Feasibility of Combination Intra-arterial Yttrium-90 and Irinotecan Microspheres in the VX2 Rabbit Model

Abstract

Purpose: To evaluate the combination of ⁹⁰Y radioembolization (Y90) and drug-eluting bead irinotecan (DEBIRI) microspheres in the VX2 rabbit model.

Materials and methods: An initial dose finding study was performed in 6 White New Zealand rabbits to identify a therapeutic but subcurative dose of Y90. In total, 29 rabbits were used in four groups: Y90 treatment (n = 8), DEBIRI treatment (n = 6), Y90 + DEBIRI treatment (n = 7), and an untreated control group (n = 8). Hepatic toxicity was evaluated at baseline, 24 h, 72 h, 1 week, and 2 weeks. MRI tumor volume (TV) and enhancing tumor volume were assessed baseline and 2 weeks. Tumor area and necrosis were evaluated on H&E for pathology.

Results: Infused activities of 84.0-94.4 MBq (corresponding to 55.1-72.7 Gy) were selected based on the initial dose finding study. Infusion of DEBIRI after Y90 was technically feasible in all cases (7/7). Overall, 21/29 animals survived to 2 weeks, and the remaining animals had extrahepatic disease on necropsy. Liver transaminases were elevated with Y90, DEBIRI, and Y90 + DEBIRI compared to control at 24 h, 72 h, and 1 week post-treatment and returned to baseline by 2 weeks. By TV, Y90 + DEBIRI was the only treatment to show statistically significant reduction at 2 weeks compared to the control group (p = 0.012). The change in tumor volume (week 2-baseline) for both Y90 + DEBIRI versus control (p = 0.002) and Y90 versus control (p = 0.014) was significantly decreased. There were no statistically significant differences among groups on pathology.

Conclusion: Intra-arterial Y90 + DEBIRI was safe and demonstrated enhanced antitumor activity in rabbit VX2 tumors. This combined approach warrants further investigation.

Keywords: Chemoembolization; Irinotecan; Magnetic resonance imaging; Radioembolization; Yttrium-90.

Figure 1.

(A) Contrast-enhanced T1W MRI demonstrates an enhancing tumor adjacent to the gallbladder (Gb) in this Y90-treated rabbit. The tumor volume (TV) was contoured along the outer margin of the enhancing tumor while the non-enhancing tumor volume (NTV) was contoured along the inner margin to encompass non-enhancing tumor that was isointense relative to the adjacent liver. (B) Gross pathology on liver explantation demonstrated a necrotic tumor adjacent to the gallbladder (Gb). (C) H&E staining of the tumor was used to define the overall tumor area (TA) taken as the outer margin of VX2 cell clusters and the necrotic area (NA) consisting of acellular material and proteinaceous debris abutting the inner layer of VX2 cells.

Figure 2.

(A) Waterfall plots demonstrating tumor volume (TV) changes from baseline imaging to imaging at 2 weeks in Group A (High Dose, black bars ) versus Group B (Low Dose, open bars ) rabbits treated with Y90. Negative values denote decreased tumor size at 2 weeks. Group A demonstrated decreased tumor volume in 38% (3/8) tumors where no tumor in Group B had decreased volume at 2 weeks. (B) Group A dosing resulted in enhancing tumor volume (ETV) reduction in 50% of tumors (4/8) versus 9% of tumors (1/11) with Group B dosing. Therefore, Group A dosing was selected for future studies as a therapeutic but subcurative Y90 dose.

Figure 3.

Laboratory toxicities after treatment over the 2 week study period: (A) ALT, (B) AST, (C) Albumin, (D) Total Bilirubin, (E) ALP (F) CK.

Figure 4.

MRI findings on contrast-enhanced T1W and T2W images. (A) Y90+DEBIRI. (B) DEBIRI treatment effects observed at 2-weeks included increased necrosis with thinned layers of rim enhancement along the margin of the tumor. (C) Y90 treatment group. (D) Control group with characteristic enhancement on T1w-MRI, hyperintensity on T2w images, and large central areas of necrosis with thick viable tumor periphery.

Figure 5.

Waterfall plots demonstrating (A) tumor volume (TV) changes and (B) enhancing tumor volume (ETV) changes from baseline imaging to imaging at 2 weeks (left to right) in the Control (black bars ), DEBIRI (open bars ), Y90 (blue bars, ), and Y90+DEBIRI Groups (green bars, ). Negative values denote decreased tumor size at 2 weeks. The Y90 and Y90+DEBIRI groups were the only groups to demonstrate decreased TV and/or ETV at 2 weeks. The addition of DEBIRI to Y90 in the Y90+DEBIRI group resulted in decreased TV in 55.6% (5/9) versus 33.3% (4/12) and decreased ETV in 66.7% (6/9) versus 41.7% (5/12) in comparison to Y90 alone.

Figure 6.

MRI measurements of tumor volumes (TV) and enhancing tumor volumes (ETV). Error bars represent SD. (A) TV was significantly reduced in the Y90+DEBIRI group compared to the Control group (p=0.012). (B) ETV was not significantly different among groups.