Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial)

Abstract

Purpose: The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (¹⁶⁶Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume).

Methods: In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of ¹⁶⁶Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of ¹⁶⁶Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort.

Results: Twelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up.

Conclusion: Adjuvant (super-)selective infusion of ¹⁶⁶Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm.

Trial registration: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Keywords: Adjuvant therapy; Dose-escalation study; Hepatocellular carcinoma; Holmium-166; Radiofrequency ablation; Trans-arterial radioembolization.

Fig. 1

Schematic drawings of the study procedure. A HCC lesion of 2–5 cm. B Thermal ablation of HCC lesion. C Potential sites of local recurrences due to impaired heat propagation, heat-sink effect, or satellite nodules. D Target volume for adjuvant TARE. E Deposition of ¹⁶⁶Ho-MS with preferential flow of microspheres to the hyperemic zone surrounding the ablated tissue (i.e., target volume). F Liver volume infused with ¹⁶⁶Ho-MS TARE (i.e., treatment volume) [22].

Fig. 2

Flowchart of the study population.

Fig. 3

HORA EST HCC treatment sequence: A Arterial scan phase of diagnostic MRI showing a hypervascular HCC lesion of 31 mm in the liver. B Portal venous scan phase of MRI showing central wash-out in the HCC lesion. C Intraprocedural CT after placement of six cooled-tip RFA needles with 3-cm exposed tip. D Intraprocedural contrast enhanced CT scan in arterial phase showing hyperemia around the ablation zone on post-ablation CECT. E Super-selective catheterization of hepatic arteries with vascular supply to the target volume. F CBCT of the treatment volume with an identical catheter position as in E. G SPECT-CT of [^99mTc]Tc-MAA dose distribution used for dose planning. H SPECT-CT of ¹⁶⁶Ho-MS distribution. I MRI-based dosimetry of ¹⁶⁶Ho-MS distribution.

Fig. 4

Dose distribution per patient within treatment volume, based on SPECT imaging. The bars in black represent the mean absorbed dose on the target volume directly surrounding the ablation volume per patient. The cutoff point of an absorbed target volume dose of $\ge$ 120 Gy is indicated by the horizontal dashed line. The bars in white show the absorbed dose to the non-target volume within the treatment volume. The first two patients were treated with 60 Gy to the treatment volume, whereas the other patients were treated with 90 Gy to the treatment volume. The median ratio of target volume dose vs non-target volume dose was 1.97 (IQR, [1.75–2.17]).

Fig. 5

Histology of explanted liver treated with radiofrequency ablation and adjuvant ¹⁶⁶Ho TARE. Digitalized histology using Ultra Fast Scanner (Philips Healthcare, Best, The Netherlands) with a magnitude of 40×. A Zoom 10×. Transition from liver tissue with ductal proliferation to fibrosis with marked depositions of ¹⁶⁶Ho-MS. B Zoom 5×. Overview of transition from ductal proliferation to necrotic tissue with marked ¹⁶⁶Ho-MS.