Pieter J Steinkamp1, Bobby K Pranger1, Mei-Fang Li2, Matthijs D Linssen3,4, Floris J Voskuil5, Lukas B Been1, Barbara L van Leeuwen1, Albert J H Suurmeijer6, Wouter B Nagengast4, Schelto Kruijff1,7, Robert J van Ginkel1, Gooitzen M van Dam8,7,9. 1. Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 2. ChangJiang Scholar's Laboratory, Shantou University Medical College, Shantou, China. 3. Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 5. Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 6. Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 7. Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and. 8. Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands g.m.van.dam@umcg.nl. 9. AxelaRx/TRACER BV, Groningen, The Netherlands.
Abstract
Resection of soft-tissue sarcoma (STS) is accompanied by a high rate of tumor-positive surgical margins (14%-34%), which potentially lead to decreased disease-free survival. Vascular endothelial growth factor 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 in STS for in vivo and ex vivo tumor detection. Methods: Patients with a histopathologic diagnosis of STS were included. In the dose-escalation phase, patients received bevacizumab-800CW intravenously 3 d before 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 were obtained in vivo and ex vivo during all stages of standard care. The optimal dose was determined by calculating in vivo and ex vivo tumor-to-background ratios (TBR) and correlating these results with histopathology. Results: Fifteen patients with STS completed this study. All tumors could be visualized during in vivo 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 a median ex vivo TBR of 2.67 (±1.6). All 7 tumor-positive margins could be observed in real time after surgical resection. Conclusion: GS using 10 mg of bevacizumab-800CW is feasible and safe for intraoperative imaging of STS, potentially allowing tumor detection and margin assessment during surgery. An additional follow-up phase 2 study is needed to confirm the diagnostic accuracy.
Resection of soft-tissue sarcoma (STS) is accompanied by a high rate of tumor-positive surgical margins (14%-34%), which potentially lead to decreased disease-free survival. Vascular endothelial growth factor 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 in STS for in vivo and ex vivo tumor detection. Methods:Patients with a histopathologic diagnosis of STS were included. In the dose-escalation phase, patients received bevacizumab-800CW intravenously 3 d before 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 were obtained in vivo and ex vivo during all stages of standard care. The optimal dose was determined by calculating in vivo and ex vivo tumor-to-background ratios (TBR) and correlating these results with histopathology. Results: Fifteen patients with STS completed this study. All tumors could be visualized during in vivo 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 a median ex vivo TBR of 2.67 (±1.6). All 7 tumor-positive margins could be observed in real time after surgical resection. Conclusion: GS using 10 mg of bevacizumab-800CW is feasible and safe for intraoperative imaging of STS, potentially allowing tumor detection and margin assessment during surgery. An additional follow-up phase 2 study is needed to confirm the diagnostic accuracy.
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