Everolimus Reduces ⁸⁹Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

Abstract

Everolimus increases progression-free survival in patients with advanced neuroendocrine tumors (NETs). Currently, no biomarkers are available for early selection of patients who will benefit from everolimus. Everolimus can reduce vascular endothelial growth factor A (VEGF-A) production by tumor cells. Therefore, we aimed to investigate the effect of everolimus on tumor uptake of the radioactive-labeled VEGF-A antibody bevacizumab with PET in NET patients. Methods: Patients with advanced progressive well-differentiated NETs underwent 89 Zr-bevacizumab PET scans before and at 2 and 12 wk during everolimus treatment. 89 Zr-bevacizumab uptake was quantified by the maximum standardized uptake value (SUV max ). Tumor response and the percentage change in the sum of target lesion diameters were determined according to Response Evaluation Criteria in Solid Tumors 1.1 on CT (3 monthly). Results: In 4 of the 14 patients entered, no tumor lesions were visualized with 89 Zr-bevacizumab PET. In the remaining patients, 19% of tumor lesions 1 cm or greater known by CT were visualized. Tumor SUV max decreased during everolimus treatment, with a median of −7% at 2 wk (P 5 0.09) and a median of −35% at 12 wk (P , 0.001). The difference in SUV max at 2 and 12 wk with respect to SUV max at baseline correlated with percentage change on CT at 6 mo (r 2 5 0.51, P , 0.05, and r 2 5 0.61, P , 0.01, respectively). Conclusion: This study demonstrates variable 89 Zr-bevacizumab PET tumor uptake in NET patients. 89 Zr-bevacizumab tumor uptake diminished during everolimus treatment. Serial 89 Zr-bevacizumab PET might be useful as an early predictive biomarker of anti-VEGFdirected treatment in NET patients.

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

“…Normal-organ uptake ( Fig. 2A) was consistent with a previous study (14) and with distribution of other antibody tracers (16,17).…”

“…Baseline tumor 89 Zr-bevacizumab uptake in our study was higher than in patients with early breast cancer and in patients with metastatic neuroendocrine tumors (13,14). This observation probably reflects the unique pathobiology of Von Hippel-Lindau gene inactivation in RCC, resulting in high VEGF-A production by tumor cells.…”

“…Local VEGF-A concentration potentially reflects whether angiogenesis drives tumor progression and might predict sensitivity to antiangiogenic treatment. Therefore, we developed the PET tracer 89 Zr-bevacizumab, which enables noninvasive whole-body VEGF-A imaging and quantification (12)(13)(14). Sunitinib and bevacizumab plus interferon-a (IFNa) are standard treatments for mRCC (1,2).…”

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with 89Zr-Fresolimumab PET

“…The median SUV max of 4.6 found in the gliomas is comparable to the SUV max of 5.8 (range, 1.7-15.1) found with 89 Zr-bevacizumab PET in metastatic lesions in patients with neuroendocrine tumors (16). The maximum concentration per dose of 89 Zr-fresolimumab 1 h after injection of 0.37 mg/mL/mg is comparable to the pharmacokinetic results of an earlier study with fresolimumab (17).…”

The future of nuclear medicine imaging of neuroendocrine tumors: on a clear day one might see forever…

“…This concept has been applied to the evaluation of a variety of NETs treated with everolimus. A decrease in the SUV led to the proposal that this technique could be of value as an early predictor of anti-angiogenetic therapeutic efficacy [42].…”