Monika Uhrig

Monitoring targeted therapy using dual-energy CT: Semi-automatic RECIST plus supplementary functional information by quantifying iodine uptake of melanoma metastases

Abstract Aim: Supplementary functional information can contribute to assess response in targeted therapies. The aim of this study was to evaluate semi-automatic RECIST plus iodine uptake (IU) determination in melanoma metastases under BRAF inhibitor (vemurafenib) therapy using dual-energy computed tomography (DECT). Methods: Nine patients with stage IV melanoma treated with a BRAF inhibitor were included. Contrast-enhanced DECT was performed before and twice after treatment onset. Changes in tumor size were assessed according to RECIST. Quantification of IU (absolute value for total IU (mg) and volume-normalized IU (mg/ml)) was based on semi-automatic tumor volume segmentation. The decrease compared with baseline was calculated. Results: The mean change of RECIST diameter sum per patient was −47% at the first follow-up (FU), −56% at the second FU (P < 0.01). The mean normalized IU per patient was −21% at the first FU (P < 0.2) and −45% at the second FU (P < 0.01). Total IU per patient, combining both normalized IU and volume, showed the most pronounced decrease: −89% at the first FU and −90% at the second FU (P < 0.01). Conclusion: Semi-automatic RECIST plus IU quantification in DECT enables objective, easy and fast parameterization of tumor size and contrast medium uptake, thus providing 2 complementary pieces of information for response monitoring applicable in daily routine.

Histogram analysis of iodine maps from dual energy computed tomography for monitoring targeted therapy of melanoma patients

AIM Iodine quantification with dual energy computed tomography (DECT) enables quantitative assessment of contrast medium uptake. Our purpose was to investigate patterns of enhancement under BRAF inhibitor therapy by performing histogram analyses (HAs) of iodine maps. MATERIALS & METHODS A total of 11 stage IV melanoma patients (32 metastases) underwent DECT at baseline and at least one follow up. Iodine uptake and HAs including maximum HU value (MAX), mean HU value (MEAN) and standard deviation (STD) was calculated. RESULTS For BRAF-responders MEAN, MAX and STD decreased significantly (p < 0.05). Nonresponder showed increasing MAX and STD for six out of seven lesions, while MEAN and Iodine uptake decreased (four) and increased (three). CONCLUSION HA based on DECT enables a quantitative and functional criterion and contributes to accurate response assessment for promising targeted therapies.

Therapy response assessment in metastatic melanoma patients treated with a BRAF inhibitor: adapted Choi criteria can reflect early therapy response better than does RECIST.

PURPOSE Targeted therapy can lead to considerable tumor reduction and may result initially in altered tissue at constant tumor size. In this setting, Response Evaluation Criteria in Solid Tumors (RECIST) can be inadequate for assessing early treatment response. Choi-criteria combine both size and density measurements. Our purpose was to evaluate computed tomography (CT) images of melanoma patients under BRAF-inhibitor therapy according to Choi-criteria which were adapted to our study (aChoi). MATERIAL AND METHODS Twelve patients (four male, eight female, mean age 49) with stage IV melanoma treated with a BRAF inhibitor were included. Response was assessed according to RECIST for 39 lesions in contrast-enhanced CT. Target volumes are semiautomatically segmented to calculate mean density for aChoi-criteria, thus using a two-dimensional nonstandardized region of interest could be prevented. RESULTS Eight patients are RECIST responders. aChoi-criteria indicate therapy response earlier compared to RECIST in five of eight patients. In seven cases, tumor density in CT had decreased 8 weeks after therapy start, whereas in some cases tumor size diminished less or even increased. Response according to aChoi was diagnosed in seven patients who showed in RECIST-evaluation stable disease in five and partial response in two cases. Fifteen weeks after therapy start almost all patients within the aChoi responders were RECIST responders, too. Only one aChoi responder showed still stable disease in RECIST. CONCLUSION Our initial data indicate that aChoi-criteria can reflect response to vemurafenib earlier compared to RECIST. This is of clinical significance as BRAF-inhibitors are cost-intensive targeted therapies and can cause severe side effects, so criteria for early therapy response have to be evaluated.

Improved detection of melanoma metastases by iodine maps from dual energy CT

OBJECTIVE Metastatic disease in melanoma has an unpredictable nature with deposits in rare locations such as musculature. Dual energy CT (DECT) provides high contrast-visualization of enhancement by using spectral properties of iodine. Purpose of this study was to evaluate whether iodine maps from DECT improve lesion detection in staging examinations of melanoma patients. METHODS This retrospective study was approved by IRB and written informed consent was obtained from all patients. 75 contrast-enhanced DECT scans (thorax and abdomen) from 75 melanoma patients (n=69 stage IV; n=6 stage III) were analysed. For each patient, conventional CT and iodine maps were reviewed independently by two radiologists. The number of lesions detected by reviewing the iodine maps following conventional CT was recorded. Unweighted Cohens Kappa coefficient (κ) was used for concordance analysis, Wilcoxon test for comparing lesion detection rates. RESULTS In 26 patients, at least one reader found additional lesions on iodine maps (inter-reader agreement 89%, κ=0.74 (0.742-0.747)). Compared to grey-scale images, mean detection rate for metastases improved from 86% (range 82-90) to 94% (90-99%) (p≤0.01), for muscle metastases from 8% (8-8%) to 99% (98-100%) (p≤0.06). Findings included 2 pulmonary emboli. CONCLUSION Iodine maps from DECT improve detection of metastases, especially muscle metastases, and relevant findings in staging examinations of melanoma patients.

Dual-energy CT for therapy monitoring: histogram analyses of iodine maps reveal typical pattern of enhancement

Aim Functional information for appropriate therapy monitoring of advanced targeted therapies is essential, but standard follow up (FU) examinations with computed tomography (CT) still focus on traditional size measurements. Iodine quantification with dual energy CT (DECT) enables additional quantitative assessment of contrast media uptake. Our purpose was to investigate patterns of contrast media enhancement under BRAF inhibitor therapy (BRAF-I) by performing histogram analyses (HA) of iodine maps based on DECT.

SU-FF-T-116: Multicriteria IMRT Planning with Equivalent Uniform Dose (EUD) Objectives: Tumor Dose Homogeneity vs. Critical Structure Sparing

Purpose: To quantify the tradeoff between target dose homogeneity and critical structure sparing in two typical IMRT situations (prostate, para‐spinal). Furthermore, to determine the sensitivity to the response model used for critical structures (maximum vs. mean dose). Method and Materials: An EUD‐based multicriteria linear programming environment has been developed. In this work, we enforce a tumor minimum dose and compute solutions which efficiently tradeoff the tumor maximum dose and organ‐at‐risk (OAR) EUD (α⋅max dose+(1 − α) ⋅mean dose). Pareto surfaces resulting from different OAR α values are compared. The technique is applied to the RTOG horseshoe target and circular OAR geometry (varying the OARs size and location), and to two clinical cases. Results: Mathematically, if the maximum and mean doses of a structure are correlated then the choice of α does not affect the shape of the Pareto frontier. We demonstrate that this correlation is stronger for smaller OARs (a single voxel has a large impact on the mean), and also for symmetrically located OARs, which have a large set of outer ring voxels near the maximum level, as opposed to asymmetrically located OARs where the maximum dose is more localized. As the dose requirements in the tumor get more strict, we see less variance with α, since the feasible solution space is smaller. We consistently see little to no difference between Pareto surfaces for α from 0.5 to 1. Conclusion: By characterizing the conditions under which the Pareto frontier is insensitive to α, we highlight situations where it may not be necessary to know the best value of α, i.e., the exact tissue organization between purely serial and purely parallel. In general we see smooth Pareto surfaces but in some cases there were kinks pointing to outstanding treatment plans.

Incidental pulmonary emboli in stage IV melanoma patients: Prevalence in CT staging examinations and improved detection with vessel reconstructions based on dual energy CT

Objectives Malignancy is the strongest predictor for venous thromboembolism. Dual energy CT (DECT) can support assessment of pulmonary emboli (PE) by providing vessel reconstructions (DECT-VR) and highlighting thrombi. Purpose was to determine prevalence and risk factors of PE in staging examinations of stage IV-melanoma patients and to evaluate the potential of DECT-VR to improve PE diagnosis. Material and methods This retrospective study was approved by IRB. Contrast-enhanced, conventional grey scale CT (cCT) and DECT-VR of 200 stage IV-melanoma patients were reviewed by three radiologists in consensus. Overall prevalence was determined. One-sided Wilcoxon-test was performed to compare the number of detected emboli between cCT and cCT with supplementary DECT-VR. Frequencies of risk factors were compared with χ2 test. Results On cCT, 9 PE were detected (6 patients, correlating to 3% of the study population with 0.05 emboli per patient). With the supplementary DECT-VR, number of diagnosed emboli increased from 9 to 17 (p < 0.05) (in total 9 patients, correlating to 0.09 emboli per patient). Emboli on DECT-VR were mainly subsegmentally (7 of 8). There was no significant difference in the frequency of risk factors. Conclusions The prevalence of pulmonary emboli in our cohort of 200 stage IV melanoma patients was 5%. DECT-VR improved significantly diagnosis of PE, especially when located subsegmentally.

SU‐FF‐T‐112: First Evaluation of a New Multicriteria Optimization Tool‐Investigation of Pareto‐Surfaces for IMRT Prostate Plans

Purpose: The aim of this paper is a first evaluation of the performance of a new multi-criteria optimization (MCO) tool developed for IMRT treatment planning Method and Materials: The new MCO-tool computes a set of Pareto-optimal plans by simultaneously minimizing dose indicators for tumor targets and considered organs at risk. For the tumor, the dose homogeneity in the target is maximized for a given, prescribed mean dose while relative deviations to upper equivalent uniform dose (EUD) limits are minimized for organs at risk. The exploration of the solution space is done with a visual navigation tool, which provides control bars for each defined dose indicator. The navigation tool uses real-time interpolation to allow a smooth transition between the pre-computed plans. As a clinical example we consider a simplified prostate case where the only structures to be optimized are the PTV, rectum and bladder. The complete database of plans is visualized using EUD-values of the organs at risk and the standard deviation of the target dose as axes. This approximation of the 3D-Pareto-surface is then examined. The sensitivity of the navigation process on the individual dose indicators is analyzed in terms of the gradients on the Pareto-surface. Moreover, effects of rescaling the target dose homogeneity in terms of TCP-values are analyzed. Results: The database provided by the MCO optimization for the simplified prostate case can indeed be presented as a 3D-Pareto-surface. The sensitivity of the navigation process is well reflected by the respective gradient on the Pareto-surface. The rescaling of the target dose homogeneity in terms of TCP values allows studying the sensitivity of the Pareto-surface in terms of the assumed radio-sensitivity of the tumor. Conclusion: A first evaluation of a new MCO-tool has been successfully completed for a simplified prostate case with 3 mutually conflicting optimization criteria.