The role and data driven basis for radioembolization remains ill-defined with recent phase III randomized trials negative for patients with hepatocellular carcinoma (HCC), and only a single second line trial in metastatic colorectal cancer (CRC) meeting its primary endpoint progression-free survival (EPOCH, NCT01483027) [1]. Few studies are currently underway to define and/or clarify the role of radioembolization. The search term “radioembolization OR SIRT OR TheraSphere OR TARE” (status: Aug. 2022), revealed 44 clinical trials at clinicaltrials.gov, of which only 25 are currently recruiting. However, additional active trials can be found in registries such as the European Union´s register EudraCT (2 additional active trials) [2] or national such as the German DRKS (3 additional active trials) [3]. Stratifying ongoing clinical trials as published in PubMed or clinicaltrials.gov, the following categories can be defined: (a) clinical trials evaluating the efficacy of SIRT in different tumor biologies metastatic to or primaries of the liver; as the most important subgroup, evaluation of combination therapies with systemic treatment, predominantly combining with checkpoint inhibition, including basic research seeking immune-modulating mechanisms and proof in tissue or blood; (b) assessing new technologies such as Holmium-166 for SIRT; and (c) new approaches (e.g., highly selected patient group) and indications for SIRT, also outside the liver.

The only phase III trial ongoing likely is STOP-HCC (NCT01556490), with advanced HCC patients receiving sorafenib ± radioembolization. Primary endpoint is overall survival, results are expected for end of 2022. However, this concept may come late given most recent developments in systemic HCC treatment shifting to immune checkpoint inhibition [4, 5]. Considering the presumptive immunomodulatory effect of radioembolization such combination therapies might be the future domain of radioembolization, which is supported by the results of a recently published phase II study from Singapore (NCT03033446, radioembolization + Nivolumab) [6] as well as by the promising preliminary results of a phase I (NCT03099564, radioembolization + Pembrolizumab) [7] and phase II study (NCT03380130, radioembolization + Nivolumab) [8]. Therefore, phase II trials such as IMMUWIN (NCT04522544; randomized, radioembolization or transarterial chemoembolization [TACE] combined with Durvalumab/Tremelimumab, primary endpoint objective response rate [ORR], completion 2024), SOLID (NCT04124991; single arm, radioembolization + Durvalumab, time-to-progression, completion 2022) or ROWAN (NCT05063565; randomized, radioembolization alone vs. radioembolization + Durvalumab/Tremelimumab, ORR, completion 2026) are of utmost interest for positioning radioembolization in HCC future treatment strategies. Recently evolved, the ZUGSPITZE trial, may add mechanistic as well as conceptual data through an extensive basic research program (EudraCT 2020-003,925-42, Sponsor LMU München, randomized three arm study, radioembolization standard vs. personalized dose + Durvalumab/Tremelimumab vs.checkpoint first followed by radioembolization on demand, endpoint ORR, completion estimated 2025). Further Phase II single arm studies combining radioembolization and immune checkpoint inhibition target cholangiocellular carcinoma (IMMUWHY, NCT04238637), CRC (SIRTCI, NCT04659382; iRE-C, NCT04108481) or neuroendocrine tumors (NCT03457948). Finally, the only active clinical cancer trial for non-liver indications seems to be POEM (DRKS00021723), a phase I/II trial assessing safety and efficacy as a composite endpoint when using the bronchial arteries to target primary or secondary lung malignancies. Completion is expected 2023. Table 1 provides a selected overview of currently ongoing trials with comments regarding the crucial characteristics of each study.

Table 1 Selected overview of ongoing trials
Full size table

In summary, only a small number of clinical trials are currently active, almost all limited to small Phase II concepts. Given the lack of comprehensive data on the clinical benefit of radioembolization, emerging data clearly will not suffice to secure radioembolization as integral part of future treatment strategies and guidelines.