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

  • Laboratory Investigation
  • Interventional Oncology
  • Published:
CardioVascular and Interventional Radiology Aims and scope Submit manuscript

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.

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Abbreviations

ALP:

Alkaline phosphatase

ALT:

Alanine transaminase

ANOVA:

Analysis of variance

AST:

Aspartate transaminase

CE:

Contrast enhanced

DSA:

Digital subtraction angiography

DEBIRI:

Drug-eluting beads loaded with irinotecan chemoembolization

ETV:

Enhancing tumor volume (imaging)

ETV%:

Enhancing tumor volume percentage (imaging)

H&E:

Hematoxylin and eosin

IV:

Intravenous

LFTs:

Liver function tests

MRI:

Magnetic resonance imaging

NA:

Necrotic area (pathology)

NTV:

Non-enhancing tumor volume (imaging)

ROI:

Regions of interest

T1W:

T1-weighted MRI

TACE:

Transarterial chemoembolization

TA:

Overall tumor area (pathology)

TV:

Tumor volume (imaging)

VA:

Viable tumor area (pathology)

VA%:

Percentage of tumor that is viable (pathology)

Y90:

Yttrium-90 radioembolization

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Acknowledgements

The authors thank Northwestern University Healthy Physics (Jose Macatangay, Joseph Princewill, Thomas E. Whittenhall Jr., Angelica E. Gheen). Animal housing and husbandry was provided by the Center for Comparative Medicine (Dr. Stephen I. Levin, Giovanni Pompilio). Imaging for our studies was made possible by Northwestern University's Center for Translational Imaging (Daniel Procissi, Sol Misener). Survival studies were supported through dedicated housing and accommodation by the Center for Comparative Medicine (Dr. Stephen I. Levin, Giovanni Pompilio).

Funding

We are grateful for the generous funding provided by the SIR Foundation Allied Scientist Grant (ACG) and the Department of Radiology of the Feinberg School of Medicine. ACG Medical Scientist Training Program (T32GM008152). Dose vials, administration kits, and additional funding for research materials were provided through a research grant from BTG. RS is supported in part by NIH grant CA126809. SBW receives salary support from NIH grant 5R25 CA 132822-03 and a RSNA Foundation Research Scholar Grant. The listed authors performed data collection, analysis, and manuscript preparation independently without assistance from funding sources. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 and the Robert H Lurie Comprehensive Cancer Center Pathology Core Facility (Bernice Frederick, Adriana Rosca, Demirkan Gürsel).

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Authors and Affiliations

  1. Department of Radiology, Northwestern University Feinberg School of Medicine, 737 N. Michigan Ave, 16th Floor, Chicago, IL, 60611, USA

    Andrew C. Gordon, Yihe Yang, Vanessa L. Gates, Daniel Procissi, Kathleen R. Harris, Zhuoli Zhang, Tianchu Lyu, Xiaoke Huang, Riad Salem, Robert J. Lewandowski & Andrew C. Larson

  2. Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA

    Andrew C. Gordon & Andrew C. Larson

  3. Department of Radiology, Division of Vascular and Interventional Radiology, Medical College of Wisconsin, Milwaukee, WI, USA

    Sarah B. White

  4. BTG International Inc, West Conshohocken, PA, USA

    Matthew R. Dreher

  5. Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    Reed A. Omary

  6. Department of Medicine-Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Riad Salem & Robert J. Lewandowski

  7. Department of Surgery-Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Riad Salem & Robert J. Lewandowski

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  1. Andrew C. Gordon
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Corresponding author

Correspondence to Andrew C. Gordon.

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Conflict of interest

RAO and ACL are founders and owners of IO-RAD and received grant funding from BTG for this study. SBW is a consultant for IO-RAD and Guerbet, and receives research support from Siemens and Guerbet. RJL and RS served as scientific advisors to BTG. RJL is a consultant for ABK. MRD is an employee of BTG. None of the other authors have identified any conflict of interest.

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Gordon, A.C., White, S.B., Yang, Y. et al. Feasibility of Combination Intra-arterial Yttrium-90 and Irinotecan Microspheres in the VX2 Rabbit Model. Cardiovasc Intervent Radiol 43, 1528–1537 (2020). https://doi.org/10.1007/s00270-020-02538-x

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