Transcatheter embolization therapy in liver cancer: an update of clinical evidences

Abstract

Transarterial chemoembolization (TACE) is a form of intra-arterial catheter-based chemotherapy that selectively delivers high doses of cytotoxic drug to the tumor bed combining with the effect of ischemic necrosis induced by arterial embolization. Chemoembolization and radioembolization are at the core of the treatment of liver hepatocellular carcinoma (HCC) patients who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. TACE for liver cancer has been proven to be useful in local tumor control, to prevent tumor progression, prolong patients' life and control patient symptoms. Recent evidence showed in patients with single-nodule HCC of 3 cm or smaller without vascular invasion, the 5-year overall survival (OS) with TACE was similar to that with hepatic resection and radiofrequency ablation. Although being used for decades, Lipiodol(®) (Lipiodol(®) Ultra Fluid(®), Guerbet, France) remains important as a tumor-seeking and radio-opaque drug delivery vector in interventional oncology. There have been efforts to improve the delivery of chemotherapeutic agents to tumors. Drug-eluting bead (DEB) is a relatively novel drug delivery embolization system which allows for fixed dosing and the ability to release the anticancer agents in a sustained manner. Three DEBs are available, i.e., Tandem(®) (CeloNova Biosciences Inc., USA), DC-Beads(®) (BTG, UK) and HepaSphere(®) (BioSphere Medical, Inc., USA). Transarterial radioembolization (TARE) technique has been developed, and proven to be efficient and safe in advanced liver cancers and those with vascular complications. Two types of radioembolization microspheres are available i.e., SIR-Spheres(®) (Sirtex Medical Limited, Australia) and TheraSphere(®) (BTG, UK). This review describes the basic procedure of TACE, properties and efficacy of some chemoembolization systems and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key clinical trials of transcatheter arterial therapy for liver cancer are summarized.

Keywords: Lipiodol®; Transarterial; chemoembolization; drug-eluting particles; hepatocellular carcinoma (HCC); microspheres; radioembolization; yttrium-90.

Figure 1

EASL-EORTC (European Association For The Study Of The Liver- European Organisation For Research And Treatment Of Cancer) clinical practice guidelines: management of hepatocellular carcinoma. Updated Barcelona Clinic Liver Cancer (BCLC) staging system and treatment strategy, 2011 [cited with permission from ref. (23), J Hepatol 2012;56:908-43].

Figure 2

Consensus-based treatment algorithm for HCC proposed by JSH revised in 2010. Footnotes: *1, Treatment should be performed as if extrahepatic speed is negative, when extrahepatic spread is not regarded as a prognostic factor; *2, Sorafenib is the first choice of treatment in this setting as a standard of care; *3, Intensive follow-up observation is recommended for hypovascular nodules by the Japanese Evidence-Based Clinical Practice Guidelines. However, local ablation therapy is frequently performed in the following cases: (I) when the nodule is diagnosed pathologically as early HCC; (II) when the nodules show decreased uptake on Gd-EOB-DPTA MRI; (III) when the nodules show decreased portal flow by CTAP, since these nodules are known to frequently progress to the typical advanced HCC; *4, Even for HCC nodules exceeding 3 cm in diameter, combination therapy of TACE and ablation is frequently performed when resection is not indicated; *5, TACE is the first choice of treatment in this setting. HAIC using an implanted port is also recommended for TACE refractory patients. The regimen for this treatment is usually low-dose FP (5-FU + CDDP) or intra-arterial 5-FU infusion combined with systemic IFN therapy. Sorafenib is also a treatment of choice for TACE refractory patients with Child-Pugh A liver function; *6, Resection is sometimes performed even when numbers of nodules are over 4. Furthermore, ablation is sometimes performed in combination with TACE; *7, Milan criteria: tumor size ≤3 cm and tumor number ≤3; or solitary tumor ≤5 cm. Even when liver function is good (Child-Pugh A/B), transplantation is sometimes considered for frequently recurring HCC patients; *8, Sorafenib and HAIC are recommended for HCC patients with Vp3 (portal venous invasion at the first portal branch) or Vp4 (portal invasion at the main portal trunk); *9, Resection and TACE is frequently performed when portal invasion is minimum such as Vp1 (portal invasion at the third or more peripheral portal branch) or Vp2 (portal invasion at the second portal branch); *10, Local ablation therapy or subsegmental TACE is performed even for Child-Pugh C patients when transplantation is not indicated when there is no hepatic encephalopathy, no uncontrollable ascites, and a low bilirubin level (<3.0 mg/dL). However, it is regarded as an experimental treatment since there is no evidence of its survival benefit in Child-Pugh C patients. A prospective study is necessary to clarify this issue. Even in Child-Pugh A/B patients, transplantation is sometimes performed for relatively younger patients with frequently or early recurring HCC after curative treatments. HCC, hepatocellular carcinoma; JSH, Japan Society of Hepatology; CTAP, computed tomography arterial portography; TACE, transarterial chemoembolization; FU, fluorouracil; HAIC, hepatic arterial infusion chemotherapy. Reproduced with the permission from ref. (2).

Figure 3

The Hong Kong Liver Cancer (HKLC) prognostic classification scheme. Early tumor: ≤5 cm, ≤3 tumor nodules and no intrahepatic venous invasion. Intermediate tumor: (I) ≤5 cm, either >3 tumor nodules or with intrahepatic venous invasion, or (II) >5 cm, ≤3 tumor nodules and no intrahepatic venous invasion. Locally-advanced tumor: (I) ≤5 cm, ≤3 tumor nodules and with intrahepatic venous invasion, or (II) >5 cm, >3 tumor nodules or/and with intrahepatic venous invasion, or (III) diffuse tumor. Abbreviation: EVM, extrahepatic vascular invasion/metastasis. Reproduced with the permission from ref. (24).

Figure 4

Principle of conventional transarterial chemoembolization. Reproduced with the permission from ref. (31).

Figure 5

One patient with a giant hepatocellular carcinoma underwent TACE treatment. Radiographic image was obtained during the injection of the mixture drug/Lipiodol^® through a micro-catheter. Note the typical aspect of lipid droplets progressing through arteries and filled the HCC tumorous vasculatures. TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma.

Figure 6

One patient with a giant hepatocellular carcinoma underwent TACE treatment composed of a mixture of pirarubicin 10 mg, cisplatin 30 mg, bleomycin 8 mg, and 20 mL Lipiodol^®. (A) contrast-enhanced X-ray computed tomographic (CT) images show the giant tumor (arrows); (B) follow-up contrast-enhanced X-ray CT 3 months post-TACE, the tumor appears smaller and Lipiodol^® continues to deposit within the tumor.

Figure 7

One patient with a hepatocellular carcinoma underwent TACE treatment. (A) Plain X-ray computed tomographic (CT) images show the tumor (arrows). Two courses of chemoembolization mixture composed of cisplatin 40 mg, mitomycin 6 mg, pirarubicin 30 mg, 10 mL Lipiodol^®, and of cisplatin 20 mg, pirarubicin 20 mg, 5 mL Lipiodol^® were administered with an interval of 2 months; (B) follow-up contrast-enhanced X-ray CT 2 months after the first-TACE; (C) follow-up contrast-enhanced X-ray CT 4 months after the second TACE. The tumor appears smaller and Lipiodol^® continues to deposit within the tumor.

Figure 8

Photomicrographs of doxorubicin-loaded DC Beads^® (A) and Hepaspheres^® (B) microspheres and irinotecan-loaded DC Bead (C) and Hepasphere (D) microspheres. In the lower left corners, insets show the aspect of the beads retrieved after the release experiment (1-week exposure to 5 mL/min NaCl 0.9% flow). Scale bars indicate 500 µm. Reproduced with the permission from ref. (85).