Abstract
Simple SummarySince the knowledge of tumor biology has advanced, a variety of targeted therapies has been developed. These do not immediately affect the tumor size, so optimized oncological imaging is needed. In this phase I study of patients with advanced malignant disease, a multiparametric imaging approach was used to assess changes in tumor perfusion after vessel-occluding therapy with the CD13 targeted truncated tissue factor with a C-terminal NGR-peptide. It comprises different sequences and the use of two different contrast media, ferucarbotran and gadobutrol. This multiparametric MRI protocol enables assessing the therapy effectiveness as early as five hours after therapy initiation.Early assessment of target hit in anti-cancer therapies is a major task in oncologic imaging. In this study, immediate target hit and effectiveness of CD13-targeted tissue factor tTF-NGR in patients with advanced malignant disease enrolled in a phase I trial was assessed using a multiparametric MRI protocol. Seventeen patients with advanced solid malignancies were enrolled in the trial and received tTF-NGR for at least one cycle of five daily infusions. Tumor target lesions were imaged with multiparametric MRI before therapy initiation, five hours after the first infusion and after five days. The imaging protocol comprised ADC, calculated from DWI, and DCE imaging and vascular volume fraction (VVF) assessment. DCE and VVF values decreased within 5 h after therapy initiation, indicating early target hit with a subsequent decrease in tumor perfusion due to selective tumor vessel occlusion and thrombosis induced by tTF-NGR. Simultaneously, ADC values increased at five hours after tTF-NGR administration. In four patients, treatment had to be stopped due to an increase in troponin T hs, with subsequent anticoagulation. In these patients, a reversed effect, with DCE and VVF values increasing and ADC values decreasing, was observed after anticoagulation. Changes in imaging parameters were independent of the mean vessel density determined by immunohistochemistry. By using a multiparametric imaging approach, changes in tumor perfusion after initiation of a tumor vessel occluding therapy can be evaluated as early as five hours after therapy initiation, enabling early assessment of target hit.
Highlights
The assessment of tumor response to novel targeted agents is one of the major challenges in modern oncological imaging [1]
Imaging of Target Hit and Effectiveness For comparison of the different imaging approaches, values are presented as percentage changes from the baseline scan prior to the first truncated tissue factor (tTF)-NGR dose application (Figure 1)
vascular volume fraction (VVF) values decreased to 57 ± 22 % five hours after treatment initiation and to 38 ± 21% after five days of tTF-NGR treatment
Summary
The assessment of tumor response to novel targeted agents is one of the major challenges in modern oncological imaging [1]. Different variations in RECIST have been introduced so far, inter alia the immune-related RECIST criteria for the response evaluation to immune checkpoint inhibitors [5,6] These were later revised to a bi-dimensional measurement [7,8] or modified RECIST for the evaluation of hepatocellular carcinomas, which focuses on the viable, contrast-enhancing tumor parts [9]. While these specific criteria aid in differentiating responders from non-responders for some diseases or treatments, not all patients that benefit from a continued therapy can be adequately identified, and a switch to a different therapy can potentially be delayed. Different imaging approaches to evaluate treatment response to novel targeted therapies, including anti-vascular therapy, are needed so that in case of non-response, therapy can be switched early before clinically progressive disease occurs (fail fast)
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