Search

Background: Palliative systemic treatment in patients with advanced or metastatic esophagogastric cancer may result in improved overall survival and quality of life but can also lead to considerable toxicity. In various cancer types, severe muscle mass depletion (sarcopenia) and poor muscle strength are associated with decreased survival and increased chemotherapy‐related toxicity. The aim of this study is to determine the impact of body composition on survival and chemotherapy toxicity in esophagogastric cancer patients treated with first‐line palliative chemotherapy. Methods: A total of 88 patients with advanced esophagogastric cancer treated with standard first‐line palliative systemic therapy consisting of capecitabine and oxaliplatin (CapOx) between January 2010 and February 2017 were included. Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, were measured using pre‐treatment of all patients and evaluation computed tomography scans after three treatment cycles of 65 patients and were used to determine sarcopenia and sarcopenic obesity (i.e. sarcopenia and body mass index >25 kg/m2). The associations between body composition (SMI, SMD, sarcopenia, and sarcopenic obesity) and survival and toxicity were assessed using univariable and multivariable Cox and logistic regression analyses, respectively. Results: Of 88 patients, 75% was male, and median age was 63 (interquartile range 56–69) years. The majority of patients had an adenocarcinoma (83%). Before start of treatment, 49% of the patients were sarcopenic, and 20% had sarcopenic obesity. Low SMD was observed in 50% of patients. During three cycles CapOx, SMI significantly decreased, with a median decrease of 4% (interquartile range −8.6–−0.4). Median progression‐free and overall survival were 6.9 and 10.1 months. SMI, SMD, sarcopenia, and sarcopenic obesity (both pre‐treatment and after three cycles) were neither associated with progression‐free nor overall survival. Pre‐treatment SMD was independently associated with grade 3–4 toxicity (odds ratio 0.94; 95% confidence interval 0.89–1.00) and sarcopenic obesity with grade 2–4 neuropathy (odds ratio 3.82; 95% confidence interval 1.20–12.18). Conclusions: Sarcopenia was not associated with survival or treatment‐related toxicity in advanced esophagogastric cancer patients treated with CapOx. Pre‐treatment sarcopenic obesity was independently associated with the occurrence of grade 2–4 neurotoxicity and skeletal muscle density with grade 3–4 toxicity. [ABSTRACT FROM AUTHOR]

Purpose: To compare 6 diffusion-weighted imaging (DWI) MRI models for response evaluation in patients with pancreatic ductal adenocarcinoma (PDAC).Materials and Methods: DWI images were acquired at 3T for b = 0-600 s/mm2 in fourteen patients with advanced PDAC during 2 separate pretreatment sessions and 9 patients with (borderline) resectable PDAC pre and post neoadjuvant chemoradiation. Data was fitted with a mono-exponential (ADC), double mono-exponential to b = 0 and 100 s/mm2 (ADCfast), and b = 100 and 600 s/mm2 (ADCslow), IVIM model with D* free (D, f, D*) and fixed (D, f), tri-exponent (D, f1, f2), and stretched exponent model (DDC, α). Goodness of fit (adjusted R2), tumor to normal tissue contrast, repeatability (coefficient of variation), and parameter correlations (Spearman's rho) were assessed for the repeated measures. Treatment induced changes were assessed and compared to the repeatability.Results: The mono-exponential model had the lowest goodness of fit in both tumor (R2 = 0.94) and normal-appearing pancreas (R2 = 0.88). Tumour to normal tissue contrast was higher for the 'non-diffusion' parameters (ADCfast, f, D*, f1, f2, α), with better repeatability for the diffusion parameters (ADC, ADCslow, D, DDC). Diffusion parameters were strongly correlated between the models (rho ≥0.81) and showed a general treatment associated increase. All models were able to identify individual treatment effects, showing a change greater than the repeatability in 5 out of 9 patients for at least one of the parameters.Conclusions: Individual treatment evaluation is possible with all investigated DWI models, with treatment associated changes exceeding the repeatability. The double monoexponential fit with ADCfast and ADCslow is able to discriminate between non-diffusion and diffusion related effects, is measured fast and can be performed on most commercial scanners, making it an attractive alternative for the more advanced multiparametric models in radiotherapy treatment evaluation. [ABSTRACT FROM AUTHOR]

In this study we investigate a CT radiomics approach to predict response to chemotherapy of individual liver metastases in patients with esophagogastric cancer (EGC). In eighteen patients with metastatic EGC treated with chemotherapy, all liver metastases were manually delineated in 3D on the pre-treatment and evaluation CT. From the pre-treatment CT scans 370 radiomics features were extracted per lesion. Random forest (RF) models were generated to discriminate partial responding (PR, >65% volume decrease, including 100% volume decrease), and complete remission (CR, only 100% volume decrease) lesions from other lesions. RF-models were build using a leave one out strategy where all lesions of a single patient were removed from the dataset and used as validation set for a model trained on the lesions of the remaining patients. This process was repeated for all patients, resulting in 18 trained models and one validation set for both the PR and CR datasets. Model performance was evaluated by receiver operating characteristics with corresponding area under the curve (AUC). In total 196 liver metastases were delineated on the pre-treatment CT, of which 99 (51%) lesions showed a decrease in size of more than 65% (PR). From the PR set a total of 47 (47% of RL, 24% of initial) lesions were no longer detected in CT scan 2 (CR). The RF-model for PR lesions showed an average training AUC of 0.79 (range: 0.74–0.83) and 0.65 (95% ci: 0.57–0.73) for the combined validation set. The RF-model for CR lesions had an average training AUC of 0.87 (range: 0.83–0.90) and 0.79 (95% ci 0.72–0.87) for the validation set. Our findings show that individual response of liver metastases varies greatly within and between patients. A CT radiomics approach shows potential in discriminating responding from non-responding liver metastases based on the pre-treatment CT scan, although further validation in an independent patient cohort is needed to validate these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: One of the reasons for treatment resistance of PDAC is the desmoplastic reaction initiating the production of large amounts of tumor stroma. LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion. This suggests a clinical benefit of gemcitabine and nab-paclitaxel in combination with LDE225 in patients who received prior FOLFIRINOX. Future phase III clinical trials should confirm these results. Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients. Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI. Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9–8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity. Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion. [ABSTRACT FROM AUTHOR]