Holmium-166 Radioembolization: Current Status and Future Prospective

Radioembolization, also known as selective internal radiation therapy, is a minimally invasive procedure that combines low-volume embolization and radiation to treat liver cancer. This procedure relies on the principle that hepatic tumors are mainly supplied by hepatic arteries [1]. Thus, radioactive microspheres will predominantly lodge in and around tumorous tissue, sparing healthy liver tissue.

The possibilities to use holmium-166 (¹⁶⁶Ho) as a potential isotope for the internal radiation therapy of hepatic tumors was first proposed in 1991 by Mumper et al. [2]. Shortly after, Turner et al. [3] investigated single-photon emission computed tomography (SPECT) dosimetry in pigs, while in 2001 Nijsen et al. [4] performed liver tumor targeting in rats by selective delivery of ¹⁶⁶Ho microspheres. Following these promising results in animals’ studies, in 2010 Smits et al. [5] designed the first phase I human trial to evaluate the safety and toxicity profile of ¹⁶⁶Ho radioembolization. Since the first publication on ¹⁶⁶Ho liver radioembolization, there was a growing interest in this treatment possibility, especially in the last years, as suggested by the increasing publications on this topic.

¹⁶⁶Ho microspheres were developed at the Department of Radiology and Nuclear Medicine of the University Medical Center Utrecht and were granted a patent in 2007. In 2015, ¹⁶⁶Ho microspheres received CE mark under the commercial name of QuiremSpheres™ (Quirem BV, Deventer, the Netherlands). A test dose of 250 MBq ¹⁶⁶Ho microspheres, identical to the ones used for the treatment, received CE mark in 2018 as QuiremScout™ (Quirem BV, Deventer, the Netherlands). A scout dose of ¹⁶⁶Ho microspheres can be used to safely evaluate the distribution of intra-arterially injected microspheres prior to treatment and eventually adjust it. In terms of clinical application in liver tumors, ¹⁶⁶Ho microspheres are an alternative to the existing yttrium-90 (⁹⁰Y) devices (either resin or glass).

¹⁶⁶Ho microspheres are made of poly-l-lactic acid (PLLA), containing the isotope ¹⁶⁶Ho. First in the microspheres production process, holmium-165 (¹⁶⁵Ho) is embedded within the matrix structure of PLLA. Then, a part of ¹⁶⁵Ho is activated to ¹⁶⁶Ho by neutron activation in a nuclear reactor. ¹⁶⁶Ho microspheres characteristics are summarized in Table 1.

The radioactive isotope ¹⁶⁶Ho is a high-energy beta-emitting isotope for therapeutic use, but it also emits primary gamma photons that can be used for SPECT. Furthermore, being a lanthanide, it can be imaged by magnetic resonance imaging (MRI) thanks to its paramagnetic properties, enabling the visualization of its distribution in the liver and quantification of the absorbed tumor dose [6, 7].

The clinical workflow for ¹⁶⁶Ho radioembolization follows similar steps as for radioembolization with other devices. These are summarized in Fig. 1, together with an exemplary clinical case.

Traditionally, radioembolization with ⁹⁰Y requires the use of technetium-99m macroaggregated albumin (^99mTc-MAA) as surrogate compound to perform the radioembolization scout procedure. However, ^99mTc-MAA differs from the particle used for treatment (either ⁹⁰Y or ¹⁶⁶Ho microspheres) with respect to shape, size, density and number of injected particles, resulting in a different biodistribution. ¹⁶⁶Ho radioembolization offers the possibility to use ¹⁶⁶Ho microspheres for both scout and treatment procedure, reducing the variables among these and theoretically reducing the discrepancy between the planning and the procedure. ¹⁶⁶Ho scout was shown to have a superior predictive value for intrahepatic distribution in comparison with the commonly used ^99mTc-MAA [14]. From the analysis of 71 lesions that received two separate scout dose procedures (^99mTc-MAA and ¹⁶⁶Ho scout), the qualitative analysis showed that ¹⁶⁶Ho scout was superior to ^99mTc-MAA with a median score of 4 versus 2.5 (P < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for ¹⁶⁶Ho scout in comparison with ^99mTc-MAA when evaluating lesion absorbed dose (− 90.3 and 105.3 Gy vs. − 164.1 and 197.0 Gy, respectively).

As for any procedure that involves the use of radioactive material, the radiation exposure for personnel should be reduced as much as possible based on the ALARA (as-low-as-reasonably-achievable) principal. During treatment, measurements indicated that the additional radiation exposure to staff caused by the ¹⁶⁶Ho microspheres procedure is negligible compared to the scattered X-rays from the X-ray tube prior and throughout the procedure [19]. Similar to ⁹⁰Y procedures, precautionary measures, such as the use of a new microcatheter for each injection position and a fluid-absorbing drape should be considered in order to prevent radioactive contamination. Regulation concerning treatment administration and the release of the angiography suite after a ¹⁶⁶Ho treatment vary between centers and countries. Unforeseen ¹⁶⁶Ho radioactive contaminations may be more easily detected than ⁹⁰Y microspheres, because of the primary gamma photon emitted by ¹⁶⁶Ho. Depending on the amount of administered therapeutic activity, patients can be released after treatment with minimal contact restrictions (2 days), based on reduction of radiation by distance and time and in consensus with the instructions by the Nuclear Regulatory Commission for patients with permanent implants. 48 h after infusion, exposure rate and activity excretion have been assessed. Exposure rate at discharge, assessed in 15 patients, was 26 μSv/h, which, extrapolated to a whole liver dose of 60 Gy, would lead to a total effective dose equivalent < 5 mSv [20]. Renal and intestinal ¹⁶⁶Ho activity excretion was found in all four cases under investigation, independent of the activity of the injected microspheres. The highest total excretion fraction was 0.005% of the injected activity with intestinal excretion being lower than renal excretion [21]. Bakker et al. [22], assessing 1-h blood plasma and 24-h urine, found the median percentage of ¹⁶⁶Ho compared to the total amount injected to be 0.19% and 0.32%, respectively.

From 2009, eight clinical studies using ¹⁶⁶Ho microspheres for radioembolization have been carried out. Type of study, patients’ population, study phase and design, and primary objective are summarized in Fig. 4. Six other studies, mainly exploring the additional value of individualized treatment are currently in preparation. The findings regarding the primary end-point of the prospective studies completed within 2021 are summarized in Table 4. The first study in humans, a dose escalation study, identified the maximum tolerated dose for ¹⁶⁶Ho radioembolization at 60 Gy, using the current MIRD method [23]. In addition, it was demonstrated that in vivo dosimetry was feasible by both SPECT and MRI imaging [7]. Subsequently, a phase II study investigated ¹⁶⁶Ho radioembolization efficacy [24]. A total of 73% of the study population showed complete response, partial response or stable disease at three-month follow-up, with a median overall survival of 14.5 months, confirming safety and showing efficacy. Another phase II study showed that additional ¹⁶⁶Ho radioembolization after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms is safe and efficacious [25]. Specifically, 43% of patient population achieved an objective response in the treated volume, according to the per-protocol analysis. In nine patients suffering from hepatocellular carcinomas, Radosa et al. [26] showed that ¹⁶⁶Ho radioembolization is a feasible and safe treatment option with no significant hepatotoxicity. At six-month follow-up, 89% of patients showed either a complete response, partial response or stable disease. A within-patient randomized study aiming at assessing whether the use of an anti-reflux catheter improves tumor targeting for colorectal cancer patients treated with ¹⁶⁶Ho radioembolization confirmed efficacy and toxicity findings of previous studies. Laboratory toxicity was reported for 14% of the patients, while clinical toxicity was found in 19%. One patient (5%) died due to radioembolization-induced liver disease. Median overall survival was 7.8 months. At a tumor-level, a significant dose–response relationship was established with mean tumor-absorbed dose in tumors with complete metabolic response 138% higher, on average, than in progressive tumors (222 Gy vs. 103 Gy, respectively). [27]. To conclude, a phase II study assessing toxicity profile of ¹⁶⁶Ho in patients with hepatocellular carcinoma reported unacceptable toxicity in 10% of the treated patients, but no cases of radioembolization-induced liver disease [28]. Additionally, target liver lesions with complete or partial response were found to be 54% and 84% at three- and six-month follow-up, respectively. Median overall survival was 14.9 months. An observational retrospective study recently started (RECORD), aims at further describe the general safety and clinical performance of ¹⁶⁶Ho microspheres, with specific attention to outcomes per tumor origin.

Many possibilities offered by ¹⁶⁶Ho liver radioembolization are still to be exploited, especially in clinical practice. Here, the three main directions following from current research are summarized.

Since their introduction as an alternative to ⁹⁰Y microspheres, ¹⁶⁶Ho microspheres showed unique imaging properties. Additionally, using the ¹⁶⁶Ho microspheres for both pretreatment and treatment has the benefit of improving the intrahepatic distribution prediction in comparison with current clinical standard. The combination of these features would enable a better patient selection and individualized treatment planning, paving the way to personalized medicine. To this purpose, safety and efficacy dose thresholds should be further investigated, together with the possibility to fully automatize the segmentation and registration processes necessary for adoption of partition modeling for activity calculation.