PET/CT imaging of renal cell carcinoma with (18)F-VM4-037: a phase II pilot study

Abstract

Background: Carbonic anhydrase IX (CA-IX) is a potential imaging biomarker of clear cell renal cell carcinoma (ccRCC). Here, we report the results of a phase II clinical trial of a small molecule radiotracer targeting CA-IX ((18)F-VM4-037) in ccRCC.

Methods: Between October 2012 and May 2013, 11 patients with kidney masses underwent (18)F-VM4-037 PET/CT prior to surgery. Dynamic imaging was performed for the first 45 min post injection and whole-body imaging was obtained at 60 min post injection. Tumors were surgically excised or biopsied within 4 weeks of imaging.

Results: All patients tolerated the radiotracer well with no adverse events. Ten of the 11 patients had histologically confirmed malignancy. One patient had a Bosniak Type 3 cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors only in the kidney. Primary ccRCC lesions were difficult to visualize on PET alone due to high uptake of the tracer in the adjacent normal kidney parenchyma, however when viewed in conjunction with CT, the tumors were easily localized. Metastatic lesions were clearly visible on PET. Mean SUV for primary kidney lesions was 2.55 in all patients; in patients with histologically confirmed ccRCC, the mean SUV was 3.16. The time-activity curves (TAC) are consistent with reversible ligand binding with peak activity concentration at 8 min post injection followed by washout. Distribution Volume Ratio (DVR) of the lesions was measured using the Logan graphical analysis method. The mean DVR value across the 9 kidney lesions was 5.2 ± 2.8, (range 0.68-10.34).

Conclusion: 18F-VM4-037 is a well-tolerated PET agent that allows same day imaging of CA-IX expression. The agent demonstrated moderate signal uptake in primary tumors and excellent visualization of CA-IX positive metastases. While the evaluation of primary ccRCC lesions is challenging due to high background activity in the normal kidney parenchyma, 18F-VM4-037 may be most useful in the evaluation of metastatic ccRCC lesions.

Keywords: 18F-VM4-037; Carbonic anhydrase IX; Positron emission tomography (PET); Renal cell carcinoma.

Conflict of interest statement

Conflict of interest All authors declare that they have no conflict of interest.

Figures

Fig. 1.

A 78-year-old man with left-sided ccRCC detected on contrast enhanced CT (arrow) (A). Axial 18F-VM4-037 PET (B) and PET/CT (C) show uptake within the left kidney lesion (arrow) with an SUVmean of 1.86. Coronal 18F-VM4-037 PET/CT shows the uptake within the left sided lesion (arrow) and the high uptake of the tracer in normal kidney parenchyma as well as in the liver (D).

Fig. 2.

A 44-year-old male with left-sided ccRCC detected on contrast enhanced CT (arrow) (A). Axial 18F-VM4-037 PET (B) and PET/CT (C) show uptake within the left kidney lesion (arrow) with an SUVmean of 2.45. Axial CT shows bilateral metastases in lung bases (SUV = 2.22 in the right lower lobe lesion with histology confirmation of poorly differentiated ccRCC) (arrows) (D). Axial 18F-VM4-037 PET/CT (E) show uptake of 18F-VM4-037 both lesions (arrows).

Fig. 3.

A 62-year-old female with metastatic ccRCC in the left ilium detected on CT (A). The lesions show uptake on axial 18F-VM4-037 PET (B) and PET/CT (C) with SUVmax of 9.61.

Fig. 4.

Time-activity curves (TAC) for the 11 subjects. Note, subject 9 only had a few voxels of liver activity and thus the liver TAC is not well sampled. Visual inspection shows the tumor lesion demonstrating reversible binding of the ligand, while the kidney and liver tissue do not. Also note subject #1 had a benign lesion with no uptake.

Fig. 5.

Logan graphical analysis for the primary lesions. Subjects 1 and 4 had very low uptake and thus the axis were rescaled (color blue). The rest of the Logan plots are graphed using the same X and Y axis scales so one can visually compare the slopes (DVR) of the graphical analysis.

Fig. 6.

The results of both the Logan and Patlak graphical analysis. The Logan graphical analysis showed a strong linear fit for all subjects except subject #5 with an R2 greater than .95. In contrast, the Patlak graphical analysis shows very poor linear fits with R2 fit values much less than .9, thus demonstrating that the ligand shows reversible binding.