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We include the input data, analysis scripts, analysis results and scripts to create the visualizations and plots used in the manuscript and supplement to our article "Longitudinal and multimodal radiomics models for head-and-neck cancer outcome prediction".

Background Pancreatic cancer is a devastating disease with a five-year survival rate of 20-25%. As approximately only 20% of the patients diagnosed with pancreatic cancer are initially staged as resectable, it is necessary to evaluate new therapeutic approaches. Hence neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e., [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography / computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy. Methods Patients with histologically proven resectable, borderline resectable or irresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by a neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the Standardized Uptake Value (SUV) measured with (FDG-PET). Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was done using contrast-enhanced CT and contrast enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen. Results A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal Standardized Uptake Value (SUVmax) during therapy (p

Background The analysis aimed to compare the radiotracers [68Ga]-Ga-PSMA-11 and [18F]-F-PSMA-1007 intraindividually in terms of malignant lesions, mi(molecular-imaging)TNM staging and presumable unspecific lesions retrospectively as used in routine clinical practice. Methods A retrospective analysis of 46 prostate cancer patients (median age: 71 years) who underwent consecutive [18Ga]-Ga-PSMA-11- and [18F]-F-PSMA-1007-PET/CT or PET/MRI within a mean of 12 ± 8.0 days was performed. MiTNM staging was performed in both studies by two nuclear medicine physicians who were blinded to the results of the other tracer. After intradisciplinary and interdisciplinary consensus with two radiologists was reached, differences in both malignant and presumable nonspecific tracer accumulation were analyzed. Results Differences in terms of miTNM stages in both studies occurred in nine of the 46 patients (19.6%). The miT stages differed in five patients (10.9%), the miN stages differed in three patients (6.5%), and different miM stages occurred only in one patient who was upstaged in [18F]-F-PSMA-1007 PET. Concordant miTNM stages were obtained in 37 patients (80.4%). There was no significant difference between [18F]-F-PSMA-1007 and [68Ga]-Ga-PSMA-11 in the SUVmax locally (31.5 vs. 32.7; p = 0.658), in lymph node metastases (28.9 vs. 24.9; p = 0.30) or in bone metastases (22.9 vs. 27.6; p = 0.286). In [18F]-F-PSMA-1007 PET, more patients featured presumable unspecific uptake in the lymph nodes (52.2% vs. 28.3%; p: 18F]-F-PSMA-1007-positive lesions mainly occurred in the ribs (58.7%), axillary lymph nodes (39.1%) and cervical ganglia (28.3%). Conclusion In terms of miTNM staging, both tracers appeared widely exchangeable, as no tracer relevantly outperformed the other. The differences between the two tracers were far more common in presumable unspecific lesions than in malignant spots. A routinely performed two-tracer study could not be shown to be superior. Since it seems at least challenging for most nuclear medicine departments to provide both [18F]-F-PSMA-1007 and [68Ga]-Ga-PSMA-11, it appears reasonable to choose the PSMA radiotracer depending on local availability with attention to the greater occurrence of nonspecific bone findings with [18F]-F-PSMA-1007.

Background and purpose: Positron emission tomography (PET) is a functional imaging modality which is able to deliver tracer specific biological information, e.g. about glucose uptake, inflammation or hypoxia of tumors. We performed a proof-of-principle study that used different tracers and expanded the analytical scope to non-tumor structures to evaluate tumor-host interactions. Materials and Methods: Based on a previously reported prospective imaging study on 50 patients treated with curative intent chemoradiation (CRT) for head and neck squamous cell carcinoma, PET-based hypoxia and normal tissue inflammation measured by repeat 18F-fluoromisonidazole (FMISO) PET and 18F-fluorodesoxyglucose (FDG) PET, respectively, were correlated using the Spearman correlation coefficient R. PET parameters determined before and during CRT (week 1, 2 and 5), were associated with local tumor control and overall survival. Results: Tumor hypoxia at all measured times showed an inverse correlation with mid-treatment FDG-uptake of non-tumor affected oral (sub-)mucosa with R values between -0.35 and -0.6 (all p

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 to surgery alone. The aim of this exploratory study was to evaluate the prognostic value of different baseline positron emission tomography (PET) parameters and their potentially additional prognostic impact at the end of neoadjuvant radiochemotherapy. Furthermore, the standard uptake ratio (SUR) as a new parameter for quantification of tumor metabolism was compared to the conventional PET parameters metabolic active volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) taking into account known basic parameters. Methods: 18F-FDG-PET/CT was performed in 76 consecutive patients ((60±10) years, 71 males) 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. SUR values were computed as scan time corrected ratio of tumor SUVmax 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, independence of PET parameters from standard clinical factors was analyzed with multivariate Cox regression. Results: In multivariate analysis two parameters showed a significant correlation with all endpoints: restaging MTV and restaging SUR. Furthermore, restaging TLG was prognostic for LCR 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 of restaging parameters compared to baseline PET; therapy-adjustments would still be possible at this point of time. Further investigations are required to confirm these hypothesis-generating results.

Purpose: This secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinomas (HNSCC) assessed the prognostic value of synchronous hypoxia in primary tumor (Tu) and lymph node metastases (LN), and evaluated whether the combined reading was of higher prognostic value than that of primary tumor hypoxia only. Methods: This analysis included forty-five LN-positive HNSCC patients. FMISO-PET/CTs were performed at baseline, weeks 1, 2 and 5 of radiochemotherapy. Based on a binary scale, Tu and LN were categorized as hypoxic or normoxic, and two prognostic parameters were defined: Tu-hypoxia (independent of the LN oxygenation status) and synchronous Tu-and-LN-hypoxia. In fifteen patients with large LN (N = 21), additional quantitative analyses of FMISO-PET/CTs were performed. Imaging parameters at different time-points were correlated to the endpoints, i.e., locoregional control (LRC), local control (LC), regional control (RC) and time to progression (TTP). Survival curves were estimated using the cumulative incidence function. Univariable and multivariable Cox regression was used to evaluate the prognostic impact of hypoxia on the endpoints. Results: Synchronous Tu-and-LN-hypoxia was a strong adverse prognostic factor for LC, LRC and TTP at any of the four time-points (p ≤ 0.004), whereas Tu-hypoxia only was significantly associated with poor LC and LRC in weeks 2 and 5 (p ≤ 0.047), and with TTP in week 1 (p = 0.046). The multivariable analysis confirmed the prognostic value of synchronous Tu-and-LN-hypoxia regarding LRC (HR = 14.8, p = 0.017). The quantitative FMISO-PET/CT parameters correlated with qualitative hypoxia scale and RC (p < 0.001, p ≤ 0.033 at week 2, respectively). Conclusions: This secondary analysis suggests that combined reading of primary tumor and LN hypoxia adds to the prognostic information of FMSIO-PET in comparison to primary tumor assessment alone in particular prior and early during radiochemotherapy. Confirmation in ongoing trials is needed before using this marker for personalized radiation oncology. © 2018 Elsevier B.V.

Background and purpose: The development of radiomic risk models to predict clinical outcome is usually based on pre-treatment imaging, such as computed tomography (CT) scans used for radiation treatment planning. Imaging data acquired during the course of treatment may improve their prognostic performance. We compared the performance of radiomic risk models based on the pre-treatment CT and CT scans acquired in the second week of therapy. Material and methods: Treatment planning and second week CT scans of 78 head and neck squamous cell carcinoma patients treated with primary radiochemotherapy were collected. 1538 image features were extracted from each image. Prognostic models for loco-regional tumour control (LRC) and overall survival (OS) were built using 6 feature selection methods and 6 machine learning algorithms. Prognostic performance was assessed using the concordance index (C-Index). Furthermore, patients were stratified into risk groups and differences in LRC and OS were evaluated by log-rank tests. Results: The performance of radiomic risk model in predicting LRC was improved using the second week CT scans (C-Index: 0.79), in comparison to the pre-treatment CT scans (C-Index: 0.65). This was confirmed by Kaplan–Meier analyses, in which risk stratification based on the second week CT could be improved for LRC (p = 0.002) compared to pre-treatment CT (p = 0.063). Conclusion: Incorporation of imaging during treatment may be a promising way to improve radiomic risk models for clinical treatment adaption, i.e., to select patients that may benefit from dose modification.

Purpose/Objective: In order to improve radiotherapy outcomes, further treatment personalisation is considered beneficial. Radiomics analyses aim to predict treatment outcomes based on medical imaging data. Commonly, hand-crafted imaging features are used that require domain knowledge and further feature selection steps. This may cause relevant information to be lost. Deep convolutional neural networks (CNNs) on the other hand can act as automatic feature detectors and are able to learn highly nonlinear relationships directly from imaging data, thus addressing the drawbacks of conventional radiomics approaches and enabling end-to-end learning. We investigated whether CNNs are capable of quantifying loco-regional tumour control (LRC) based on CT imaging of patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Material/Methods: A multicentre cohort consisting of 302 patients with locally advanced HNSCC was collected and divided into an exploratory and a validation cohort (207 and 95 patients, respectively). All patients received a non-contrast-enhanced CT scan for treatment-planning and were treated by primary radio(chemo)therapy. 9725 transverse CT slices from the exploratory cohort were used to train a CNN with eight convolutional layers. For every patient (with one exception) we used 23 CT slices cranial and caudal of the slice with the largest tumour area, resulting in 47 slices per patient. Discriminative performance was evaluated using 4465 slices of the validation data set. The hazard of loco-regional recurrence was estimated by the CNN maximising the likelihood of the Cox proportional hazards model, which allows for incorporation of nonlinear relationships between the imaging features and the hazard prediction. The final hazard for every patient was obtained by averaging the results of the individual slices. The prognostic value of the model was evaluated by the concordance index (C-Index). Patients were stratified into groups of low and high risk of recurrence using the median hazard in the exploratory cohort. Results: The validation of our CNN model revealed a C-Index of 0.68 (95% confidence interval: 0.57-0.79) for the prognosis of LRC. The estimated hazards were used to stratify patients into two risk groups. LRC significantly differed between these groups, both in the exploratory and the validation cohort (log-rank p

In prostate cancer, disease progression after primary treatment and subsequent androgen deprivation therapy is common. Intensification of systemic treatment is the standard of care. Recently, 68[16_TD$DIFF]Ga prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging was introduced to identify oligometastatic prostate cancer patients. In this retrospective, exploratory study, we report on the efficacy of PSMA-PET-guided local ablative radiotherapy (aRT) in 15 oligometastatic castrationresistant prostate cancer (CRPC) patients, selected from our prospective institutional database and treated between 2013 and 2016. After multidisciplinary discussion, aRT was delivered with two different schedules. Androgen deprivation therapy remained unchanged. Prostate-specific antigen (PSA) response and time to PSA progression were analysed. For comparison, individual time to PSA progression without aRT was estimated by individual PSA doubling time (PSADT). PSA response was observed in 11 patients (73%). Mean time to PSA progression or last follow-up was 17.9 mo, as opposed to 2.9 mo estimated from the PSADT without aRT (p 12 mo.

Purpose: Tumour hypoxia is well known to increase radio-resistance of tumours. In a recent prospective biomarker imaging trial, hypoxia has been measured by [18F]fluoromisonidazole positron emission tomography (FMISO-PET) scans [1,2]. Here, we compared hypoxia imaging with the expression of hypoxia-associated gene signatures for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCHT). Material and methods: FMISO-PET imaging and gene expression analyses were performed on the cohort of 50 HNSCC patients [1,2]. For this study, the FMISO-PET parameters tumour-to-background ratio (TBPpeak) and hypoxic tumour volume (HV1.6) analysed before RCHT were considered. Expressions of 15-, 26- and 30-gene hypoxia-associated signatures [3-5] were analysed from formalin-fixed paraffin-embedded (FFPE) tumour biopsies obtained before RCHT using the GeneChip® Human Transcriptome Array 2.0 (Affymetrix) and nanoString analysis. Gene expressions were compared between the two methods using the Pearson correlation coefficient. Linear regression was applied to relate TBRpeak and HV1.6 to the mean expression of the gene signatures, including the interaction with tumour volume which was assessed on the planning CT by an experienced radiation oncologist. The association of FMISO-PET parameters and gene expressions to loco-regional control (LRC) and progression-free survival (PFS) was assessed by Cox regression. Results: The mean expressions of all hypoxia-associated gene signatures were highly correlated between Affymetrix and nanoString analyses (R>0.5). While TBRpeak and HV1.6 were weakly correlated with the expression of hypoxia-associated genes alone, significant correlations were observed if the interaction term of gene expression and tumour volume was included (R>0.5). Both FMISO-PET parameters were significantly correlated with LRC and PFS (p

Purpose: Primary tumor (Tu) hypoxia based on hypoxia-PET is a known prognostic parameter for locally-advanced head-and-neck squamous cell carcinoma (HNSCC) patients. This secondary analysis of the prospective clinical trial [1] on repeat [18F]fluoromisonidazole (FMISO) PET/CT before and during radiochemotherapy (RCT) compared the prognostic value of synchronous Tu and lymph node metastases (LN) hypoxia with that of hypoxia only determined in Tu. Methods: Forty-five LN-positive patients with 103 LNs were included in this analysis. FMISO-PETs were performed at baseline, week 1, 2 and 5 of RCT. Based on a qualitative scale, Tu and LN were independently categorized as hypoxic or normoxic, being FMISO uptake higher than or equal to background, respectively. Two prognostic parameters were defined: Tu-hypoxia (patients with a hypoxic Tu, independent of the LN oxygenation status) and synchronous Tu-and-LN-hypoxia. In fifteen patients with a large LN (n = 21) a quantitative analysis of FMISO PET was performed to validate hypoxia scale and to correlate with regional control (RC). Log-rank, uni- and multivariate Cox test were used to assess the parameters’ prognostic impact on locoregional control (LRC), RC and time to progression (TTP). Results: Synchronous Tu-and-LN-hypoxia was a strong adverse prognostic factor for LRC and TTP at all time-points (p ≤ 0.005) whereas Tu-hypoxia only was significantly associated with poor LRC in week 2 and 5 (p ≤ 0.004) and with short TTP in week 1, 2 and 5 (p ≤ 0.043). The quantitative FMISO parameters correlated with RC. There was a significant correlation between the qualitative and quantitative FMISO parameters (R > 0.6–0.8). Conclusions: FMISO-based synchronous hypoxia in the primary tumor and lymph node metastases holds strong prognostic information in HNSCC patients outperforming that based on primary tumor hypoxia only. Confirmation in ongoing prospective trials is intended before introducing in personalized radiation oncology.

Purpose/Objective: Radiomics aims to characterise the tumour phenotype using advanced image features to predict patient-specific outcome. Commonly, image features are calculated from the entire gross tumour volume (GTVe). However, tumours are biologically complex, e.g., expressing necrosis merely in the core and tumour cell proliferation at the periphery. The identification of sub-volumes to incorporate regional tumour variation into the risk models may lead to an improved outcome prediction. Therefore, we investigated different sub-volumes of the GTVe using CT imaging, developed radiomic signatures, and compared prognostic power and stratification performance of the signatures. Material/Methods: A multicentre cohort consisting of 302 patients with advanced stage head and neck squamous cell carcinoma (HNSCC) was collected and divided into an exploratory and a validation cohort (208 and 94 patients, respectively). All patients received primary radio-chemotherapy at one of the six DKTK partner sites and underwent a non-contrast-enhanced CT scan for treatment-planning purposes. The analysis was divided into two subsequent steps (Fig. 1): (a) two distinct sub-regions were extracted from GTVe: the tumour boundary of different widths (3,5,10 mm) and the corresponding remaining core volumes. (b) extension of the highest prognostic tumour-boundary sub-volume by different widths (1,2,3,5 mm) beyond the GTVe. 1555 image features were extracted from each sub-volume. Different machine-learning algorithms were used to build radiomic models for the prediction of loco-regional tumour control (LRC). The prognostic performance was measured by the concordance index (C-Index). Finally, patients were stratified into groups of low and high risk of recurrence using the median risk value. Differences in LRC were evaluated by log-rank tests. Results: The validation C-Index averaged over all learning algorithms and feature selection methods using the GTVe revealed a high prognostic performance for LRC (C-Index: 0.63±0.03 (mean±std)). The boundary sub-volumes GTV5mm and GTV10mm showed a slightly improved accuracy (C-Index: 0.64±0.03 and 0.64±0.02, respectively), while models based on the corresponding core volumes had a lower accuracy (C-Index: 0.59±0.03 and 0.60±0.03, respectively, (Fig. 2A)). Also the risk groups could be better separated using the GTV5mm (p

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Background and purpose: Pronounced early side effects have been suggested to be a positive prognostic factor in patients undergoing chemo-radio-therapy (CRT) for head and neck squamous cell carcinomas (HNSCC). We assessed the utility of positron emission tomography (PET) during treatment to analyze the correlation of 18F-fluorodeoxyglucose (FDG) uptake in off target structures within the irradiated volume with outcome. Material and methods: Two independent cohorts of patients with locally advanced HNSCC, both treated within prospective clinical imaging trials with curatively intended CRT were retrospectively analyzed. The exploratory cohort included 50, the independent validation cohort 26 patients. Uptake of FDG in mucosa and submucosal soft tissues (MST) as well as in other structures was assessed at week 4 during treatment. Considered endpoints were local tumor control (LC) and overall survival (OS). The prognostic value of FDG uptake on the endpoints was measured by the concordance index (ci) using univariate and multivariate Cox regression analyses based on the continuous variables of the exploratory cohort. Results: In the exploratory cohort FDG uptake in MST was prognostic for LC (hazard ratio HR = 0.23, p = 0.025) and OS (HR = 0.30, p = 0.003) in univariate analyses. These findings remained significant upon multivariate testing (LC HR = 0.14, p = 0.011; OS HR = 0.20, p = 0.001) and were confirmed in the validation cohort for LC (HR = 0.15, p = 0.034) and OS (HR = 0.17, p = 0.003). Also the SUVmean threshold of MST that was generated within the exploratory cohort (2.375) yielded significant differences in OS (p = 0.006) and a statistical trend for LC (p = 0.078) when applied to the validation cohort. Conclusions: FDG uptake in normal tissues within the irradiated volume measured by PET during treatment has significant prognostic value in HNSCC. This effect may potentially be of use for personalized treatment adaptation.

Purpose Early side effects including oesophagitis are potential prognostic factors in patients undergoing radiochemotherapy (RCT) for locally advanced oesophageal cancer (LAEC). We assessed the prognostic value of 18F-fluorodeoxyglucose (FDG) uptake within irradiated non-tumour-affected oesophagus (NTO) during restaging positron emission tomography (PET) as a surrogate for inflammation/oesophagitis. Methods This retrospective evaluation included 64 patients with LAEC who had completed neoadjuvant RCT and had successful oncological resection. All patients underwent FDG PET/CT before and after RCT. In the restaging PET scan maximum and mean standardized uptake values (SUVmax, SUVmean) were determined in the tumour and NTO. Univariate Cox regression with respect to overall survival, local control, distant metastases and treatment failure was performed. Independence of clinically relevant parameters was tested in a multivariate Cox regression analysis. Results Increased FDG uptake, measured in terms of SUVmean in NTO during restaging was significantly associated with complete pathological remission (p = 0.002) and did not show a high correlation with FDG response of the tumour (rho < 0.3). In the univariate analysis, increased SUVmax and SUVmean in NTO was associated with improved overall survival (p = 0.011, p = 0.004), better local control (p = 0.051, p = 0.044), a lower rate of treatment failure (p < 0.001 for both) and development of distant metastases (p = 0.012, p = 0.001). In the multivariate analysis, SUVmax and SUVmean in NTO remained a significant prognostic factor for treatment failure (p < 0.001, p = 0.004) and distant metastases (p = 0.040, p = 0.011). Conclusions FDG uptake in irradiated normal tissues measured on restaging PET has significant prognostic value in patients undergoing neoadjuvant RCT for LAEC. This effect may potentially be of use in treatment personalization.

Background: Primary tumor (Tu) hypoxia based on hypoxia-specific PET-imaging is a known prognostic parameter for locally-advanced head-and-neck cancer patients. A secondary analysis of the prospective clinical trial on repeated pre- and per-treatment [18F]fluoromisonidazole (FMISO) PET/CT imaging aimed to assess whether parallel evaluation of the oxygenation status in lymph node metastases (LN) and the Tu increases its prognostic value. Patients and methods: Patients with LN-positive disease from the trial (NCT00180180, Zips et al. 2012, Seidlitz et al. 2015) were included in this analysis (n=45). The patients were treated with curatively intended radiochemotherapy (RCT). The imaging protocol consisted of FMISO PET/CT at four time points: baseline, week 1, 2 and 5. Delineation of the Tu and LNs was based on pre-treatment FDG PET/CT. Qualitative hypoxia analysis was performed for each Tu and LN using a visual binary scale: hypoxic or normoxic being FMISO uptake higher than or equal to background respectively. Based on this scale two prognostic parameters were defined: Tu hypoxia (patients with a hypoxic Tu, independently of LN oxygenation status) and synchronous Tu- and LN-hypoxia (Tu&LN-hypoxia). In the patients with a large LN (n=15) a quantitative analysis of FMISO PET/CT was performed to validate the qualitative hypoxia scale. The log-rank test and multivariate Cox-regression were used to evaluate the prognostic impact of hypoxia on local control (LC) and loco-regional control (LRC). Results: Qualitative FMISO assessment (Table 1) confirmed poor LC in patients with Tu hypoxia in week 2 and 5. Detection of synchronous Tu- and LN-hypoxia had a strong negative impact on LC and LRC at all measured time-points. These results were supported by multivariate analysis (for LRC: HR=14.8, p=0.016; HR=8.3, p=0,003 and HR=5.5, p=0,005 at baseline, in week 2 and 5, respectively). Moreover, there was a significant correlation between the qualitative and quantitative FMISO PET/CT parameters (p0.6-0.8). Conclusions: Parallel evaluation of tumor and LN hypoxia improved the prognostic information in comparison to primary tumor assessment alone, based on secondary analysis of the Dresden FMISO PET/CT trial. If this prognostic value of synchronous tumor- and LN-hypoxia is confirmed in ongoing prospective clinical trials and show to outperform tumor assessment only, it may become a powerful decision-making parameter useful for dose escalation or combined modality trials.

Background: 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 ratio, TLR). 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. Methods: 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 60min 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 . Results: Correlation analysis revealed a linear correlation of SUVliver vs. SUVblood (R2 =0.83) and of TLR vs. SURtc (R2 =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). Conclusion: 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.