Keywords

1 Introduction

Hepatic tumors, in particular hepatocellular carcinoma (HCC), present an almost exclusive arterial supply as opposed to the normal parenchyma, which is vascularized by the portal vein. The neo-angiogenesis creates the possibility of releasing high quantities of drugs or radiation directly into the tumor, minimizing systemic effects.

2 Transarterial Chemoembolization

Transarterial chemoembolization (TACE) is an interventional radiology procedure consisting of the concomitant administration, via a transarterial route, of embolic material and anti-cancer drugs into the liver [1].

The indications for TACE in HCC encompass, according to the Barcelona Clinic Liver Cancer (BCLC) group, patients with intermediate stage (BCLC stage B) with a class of recommendation IA [2] and, more recently, with very early and early stage (BCLC stage 0 and A) with a class of recommendation of IB [2].

2.1 Technical Variations

From a technical point of view, the TACE technique presents several variations according to embolic material and drugs.

Concerning embolic material, it is possible to distinguish conventional TACE (c-TACE), drug-eluting microsphere TACE (DEM-TACE) and degradable starch microsphere TACE (DSM-TACE).

c-TACE uses ethyl ester of iodized fatty acids of poppy seed oil (Lipiodol, Guerbet, France) as embolic material, mixed with anticancer drugs [1]. This emulsion is injected selectively into the arterial feeder of the HCC followed by a gelfoam solution for ensuring complete embolization [1]. c-TACE has the most consistent body of evidence regarding clinical results. Two randomized controlled trials (RCTs) showed that the c-TACE group had a relative risk of death ranging from 0.47 (95% CI 0.25–0.91) to 0.49 (95% CI 0.29–0.81) with a better overall survival compared with the control group [3, 4].

DEM-TACE uses microspheres as delivery and embolic material [1]. These microspheres allow slow release of the anti-cancer drugs used. The linkage between the beads and the drugs is based on ionic interaction. There are several different types of bead based on size and intrinsic opacity. The guidelines recommend a standard size of 100–300 μm. Two RCTs tried to demonstrate the superiority of DEM-TACE vs. c-TACE with poor results [5, 6]. In particular, the authors found no oncological benefit, but a better safety profile and drug-eluting toxicity. However, this evidence dates back to the early 2010s. More recently, Yang et al. [7], in a systematic review in 2020, showed a better 2-year overall survival of DEM-TACE vs. c-TACE (relative risk 0.89; 95% CI 0.81–0.99; p = 0.046).

DSM-TACE uses a resorbable amylomer (hydrolyzed potato starch) shaped as beads of 45 ± 7 μm in size that can be mixed with different anti-cancer drugs. The beads are enzymatically degraded by amylases, they have a half-life of about 35–50 min and are completely resorbed after approximately 2 h [8]. Very few reports exist on the value of DSM-TACE in HCC treatment. In particular, DSM-TACE was tested as first- and second-line (after kinase inhibitors discharge) treatment with promising results [8, 9]. One report by Auer et al. [10] showed comparable results between DSM-TACE and transarterial radioembolization.

The most used drug, in the USA and Europe, is doxorubicin. A few new drugs have been tested against doxorubicin in TACE. Shi et al. [11], in a RCT, showed that a mix of lobaplatin, epirubicin and mitomycin C has a better overall survival compared with doxorubicin alone. However, two RCTs failed to demonstrate the superiority of epirubicin over doxorubicin [12, 13].

3 Transarterial Radioembolization

Transarterial radioembolization (TARE) is based on the transarterial hepatic delivery of a radioisotope, yttrium 90 (90Y), a pure beta-radiation emitter [14]. 90Y is loaded onto microspheres; resin for Sirtex (SIR-Sphere, Sirtex Medical, Australia) and glass for Therasphere (TheraSphere, Boston Scientific, Marlborough, MA, USA), with differences between the two devices [14]. Both devices present potential benefits.

3.1 Technical Considerations

All patients must undergo careful pre-treatment angiographic mapping of the vascularization of the tumors less than 2 weeks before the procedure; 185 MBq of 99mTc-macroaggregated albumin allows single-photon emission computed tomography (SPECT) scanning assessment of pulmonary or digestive shunting. A lung shunt >20% or 30 Gy potentially contraindicates the treatment [14]. The careful search for and embolization of all the suspected vessels for digestive shunting is mandatory to avoid the possibly severe consequences of non-target embolization and can be done in the same treatment session [14]. This phase must possibly include preliminary cone-beam CT to ensure correct and safe delivery of the radio-device. Assessment of the treatment can be done by SPECT (bremsstrahlung photons) or positron emission tomography (PET) (Fig. 9.1). Recently, the possibility of same-day angiography assessment and treatment has been explored with good results.

Fig. 9.1
Six radiological images display the interventional radiological treatment of liver carcinoma. In image a, the microspheres are delivered to the lesion. Image b displays the lesion before it was operated. Images c and d are Spect scans of the lesion before and after the deposition of the microspheres. In images e and f, the lesion has been removed.

(a) Sixty-eight-year-old man with relapse of hepatocellular carcinoma (HCC) at segments 5/7 and previous surgical segmentectomy of segment 6. The patient underwent transarterial radioembolization (TARE) with right lobar delivery of 2.6 GBq of 90Y microspheres (SIR Spheres, SIRTEX) as a bridge to surgery (right lobectomy). (b) Pre-TARE planning strategy with angiography mapping and 99mTc macroaggregated-albumin injection, and (c) subsequent SPECT-CT which demonstrated good deposition with respect to the target lesion seen in panel a. (d) SPECT-CT demonstrating perfect correlation of the deposition of 90Y with pre-treatment imaging: the absorbed dose was 240 Gy. (e, f) CT scans at 6 and 17 months showing the complete ablation of the HCC and (f) hypertrophy of the left lobe with no need for surgery. At 3 years, imaging still shows sustained response, without relapse

Full size image

3.2 Lessons Learned

Careful patient selection has shown to be essential in treating HCC patients with TARE. The expected patient response to TARE correlates with liver function, albumin-bilirubin (ALBI) score, tumor burden, performance status, and the presence of extra-hepatic disease [15]. The ALBI score [16] seems to surpass the Child-Pugh score in selecting patients, albumin acting as a prognostic biomarker. The extent of portal vein thrombosis, when present, can also play a prognostic role [17].

Scintigraphy pre-assessment allows quantification of dosimetry with multi-compartmental or voxel dosimetry. The procedure and the doses need to be accurately tailored to the tumor burden, the vascularization, and the therapeutic purpose.

The selection of centers with multidisciplinary groups, reproducible and standardized techniques, and adequate technology with cone-beam CT are the fundamental factors of good practice.

3.3 Indications and Clinical Utility

Historically, TARE has been used in the advanced setting demonstrating good results in particular with portal thrombosis (BCLC stage B/C). The multicentric European analysis ENRY 4 provided robust evidence on tumor responses and high disease control rates with a safe profile all across BCLC stages. However, the three phase III trials, SARAH and SIRveNIB (TARE vs. sorafenib) and SORAMIC (TARE + sorafenib vs. sorafenib), conducted in advanced HCC patients failed to show any benefit in overall survival [18,19,20]. They also confirmed the non-inferiority of TARE and the clear benefits in terms of reduced toxicity (fewer adverse events) and improved quality of life compared to sorafenib [21]. The limits of these trials have been well analyzed: center selection and skills, patient selection, delay of treatment, and low dosimetry [21]. Consequently, TARE was not included in the 2018 guidelines of the European and American Associations for the Study of the Liver (EASL, AASLD) [22].

In the European Society for Medical Oncology (ESMO) guidelines [2], the indications for TARE moved from the advanced stage on to the early and intermediate stage, but with only a moderate level of evidence. In fact, the concept of ablative setting, radiation segmentectomy or lobectomy, strictly correlated to dosimetry, has emerged more recently with outcomes at 5 years as good as other curative methods, surgery or ablation [23, 24]. The focus on dosimetry of the latest trials DOSISPHERE and LEGACY also clearly showed good results [24, 25].

This has allowed TARE to enter the BCLC stage 0–A, competing with other curative treatments [2].

Despite the fact that there were no more indications in the advanced stage in guidelines, due to the recent development of new systemic therapies, the latest ESMO update of 2021 [2] reintroduced TARE in the advanced setting for patients with liver-confined disease not suitable for TACE and/or systemic therapy.

It should also be underlined the ability of TARE to compete with portal embolization, inducing hypertrophy of the future remnant liver after lobar radioembolization, on a slower timescale than through portal embolization, but with the additional value of local disease control [26] and downstaging for surgery.

3.4 Downstaging

The downstaging strategy relies on evidence that a baseline low-risk patient has the same probability of recurrence than a high-risk patient who is reassigned, after locoregional therapy, to low risk [27]. No guidelines exist on the upper limits for downstaging inclusion; however, a general consensus defines the limits as: one lesion >5 cm and ≤8 cm; two to three lesions each ≤5 cm; or four to five lesions each ≤3 cm with total tumor diameter ≤8 cm [28].

In a meta-analysis, Parikh et al. [29] reported a successful downstaging rate of 48% (95% CI 39–58%) without differences between TACE and TARE. Gabr et al. [30] showed that TACE and TARE groups have the same outcome after orthotopic liver transplantation (months to recurrence: 26.6 (95% CI 7.0–49.5) vs. 15.9 months (95% CI 7.8–46.8), respectively; p = 0.48). In addition, in one RCT, Mazzaferro et al. [31], demonstrated that, regardless of downstaging methods (locoregional, surgical or systemic), orthotopic liver transplantation improved event-free survival rate vs. the control group (76.8% [95% CI 60.8–96.9] vs. 18.3% [95% CI 7.1–47.0]). These data seem to suggest that there are no differences between the downstaging strategies. However, several issues must be clarified. First, the choice of which locoregional treatment should be used depends on the patient/disease characteristics, namely BCLC is applied for each patient. For example, TACE patients have on average a lower disease stage compared to TARE patients. Second, the downstaging strategy generally has a multidisciplinary and multimodality approach by including ablation, surgery, trans-catheter, and systemic treatment. However, a RCT comparing the downstaging results of each single modality is unfeasible due to ethical issues.

3.5 Bridging

Bridging consists of reducing the drop-out from the active transplant list. The existing 2018 guidelines (AASLD, EASL) [22] suggest bridging to liver transplantation (OLT) within the Milan criteria with the aim of limiting the drop-out and the recurrences post OLT, with low evidence, and with a strong grade of recommendation, particularly if the waiting time on the list is expected to be at least 6 months. Progression after endovascular therapies seems to have a prognostic role, and treatment response is a surrogate biomarker [32]. TACE is the most used technique for bridging, although no trial has demonstrated its superiority over the remaining locoregional strategies [33]. Ettore et al. [34] demonstrated that bridging is achievable in all patients using TARE. Gabr et al. report their experience of 207 transplants after TARE with a bridging success of 75% with survival similar to non-oncologic transplant [35]. Nevertheless, Lee et al. [36] suggest that the impact of the bridging strategy is limited only to the early stage.

3.6 Palliation

The palliative indication is reserved for those patients not amenable for curative treatment. Despite a trend in the data [37,38,39] there are no conclusive trials that demonstrate the superiority of a TARE versus C-TACE or DEB-TACE [40], TACE still being the first treatment option in all guidelines. The TRACE trial (BCLC stage A/B) was interrupted because of the clear superiority of TARE in terms of time to progression (392 vs. 299 days) and overall survival (912 vs. 489 days) [41]. The CIRT registry demonstrated that TARE is a valid tool with an excellent safety profile for palliation [42]. Moreover, Salem et al. published their institutional decision to adopt TARE as the first treatment option in limited HCC, based on 1000 patients in 15 years [43].

4 Conclusion

Transarterial treatments (TACE and TARE) are the past, the present and the future of HCC management. TACE has proven its utility in randomized trials and TARE has earned its place in the real world of HCC treatment, entering recently the first stage of BCLC.