Fluorescence-Guided Visualization of Soft-Tissue Sarcomas by Targeting Vascular Endothelial Growth Factor A: A Phase 1 Single-Center Clinical Trial

Abstract

Resection of soft tissue sarcomas (STS) is accompanied by a high rate of tumor-positive surgical margins (14-34%), which potentially leads to decreased disease-free survival. Vascular Endothelial Growth Factor-A (VEGF-A) is overexpressed in malignant tumors, including STS, and can be targeted with bevacizumab-800CW during fluorescence-guided surgery for real-time tumor detection. In this phase 1 clinical trial, we determined the feasibility, safety and optimal dose of bevacizumab-800CW for fluorescence-guided surgery (FGS) in STS for in-and ex vivo tumor detection. Materials and MethodsPatients with a histopathologically diagnosis of STS were included. In the dose-escalation phase, patients received bevacizumab-800CW intravenously 3 days prior to surgery (10, 25 and 50 mg, n=8). In the subsequent dose-expansion phase, 7 additional patients received bevacizumab-800CW at the optimal dose. Fluorescence images in-and ex vivo were obtained during all stages of standard of care. The optimal dose was determined by calculating in-and ex vivo Tumor-to-Background ratios (TBR) and correlating these results with histopathology. ResultsFifteen patients with STS completed this study. All tumors could be visualized during in-and ex vivo imaging. The optimal bevacizumab-800CW dose proved to be 10 mg with a median in vivo TBR of 2.0 (0.58) and an ex vivo TBR of 2.67 (1.6). All seven tumor-positive margins could be observed real-time after surgical resection. Conclusion 4FGS using 10 mg bevacizumab-800CW is feasible and safe for intra-operative imaging of STS, potentially allowing tumor detection and margin assessment during surgery. An additional follow-up phase II study is needed to confirm the diagnostic accuracy.

Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

“…The ex vivo TBR of 21.1 in our present experiments is encouraging for future clinical translation, based on our experience in both preclinical and clinical intra-operative imaging settings [ 32 , 33 ]. Fluorescence was low in neurosurgical background tissues such as brain, skull and muscle, allowing for clear distinction and visualization of tumor tissue.…”

Endoglin/CD105-Based Imaging of Cancer and Cardiovascular Diseases: A Systematic Review

“…Although the efficacy of endoglin-based whole-tumor imaging could be questioned due to the proclivity of endoglin expression on activated endothelium rather than on malignant cells, similar tracers and novel insights suggest differently. For example, the (pre) clinical results of other neoangiogenesis-based tracers, like cRGD-peptide- (α v β 3 integrin) and vascular endothelial growth factor (VEGF)-targeting antibodies demonstrate efficient whole-tumor imaging [ 31 , 32 ]. Next to its high presence on endothelial cells, expression of endoglin has also been shown on fibroblast-like stromal cells at the invasive fronts of colorectal and prostate cancer [ 33 , 34 ].…”

VEGF-targeted multispectral optoacoustic tomography and fluorescence molecular imaging in human carotid atherosclerotic plaques

“…The rst and most straightforward approach could be a dose-escalation study employing an increasing dose of bevacizumab-800CW to approximate the detection limit of optoacoustic imaging, as has been carried out in multiple clinical trials in uorescence-guided surgery and uorescence-guided endoscopy. (12,20) An alternative approach is to conjugate bevacizumab to a dedicated optoacoustic signaling compound, currently not clinically available but has gained increasing attention last decade. (21,22) Optoacoustic contrast agents have been reviewed extensively and ideally exhibit a high molar extinction coe cient in the NIR, a characteristic absorption spectrum with sharp peaks, high photostability, high photothermal conversion e ciency, low quantum yield and favourable biocompatibility.…”