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

Abstract

No validated predictive biomarkers for antiangiogenic treatment of metastatic renal cell carcinoma (mRCC) exist. Tumor vascular endothelial growth factor A (VEGF-A) level may be useful. We determined tumor uptake of 89 Zr-bevacizumab, a VEGF-A-binding PET tracer, in mRCC patients before and during antiangiogenic treatment in a pilot study. Methods: Patients underwent 89 Zrbevacizumab PET scans at baseline and 2 and 6 wk after initiating either bevacizumab (10 mg/kg every 2 wk) with interferon-α (3-9 million IU 3 times/wk) (n 5 11) or sunitinib (50 mg daily, 4 of every 6 wk) (n 5 11). Standardized uptake values were compared with plasma VEGF-A and time to disease progression. Results: 89 Zrbevacizumab PET scans visualized 125 evaluable tumor lesions in 22 patients, with a median SUV max (maximum standardized uptake value) of 6.9 (range, 2.3-46.9). Bevacizumab/interferon-α induced a mean change in tumor SUV max of −47.0% (range, −84.7 to 120.0%; P , 0.0001) at 2 wk and an additional −9.7% (range, −44.8 to 138.9%; P 5 0.015) at 6 wk. In the sunitinib group, the mean change in tumor SUV max was −14.3% at 2 wk (range, −80.4 to 1269.9; P 5 0.006), but at 6 wk the mean change in tumor SUV max was 172.6% (range, −46.4 to 1236%; P , 0.0001) above baseline. SUV max was not related to plasma VEGF-A at all scan moments. A baseline mean tumor SUV max greater than 10.0 in the 3 most intense lesions corresponded with longer time to disease progression (89.7 vs. 23.0 wk; hazard ratio, 0.22; 95% confidence interval, 0.05-1.00). Conclusion: Tumor uptake of 89 Zr-bevacizumab is high in mRCC, with remarkable interpatient and intrapatient heterogeneity. Bevacizumab/interferon-α strongly decreases tumor uptake whereas sunitinib results in a modest reduction with an overshoot after 2 drugfree weeks. High baseline tumor SUV max was associated with longer time to progression.

Molecular Drug Imaging: 89Zr-Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma

“…89 Zr-labeled bevacizumab PET imaging may help in assessment of the inter-and intrapatient heterogeneity of drug biodistribution in vivo, thereby predicting the presence or absence of a response in patients subsequently treated with bevacizumab. Studies in both mice and adult patients confirmed that 89 Zr-bevacizumab PET imaging was feasible and able to reveal bevacizumab accumulation in VEGF-positive tumors (7,(12)(13)(14). In addition, in adult renal cancer tumors, 89 Zr-bevacizumab uptake was correlated with a response to bevacizumab treatment (13).…”

“…In adults with renal cell carcinoma, it has been shown that a high level of baseline 89 Zr-bevacizumab uptake in tumors before treatment is positively associated with time to progression in bevacizumab-treated patients (13). A difficulty in performing such a study with DIPG patients is that current DIPG trials involve multiagent therapy regimens.…”

“…Studies in both mice and adult patients confirmed that 89 Zr-bevacizumab PET imaging was feasible and able to reveal bevacizumab accumulation in VEGF-positive tumors (7,(12)(13)(14). In addition, in adult renal cancer tumors, 89 Zr-bevacizumab uptake was correlated with a response to bevacizumab treatment (13). The results of our preclinical research with 89 Zr-bevacizumab in mice suggested poor bevacizumab uptake in intracranial tumors; using pontine, striatal, and subcutaneous glioma mouse models, we found no significant uptake of 89 Zr-bevacizumab in intracranial tumors at any stage of the disease or in the normal nonneoplastic surrounding brain in any of the tumor models used (7).…”

Molecular Fluorescence Endoscopy Targeting Vascular Endothelial Growth Factor A for Improved Colorectal Polyp Detection

“…As a consequence, the used artificial model, targeted intraperitoneal xenograft tumors stitched in a human colon specimen, demonstrates the practical feasibility of the proposed technique, but no statements can be made regarding specific tumor or adenoma accumulation in comparison to uptake in healthy human colon tissue. However, clinical studies evaluating the use of 89 Zr-labeled bevacizumab in breast and kidney cancer patients did not show aspecific accumulation of the tracer in the colon (32). Also, the significantly higher VEGF-A expression in colorectal adenomas than in adjacent normal tissue implies that bevacizumab-800CW could be a promising tracer from a diagnostic point of view.…”

Theranostics Using Antibodies and Antibody-Related Therapeutics

“…1B) (21-24). They clearly showed that a drug targeting a growth factor in the microenvironment can be visualized using protein tracer doses as low as 5 mg. For RCCs, 89 Zr-bevacizumab PET showed heterogeneous tracer accumulation in tumor lesions (21). Serial 89 Zr-bevacizumab PET showed that a therapeutic dose of bevacizumab and interferon-a reduced tracer uptake.…”