Trans-arterial embolization (TAE) is a technique wherein inert microspheres are used to block the blood supply around the tumor. The use of large microspheres, e.g., Embosphere^® (⌀ 300–750 mm, Merit Medical Systems, South Jordan, UT, USA) in tumor-affected liver lobe(s) allows blockage of the blood supply towards the tumor (Figure 1B), ultimately resulting in reduced tumor growth [10,11,12,13,14]. An overview of the different microspheres currently used for hepatic trans-arterial embolization is provided in Table 2. The clinically applied glass and synthetic spheres are non-degradable and remain in the vasculature for life. Recently, in a pre-clinical phase, biodegradable spheres were developed, which allow local occlusion of the vasculature, and after degradation they allow a follow-up injection of embolization treatment. The clinical unfavorable short- and long-term outcomes of patients with large HCCs (≥50 mm) were revealed compared to those with small HCCs (<50 mm). Detailed analyses revealed that the average rates of change in tumor size and shrinkage after TAE were 48.6 ± 35.6 mm and 30.7 ± 17.0%, respectively [23].

Instead of focusing on major vascular occlusion, chemo- or radio-embolic targeting is an alternative treatment option with microspheres that have the potential to manage hepatic tumors effectively [18].

Trans-arterial chemoembolization (TACE) uses embolization to deliver chemotherapy locally, thus limiting systemic exposure (Figure 1) [30,31]. One prime example are acrylic co-polymer microspheres (Hepasphere™, ⌀ 50–100 µm, Merit Medical Systems, Inc., South Jordan, UT, USA) that can absorb cytostatic drugs such as doxorubicin, irinotecan, epirubicin, mitomycin, cisplatin, and oxaliplatin (Table 3).

After contact with either an ionized environment, such as 0.9% NaCl and blood, or nonionic contrast media, acrylic co-polymer microspheres expand to 200–400 µm and slowly release their cytostatic payload [50]. The advantage of TACE is that it maximizes the concentration of chemotherapeutic agents within the tumor for up to seven days while keeping a minimal concentration in the systemic circulation. This approach reduces systemic side effects and the toxicity of cytostatic drugs compared to systemic chemotherapy. Furthermore, the malignancy’s arterial supply is occluded like in TAE, thus limiting nutrient availability to the tumor [51,52]. In HCC patients [5], this chemoembolization strategy has proven beneficial for patients’ survival, increasing the survival time by up to 12 months [53] and reducing the symptoms related to chemotherapy [28].

Trans-arterial radioembolization (TARE) uses radioisotopes embedded in microspheres to locally irradiate tissue after the vascular occlusion of blood vessels surrounding the tumor [54]. Herein, microspheres carrying b-emitting radioisotopes enable a more pinpointed delivery of radiation to liver tumors than other radiotherapy techniques. Although these options extend patient survival, most remain palliative [10,53]. With ¹⁶⁶Ho-microspheres and 3.8 GBq/kg liver tissue in a Phase II study including 38 patients, the target lesions showed complete response or stabilized disease for 27 patients (73%), with a median survival of 15 months [55]. Given these results, a more extensive, randomized Phase III study appears to be required. Although ⁹⁰Y, ¹⁸⁸Re, and ¹⁶⁶Ho in microspheres effectively reduce tumor size and patients’ survival, data from large Phase III trials are warranted to prove their benefits compared to other treatment modalities. In addition, the cost-effectiveness between the various radioisotopes and types of microspheres has to be determined. Besides the application of TARE in HCC, patients with intrahepatic cholangiocarcinoma (CC), which is a rare but very aggressive neoplasia with limited therapeutic options, and patients with to liver metastasized colorectal (mCRC) and neuroendocrine disease also benefit from therapy using ⁹⁰Y-loaded glass or resin microspheres, with a response of more prolonged overall survival of at least 6 months [56,57,58,59]. Various radioembolization microspheres carrying radioisotopes to be delivered in the tumor-bearing hepatic segments of patients are summarized in Table 4.

An essential issue in radioembolization studies is preventing shunting to normal tissues, such as the lungs. Shunting displaces a fraction of the administered particles towards the microvasculature of other tissues, mainly the lung, instead of the liver, leading to ineffective dose distribution and irreversible severe adverse effects such as radiation pneumonitis [88,94]. To avoid the shunting of microspheres, radioembolization is performed in a theranostic setting. In this setting, a catheter is (selectively) placed to deliver radiolabeled macro-aggregated albumin (^99mTc-MAA; ⌀ 10–40 mm) to the affected tissues. Via a scout scan using single-positron emission computed tomography (SPECT) imaging, the localization and distribution of the ^99mTc-MAA are visualized, which is an approach that helps assess the degree of shunting and, at the same time, facilitates dosimetry measurements. When this has been done, therapeutic loads of β-emitting glass or resin microparticles (⌀ 15–25 mm) [95] containing, e.g., ⁹⁰Y (SIR-Spheres^®, Sirtex Medical Inc. Woburn, MA, USA; Therasphere, Boston Scientific, Marlborough, MA, USA) or ¹⁶⁶Ho (QuiremSpheres, Quirem Medical Deventer, The Netherlands) are injected via a catheter positioned in the same way [96]. Given the overlap in size and retention properties between ^99mTc-MAA and microparticles, a ^99mTc-MAA scout scan has been deemed a sufficient standard requirement in the clinical guidelines to predict the accurate delivery of therapeutic microspheres. Despite these guidelines, a mismatch between the scout and therapeutic is inevitable, i.e., given the time span that separates these two procedures. As such, the delivery of microspheres can still lead to adverse side effects and suboptimal dose delivery in about 30% of cases [97,98,99], a complication which highlights the need for innovative solutions that help refine the correlation between the scout scan and therapeutic delivery. In this respect, the physical properties of the used radioisotope, ¹⁹⁹Ho as a b/g/paramagnetic element [100] and ⁹⁰Y as a PET/SPECT imaging agent, post-TARE imaging facilitates mapping of the dose delivery. Where the therapy is insufficient, adjuvant therapy can be considered [101,102]. Furthermore, microspheres containing these isotopes can also serve as a scout scan. Another drawback is the delay of 2 weeks between the execution of the scout scan and the therapeutic intervention due to the need for dosimetry [103,104,105] and the production/delivery time of the β-emitting microspheres [96].

Instead of focusing on major vascular occlusion with TAE, in this section, we focus on comparing chemo- or radio-embolic targeting that has the potential to facilitate vascular occlusion and realize chemo- or radio-embolic treatment of hepatic tumors [18].

Four TARE studies determined the overall survival median at 9–11 months [50]. Based on these findings, TARE was not recommended as a first-line therapy for patients with non-resectable colorectal liver metastasis. For HCC, however, the overall survival in a study with unresectable HCC patients was 19.9 months in the ⁹⁰Y-resin TARE group, which was an improvement compared to the 14 months of survival in a matching TACE group [106]. Recently, the efficacy of TARE combined with TACE was determined in 19 patients with bi-lobar HCC, and no procedure-related major clinical complications were observed, and the mean overall survival yielded a promising 27.3 months compared to untreated patients [107]. Differences between studies comparing TACE and TARE indicate that the outcome in the benefits of treatment may be related to the type of carcinoma, an observation that needs additional research. TARE also proved superior in safety regarding post-embolization syndrome, hospitalization days, and outpatient-based therapy [108,109]. TARE was a safe alternative treatment to TACE [110], especially as using a scout scan helps prevent complications related to shunting with TACE [111]. Applying the scout scan also helps personalize the dosing, a concept that could extend to TACE. Compared to TACE, TARE had a longer time-to-progression, greater ability to downsize tumors, and less post-embolization syndrome [112]. For that reason, it could be an alternative to ablation, surgical resection, or portal vein embolization [113]. On the other hand, TACE is the trans-arterial treatment of choice for patients with marginal hepatic reserve (i.e., hyperbilirubinemia, ascites) or candidates for transplantation [114].