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Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies

  • Vascular-Interventional
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Abstract

Objectives

To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE).

Methods

This prospective clinical trial (ClinicalTrials.gov: NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016–10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (Cmax) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3–4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher’s exact test, and Pearson correlation.

Results

Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-Cmax increased from 1 segment (DOX-Cmax, 83.94 ± 75.09 ng/mL; DN-DOX-Cmax, 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX-Cmax, 139.66 ± 117.73 ng/mL; DN-DOX-Cmax, 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX-Cmax, 334.35 ± 215.18 ng/mL; DN-DOX-Cmax, 7.11 ± 4.24 ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-Cmax were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE.

Conclusions

This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-Cmax and tumor response after cTACE in liver cancer.

Key Points

• Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (Cmax).

• Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin Cmax after conventional TACE.

• ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.

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Abbreviations

AE:

Adverse events

AUC:

Area under the curve

CBCT:

Cone-beam CT

C max :

Peak concentration

DEB:

Drug-eluting beads

DN:

Dose normalized

DOX:

Doxorubicin

DOXOL:

Doxorubicinol

ETV:

Enhancing tumor volume

HCC:

Hepatocellular carcinoma

IAT:

Intra-arterial therapies

PK:

Pharmacokinetic

qEASL:

Quantitative European association for the study of the liver

RM-ANOVA:

Repeated measurement ANOVA

SD:

Standard deviation

TACE:

Transarterial chemoembolization

T max :

Time of peak concentration

TTV:

Total tumor volume

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Acknowledgements

The authors thank Guerbet for funding this study. L.J.S. is aparticipant in the BIH-Charité Junior Clinician Scientist Program funded by theCharité–Universiätsmedizin Berlin and the Berlin Institute of Health and reports grants from Leopoldina Postdoctoral Fellowship outside the submitted work. J.C. reports grants from the German-Israeli Foundation for Scientific Research and Development, Boston Scientific, and Philips Healthcare. L.J.S., J.C., E.F., and T.S. report grants from the National Institutes of Health (R01 CA206180). L.J.S., J.C., and S.S. report grants from the Rolf W. Günther Foundation for Radiological Research and L.J.S. and J.C. from the Society of Interventional Oncology (SIO) (19-001324) outside the submitted work. I.T.S. reports grants from the Biomedical Education Program (BMEP) outside the submitted work. The authors declare no potential conflict of interest.

Funding

This study has received funding by Guerbet. The authors maintained control over the data.

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Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, Division of Interventional Radiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA

    Lynn J. Savic, Julius Chapiro, Eliot Funai, Isabel T. Schobert, Edvin Isufi, Sophie Stark, Juan Carlos Perez Lozada, Rajasekhara Ayyagari, Jeffrey Pollak & Todd Schlachter

  2. Institute of Radiology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität, and Berlin Institute of Health, Berlin, Germany

    Lynn J. Savic, Isabel T. Schobert & Sophie Stark

  3. Department of Stereotactic and Functional Neurosurgery, University Hospital of Cologne, Cologne, Germany

    Khaled Bousabarah

  4. PreScience Labs/Cage Pharma, Westport, CT, USA

    Jean-Francois H. Geschwind

  5. Sidney Kimmel Comprehensive Cancer Center at Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

    Ping He & Michelle A. Rudek

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  1. Lynn J. Savic
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Correspondence to Todd Schlachter.

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Guarantor

The scientific guarantor of this publication is Todd Schlachter, MD.

Conflict of interest

The authors of this manuscript declare relationships with Guerbet related to the subject matter of the article.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Yanhong Deng kindly provided statistical advice for this manuscript.

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Written informed consent was obtained from all subjects (patients) in this study.

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Institutional Review Board approval was obtained.

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• prospective

• diagnostic and prognostic

• performed at one institution

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Savic, L.J., Chapiro, J., Funai, E. et al. Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies. Eur Radiol 31, 3002–3014 (2021). https://doi.org/10.1007/s00330-020-07380-w

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