performance (AUC_Valid,TME = 0.72, AUC_Valid,MRI = 0.85, AUC_{Valid,Combined}=0.85) individual tumor phenotype prediction. We found correlation coefficients of ρ=-0.46 between hypoxia-related TME features and texture-related MRI features. Tumor volume was a strong confounder for MRI feature expression. We demonstrated a preclinical radiomics implementation and notable correlations between MRI- and TME hypoxia-related features. Developing additional TME features may help to further unravel the underlying biology.

Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

The prognosis of patients with esophageal carcinoma remains dismal despite ongoing efforts to improve treatment options. For locally advanced tumors, several randomized trials have shown the benefit of neoadjuvant chemoradiation followed by surgery compared with surgery alone. The aim of this exploratory study was to evaluate the prognostic value of different baseline PET parameters and their potentially additional prognostic impact at the end of neoadjuvant radiochemotherapy. Furthermore, the standardized uptake ratio (SUR) as a new parameter for quantification of tumor metabolism was compared with the conventional PET parameters metabolically active tumor volume (MTV), total lesion glycolysis (TLG), and SUV, taking into account known basic parameters. Methods:¹⁸F-FDG PET/CT was performed on 76 consecutive patients (60 ± 10 y old, 71 men) with newly diagnosed esophageal cancer before and during the last week of neoadjuvant radiochemotherapy. MTV of the primary tumor was delineated with an adaptive threshold method. The blood SUV was determined by manually delineating the aorta in the low-dose CT scan. SURs were computed as the scan time–corrected ratio of tumor SUV_max and mean blood SUV. Univariate Cox regression and Kaplan–Meier analysis with respect to locoregional control (LRC), freedom from distant metastases (FFDM), and overall survival (OS) was performed. Additionally, the independence of PET parameters from standard clinical factors was analyzed with multivariate Cox regression. Results: In multivariate analysis, 2 parameters showed a significant correlation with all endpoints: restaging MTV and restaging SUR. Furthermore, restaging TLG was prognostic for LRC and FFDM. For all endpoints, the largest effect size was found for restaging SUR. The only basic factors remaining significant in multivariate analyses were histology for OS and FFDM and age for LRC. Conclusion: PET provides independent prognostic information for OS, LRC, and FFDM in addition to standard clinical parameters in this patient cohort. Our results suggest that the prognostic value of tracer uptake can be improved when characterized by SUR rather than by SUV. Overall, our investigation revealed a higher prognostic value for restaging parameters than for baseline PET; therapy adjustments would still be possible at that time. Further investigations are required to confirm these hypothesis-generating results.

Objectives: Concurrent radiochemotherapy (RCHT) is standard treatment in locally advanced small cell lung cancer (SCLC) patients. Due to conflicting results on elective nodal irradiation (ENI) or selective node irradiation (SNI) there is no clear evidence on optimal target volumes. Therefore, the purposes of this study were to assess the sites of recurrent disease in SCLC and to evaluate the feasibility of SNI versus ENI. Methods: A retrospective single-institution study of 43 consecutive patients treated with RCHT was performed. After state-of-the-art staging including FDG-PET/CT, all patients underwent three-dimensional conformal radiotherapy to a total dose of 45 Gy in twice-daily fractions of 1.5 Gy starting concurrently with the first or second chemotherapy cycle. All sites of loco-regional recurrences were correlated to the initial tumor and dose delivered. The impact of potential prognostic variables on outcome was evaluated using the Cox-regression model. Results: 13 patients (30%) relapsed locally or regionally: six within the initial primary tumor volume, five within the initially affected lymph nodes, one metachronously within primary tumor and initially affected lymph nodes, and one both inside and outside of the initial nodal disease. All sites of locoregional recurrence had received 92-106% of the prescribed dose. Conclusion: In our study most recurrences occurred within the primary tumor or initially affected lymph nodes, or distantly. We did not register any case of isolated nodal failure, supporting the use of selective nodal irradiation, possibly with the addition of supraclavicular irradiation in patients with nodal disease in the upper mediastinum. (C) 2017 The Authors. Published by Elsevier Ireland Ltd on behalf of European Society for Radiotherapy and Oncology.