EASL Clinical Practice Guidelines

Chemoembolization and transcatheter therapies

Chemoembolization

Chemoembolization (TACE) is the most widely used primary treatment for unresectable HCC [[160], [165], [194]], and the recommended first line-therapy for patients at intermediate stage of the disease [[56], [139], [149]]. HCC exhibits intense neo-angiogenic activity during its progression. The rationale for TACE is that the intra-arterial infusion of a cytotoxic agent followed by embolization of the tumor-feeding blood vessels will result in a strong cytotoxic and ischemic effect. TACE should be distinguished from chemo-lipiodolization – delivery of an emulsion of chemotherapy mixed with lipiodol –, bland transcatheter embolization (TAE), where no chemotherapeutic agent is delivered, and intra-arterial chemotherapy, where no embolization is performed. Details on the distinct types and definitions of image-guided transcatheter embolization have been reviewed elsewhere [[285], [286]].

Conventional chemoembolization (TACE)

This procedure combines transcatheter delivery of chemotherapy emulsioned with lipiodol followed by vascular stagnation achieved with embolic agents. Chemoembolization achieves partial responses in 15–55% of patients, and significantly delays tumor progression and macrovascular invasion. The survival benefit of TAE or chemoembolization has been the subject of a few RCT, which provided contradictory results [[287], [288], [289], [290], [291], [292], [293]]. Survival benefits were obtained in two studies [[292], [293]], one of which identified treatment response as an independent predictor of survival [293]. Meta-analysis of these seven RCT, including a total of 516 patients, showed a beneficial survival effect of embolization/chemoembolization in comparison to the control group [139]. Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin in four studies, but none with embolization alone in three studies [139]. Overall, the median survival for intermediate HCC cases is expected to be around 16 months, whereas after chemoembolization the median survival is about 20 months. As a result of these investigations, TACE has been established as the standard of care for patients who meet the criteria for the intermediate-stage of the BCLC staging system, i.e. those with multinodular HCC, absence of cancer-related symptoms and no evidence of vascular invasion or extrahepatic spread. Recently, a meta-analysis by Cochrane investigators has challenged the efficacy of TACE [294]. Several biases contained in this approach, including the use of trials with inappropriate control arms or target populations leading to poor outcomes, diminish any impact of this investigation. The benefits of combining TACE with local ablation procedures or systemic therapies are under investigation.

The benefits of chemoembolization should not be offset by treatment-induced liver failure. Treatment-related deaths are expected in less than 2% of cases if proper selection of candidates is in place. The best candidates are patients with preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread [[285], [293]]. Macroscopic vascular invasion of any type and extrahepatic spread are major contraindications for chemoembolization. One positive trial showed no benefit in the subgroup analysis restricted to patients presenting with portal vein invasion [292]. Liver functional reserve is also a critical component for a careful selection. Patients should present relatively well-preserved liver function (mostly Child–Pugh A or B7 without ascites), while those with liver decompensation or more advanced liver failure should be excluded since the ischemic insult can lead to severe adverse events [289]. Absolute and relative contraindications for chemoembolization have been reviewed elsewhere [169]. There is no good evidence for which is the best chemotherapeutical agent and the optimal re-treatment strategy, even though it is recommended to apply the procedures 3–4 times per year and to use doxorubicin or cisplatin as the standard chemotherapy. More intense regimes, i.e. TACE every 2 months, might induce liver failure in an unacceptable proportion of patients [289]. Superselective chemoembolization is recommended to minimize the ischemic insult to non-tumoral tissue.

Chemoembolization with Drug-Eluting Beads (TACE-DEB)

Strategies to improve anti-tumoral activity and clinical benefits with chemoembolization have been launched. The ideal TACE scheme should allow maximum and sustained intratumoral concentration of the chemotherapeutic agent with minimal systemic exposure, along with calibrated tumor vessel obstruction. Embolic microspheres have the ability to sequester chemotherapeutic agents and release them in a controlled mode over a 1-week period. This strategy has been shown to increase the local concentration of the drug with negligible systemic toxicity [166]. A randomized phase II study comparing TACE and TACE-DEB reported a significant reduction in liver toxicity and drug-related adverse events for the latter arm, associated with a non-significant trend of better antitumoral effect [295].

Radioembolization and external radiation

Radioembolization is defined as the infusion of radioactive substances such as Iodine-131 (131I)-labeled lipiodol [296] or microspheres containing Yttrium-90 (90Y) [[297], [298], [299]] or similar agents into the hepatic artery. Given the hypervascularity of HCC, intra-arterially-injected microspheres will be preferentially delivered to the tumor-bearing area and selectively emit high-energy, low-penetration radiation to the tumor. A seminal RCT comparing chemoembolization versus internal radiation with 131I has not been followed by additional investigations [296]. Currently, the most popular radioembolization technique uses microspheres coated with 90Y, a ß-emitting isotope. This treatment requires a third level specialized center with sophisticated equipment and trained interventional radiologists. Severe lung shunting and intestinal radiation should be prevented prior to the procedure. Due to the minimally embolic effect of 90Y microspheres, treatment can be safely used in patients with portal vein thrombosis [298].

Cohort studies reporting long-term outcomes showed a median survival time of 17.2 months for patients at intermediate stages [297] and 12 months for patients at advanced stages and portal vein invasion [[298], [299], [300]]. Objective response rates range from 35% to 50% [[297], [298], [299]]. Around 20% of patients present liver-related toxicity and 3% treatment-related death [297]. Despite the amount of data reported, there are no RCT testing the efficacy of 90Y radioembolization compared with chemoembolization or sorafenib in patients at intermediate or advanced stage, respectively. Further research trials are needed to establish a competitive efficacy role in these populations.

Other loco-regional treatments

The use of conventional external-beam radiation therapy in HCC treatment has been limited by the low radiation tolerance of the cirrhotic liver, which often resulted in radiation-induced liver disease, previously known as radiation-induced hepatitis [301]. The benefits of external three-dimensional conformal radiotherapy have only been tested in uncontrolled investigations [302]. There is no scientific evidence to recommend these therapies as primary treatments of HCC and further research testing modern approaches is encouraged.