A global evaluation of advanced dosimetry in transarterial radioembolization of hepatocellular carcinoma with Yttrium-90: the TARGET study

Abstract

Purpose: To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres.

Methods: TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child-Pugh stage A/B7, BCLC stages A-C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD.

Results: No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy (p = 0.048). Probability of OR was higher with increasing TAD (p = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71-0.95; p = 0.009). Increased TAD was associated with higher probability of AFP response (p = 0.046 for baseline AFP ≥ 200 ng/mL).

Conclusion: Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD.

Trial registration number: NCT03295006.

Keywords: Dosimetry; Hepatocellular carcinoma; Radioembolization; Yttrium-90.

Conflict of interest statement

Marnix Lam, MD, PhD: Is a consultant for Boston Scientific, Terumo and Quirem Medical. He receives research support from Boston Scientific, Terumo and Quirem Medical. The UMC Utrecht receives royalties from Quirem Medical.

Etienne Garin, MD, PhD: Serves as a consultant for Boston Scientific.

Marco Maccauro, MD: Nothing to disclose.

S. Cheenu Kappadath, PhD: Is a consultant for Boston Scientific, Sirtex, and ABK Biomedical. He receives research support from Sirtex.

Daniel Y. Sze, MD, PhD: Was a consultant for Argon, Artio Medical, Astra-Zeneca, Bayer, BlackSwan Vascular, Boston Scientific, Bristol Myers Squibb, Eisai, FluidX, W. L. Gore, Guerbet, Koli, Sirtex, Terumo, TriSalus, and Varian; received institutional research support from Boston Scientific, W. L. Gore, Merit Medical, and Sirtex; held equity in BlackSwan Vascular, Confluent Medical, Koli, Proteus Digital Health, Radiaction, and TriSalus; and serves on data safety monitoring boards for W. L. Gore and Replimune.

Cuneyt Turkmen, MD: Nothing to disclose.

Murat Cantasdemir, MD: Is a consultant for Boston Scientific.

Paul Haste, MD: Is a consultant for Boston Scientific.

Ken Herrmann, MD: Reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from SIRTEX, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from IPSEN, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from ymabs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, outside the submitted work.

Hamad Saleh Alsuhaibani, MD: Nothing to disclose and no conflict of interest.

Matthew Dreher, PhD: Works for Boston Scientific.

Kirk D. Fowers, PhD: Works for Boston Scientific.

Riad Salem, MD: Is a consultant for Boston Scientific, Astrazeneca, Genentech, Sirtex, Cook, Eisai, Bard and QED Therapeutics.

© 2022. The Author(s).

Figures

Fig. 1

Objective response by mRECIST and tumor absorbed dose (TAD). a) Logistic regression curve of probability of objective response by TAD. b) Objective response rate (best response during follow-up) by TAD subgroups

Fig. 2

Logistic regression curve of probability of alpha fetoprotein (AFP) response 90 days post-treatment by tumor absorbed dose (TAD) for patients with baseline AFP levels of ≥ 200 ng/mL

Fig. 3

Overall survival. a Kaplan–Meier curve for all 209 patients. b Cox regression curve of probability of survival at 36 months by tumor absorbed dose TAD). c Kaplan–Meier curves by tumor absorbed dose subgroups