Trans-Arterial Radioembolisation for HCC: Personalised Dosimetry Beyond Yttrium 90

Abstract

The landscape of hepatocellular carcinoma (HCC) treatment has constantly evolved, striving for personalised, precise and more effective therapeutic options. The utilisation of radioembolisation with yttrium-90 (90Y) has been growing over the past decade despite several initial negative phase 3 randomised trials conducted in patients with advanced HCC where Y90-radioembolisation was tested against sorafenib [1, 2]. This paradox can be explained by positive signals extracted from these trials regarding toxicity and quality of life, a refinement in patient selection criteria and, more importantly, a deeper understanding of the utmost importance of dosimetric parameters. The pivotal DOSISPHERE-01 trial first demonstrated the importance of an optimised and personalised dosimetric approach, aiming to maximise tumour control while minimising the risk to non-tumoral liver tissue [3, 4]. In this context, the study by Bucalau et al. published in this issue marks a significant advancement, introducing Holmium-166 (166Ho) radioembolisation coupled with personalised predictive dosimetry as a treatment modality for patients with HCC [5].

The study by Bucalau et al. followed a rigorous methodology, employing a personalised predictive dosimetry approach to optimise treatment efficacy [5]. By administering a 166Ho-radioembolisation to a targeted population of 15 patients with early to intermediate-stage HCC mostly, the research illustrates the path towards a more individualised treatment paradigm. The investigation reveals a significant achievement as all patients showed an objective response on the targeted tumours at 3 months and a very high complete response rate (78.6%), even in patients with large tumours. This study also highlighted the potential of 166Ho in enhancing the safety of radioembolisation, with no ≥ grade 3 short treatment-related adverse event, in line with previous studies [6]. Furthermore, the study contributes valuable dosimetric data on 166Ho, offering a foundation for future research and clinical application in liver cancer therapy both on the efficacy side (dose to the tumour) and on a safety perspective (dose to the non-tumoral liver). The dual PET imaging (FDG/choline) incorporated in the study further underscores the sophistication of 166Ho-SIRT in assessing tumour metabolism and response, paving the way for its integration into comprehensive cancer management protocols.

The use of Holmium-166 has several theoretical advantages over Yttrium-90 for radioembolisation. First, Holmium-166 emits both beta particles (used for therapeutic effect) and gamma radiation, which can be detected by gamma cameras. This allows for post-procedural imaging to assess the distribution of the radioembolisation particles. Yttrium-90, in contrast, primarily emits beta particles, making imaging more challenging and typically requiring the use of Bremsstrahlung SPECT or PET scans to visualise the distribution. The authors took advantage of this and acquired a specific SPECT–CT after treatment for personalised dosimetry. Second, the radiation dose delivered to the tumour and the surrounding liver tissue can be, theoretically, more precisely calculated because the same particles, although in a lesser amount, are used during the work-up and the treatment procedure, potentially improving treatment efficacy and reducing toxicity. For instance, it has been shown recently, that the use of 166Ho to predict lung mean dose was superior to 99 technetium macro aggregated albumin (99TcMAA) [7]. Nevertheless, a striking finding was the discrepancies between the calculated (work-up) and the effectively reached dose into the tumour and the non-liver tumour. This finding is counterintuitive and needs to be elucidated. Third, the paramagnetic properties of the used particles and their visibility on MRI could help to better understand their distribution (providing valuable feedback for future treatments) and also the potential effect of the scout dose procedure on the tumour and non-tumoral liver [8]. This was not explored by the authors. Overall, the integration of all these data will possibly allow the standardisation of TARE as a treatment modality, establishing or strengthening textbook outcomes [9] to evaluate and improve results.

The significant advancement marked by the use of 166Ho in treating hepatocellular carcinoma opens new avenues for research and underscores the importance of innovation in therapeutic strategies. The RETOUCH study confirms the potential of personalised radioembolisation for HCC patients and paves the way for other tumour types that do not share the same thresholds [10]. This study also calls for further exploration into treatment combinations, particularly with immunotherapy. Combination studies with immunotherapy are currently underway (NCT05705791), exploring the potential synergy between radioembolisation and immunomodulation. Nevertheless, it is crucial not to directly extrapolate the data related to the use of yttrium-90 to the results observed with holmium-166, given the unique characteristics and more recent data associated with the latter. This underscores the need for rigorous safety trials, including translational research programs, before moving to comparative trials, pitting 166Ho radioembolisation against other therapeutic approaches such as chemoembolisation or systemic treatments. These comparative studies will provide valuable insights into the relative efficacy and specific benefits of 166Ho, thus contributing to better treatment stratification for patients with hepatocellular carcinoma.

Exploring these new therapeutic horizons must be accompanied by caution in data interpretation and the specificity of interventions. The expected outcomes of this research will not only guide clinical recommendations but will also influence individual therapeutic decisions, marking a decisive step towards a more personalised and effective approach in treating hepatocellular carcinoma.

The authors declare no conflicts of interest.