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Clinical Trial
. 2023 Aug 18;23(1):771.
doi: 10.1186/s12885-023-11280-9.

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol

Daan Andel  1 , Marnix G E H Lam  2 , Joep de Bruijne  3 , Maarten L J Smits  2 , Arthur J A T Braat  2 , Adriaan Moelker  4 , Erik Vegt  4 , Simeon J S Ruiter  5 , Walter Noordzij  6 , Gianluca Grazi  7 , Giulio E Vallati  8 , Roel J Bennink  9 , Otto M van Delden  9 , Onno W Kranenburg  10 , Jan N M Ijzermans  11 , Maarten W Nijkamp  5 , Joris I Erdmann  12 , Rosa Sciuto  13 , Jeroen Hagendoorn  10 , Inne H M Borel Rinkes  14
Affiliations
Clinical Trial

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol

Daan Andel et al. BMC Cancer. .

Abstract

Background: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant.

Methods: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank.

Discussion: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice.

Trial registration: Netherlands Trial Register NL8902 , registered on 2020-09-15.

Keywords: 166Ho; Hepatocellular carcinoma; Holmium-166; Radiation lobectomy; Radioembolization; Unilobar radioembolization.

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Conflict of interest statement

The department of Radiology and Nuclear Medicine of the University Medical Centre Utrecht receives royalties for 166Ho microspheres. MGEHL is a consultant for and receives research support from Terumo and Boston Scientific. AJATB is a consultant for Terumo and Boston Scientific. MLJS is a consultant for Terumo, Philips and Swedish Orphan Biovitrum. All other authors declared no conflicts of interest.

Figures

Fig. 1
Fig. 1
Dose escalation example. Green circles represent patients that did not experience a dose-limiting toxicity at a given dose. Red circles represent patients that did experience a dose-limiting toxicity. The y-axis represents the dose to the non-tumourous liver tissue. In this example, two patients in the 80 Gy cohort experienced a dose-limiting toxicity, meaning the maximal tolerable dose is found and set to 70 Gy (with 18 patients included). The escalation will halt if no maximal tolerable dose is found after 80 Gy. Note that the last safe cohort will always include six patients
Fig. 2
Fig. 2
Study flowchart. Eligibility is assessed during the screening visit (patient and tumor characteristics) as well as the scout dose (lung shunting, extrahepatic depositions, etc.). Patients will be considered included once they received the actual treatment dose. The post-treatment follow-up visits serve to map toxicities, as well as to evaluate eligibility for resection. *The exact interval will be at 1.5, 3, 4.5, 6 and 9 months. The last follow-up will be at 9 months following treatment (if not converted) or 3 months after hepatectomy
Fig. 3
Fig. 3
Activity planning models. While the BSA and mono-compartment models assume homogenous distribution within the perfused part of the liver (indicated in the picture with equal distribution of blue microspheres in tumour and non-tumourous liver tissue) the multi-compartment model postulates three compartments with different activity uptakes: tumour, non-tumourous liver tissue and lung tissue (not depicted). The multi-compartment model permits the selection of a prescribed dose that optimizes the dose to one of the compartments – in the case of the RALLY study this is the non-tumorous liver tissue. The expected activities in each compartment will be based on the distribution of the 166Ho scout dose. Non-tumourous liver-absorbed dose is an important factor for safety (primary objective of the RALLY study) as well as FLR response (secondary objective) and tumour-absorbed dose determines tumour response (secondary objective). As such the multi-compartment model increases safety and efficacy. Notice that in the RALLY study, microspheres are administered to one lobe and not to the whole liver
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