Elsevier

Cancer Treatment Reviews

Volume 38, Issue 6, October 2012, Pages 641-649
Cancer Treatment Reviews

Anti-Tumour treatment
Treatment of hepatocellular carcinoma (HCC) by intra-arterial infusion of radio-emitter compounds: Trans-arterial radio-embolisation of HCC

https://doi.org/10.1016/j.ctrv.2011.11.004Get rights and content

Abstract

Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50 Gy, but this is above the recommended liver radiation exposure of about 35 Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120 Gy. These are well tolerated in patients treated with this type of internal radiation therapy.

TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC.

Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria.

In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques.

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common solid malignancy in the world, and the third cause of cancer death.1 Most primary liver neoplasms are found in patients with cirrhosis, accounting for 80% of all new diagnosed HCC.2

Treatment options for HCC, as shown in the Barcelona Clinic Liver Cancer (BCLC) algorithm (Fig. 1)3, are: resection, percutaneous ablation and liver transplantation (potentially curative treatments) for the very early and early stage (BCLC 0-A) and chemo-embolisation and sorafenib for the intermediate and advanced stage (BCLC B-C). Japanese evidence-based guidelines also include surgical resection together with chemo-embolisation for the intermediate stage HCC (Fig. 2).4

It is estimated that in Europe and USA, at most 15% of patients will be considered for surgery, 50% for non-surgical treatments and 35% will be suitable only for best supportive care.5

Radiotherapy could be administered as adjuvant or neo-adjuvant therapy, together with potentially curative treatments, for very early and early stage HCC, and alone or combined with other palliative treatments for intermediate-advanced stage HCC. However the major limitation of radiotherapy comes from the risk of causing radiation-induced liver disease (RILD): a dose above 35 Gy for the whole liver, has a risk of 5% of such damage.6 Nonetheless, as long as the volume of the irradiated area is limited, the radiation dose can be escalated to tumouricidal levels without deterioration of liver function. Radiation dose can reach above 120 Gy when targeting a limited liver volume.7

A way to reach selectively high radiation dose in the area of interest of the liver is by trans-arterial radio-embolisation (TARE). TARE is a form of interstitial-radiotherapy developed for liver tumours, which merges the interventional radiology technique of hepatic artery cannulation with radiotherapy.

Different compounds are now available for TARE. The 131I-labelled lipiodol and 90Y-loaded microspheres are the most frequently reported in the literature. The more recently available 188Re based compounds show promise. Other radio-emitter compounds, using different radioactive isotopes such as 166Ho and 32P have also been employed, but there is no published data on clinical outcomes. The 166Ho-chitosan (a derivative of chitin used in East Asia) may prove to be particularly effective as it has a high level of retention within HCC and low energy emission (half-life of 27 h, Emax 1.84 MeV). Recently, the European manufacturer has withdrawn the 131I-labelled lipiodol.

The tumour response rate with TARE is 25–60%, if assessed by WHO criteria8 or even 80% by EASL criteria.[9], [10]

However the survival benefit with TARE has not been proven in well-powered, randomised studies. In a comparison of results with the frequently employed trans-arterial chemo-embolisation (TACE), TARE appears to induce a more rapid decrease in tumour size (median time to WHO partial response 4.2 vs. 10.9 months, P = 0.025).11

Section snippets

Technical considerations

The liver receives dual blood supply from the hepatic artery (25%) and the portal vein (75%). In the multistep process of hepatocarcinogenesis there is a progressive change in the vascular supply that consists of an increase in arterial supply and loss of portal blood. Dynamic imaging can characterise the vasculature of nodules. This shows good correlation with the grade of malignancy.12 This provides the rationale of using arterial obstruction with or without contemporaneous administration of

TARE as primary treatment

Trans-arterial techniques of TACE, trans-arterial embolisation (TAE) and TACE with Drug-Eluting Beads (DEB-TACE) are primary treatments for intermediate stage HCC (BCLC B).3 All these trans-arterial techniques could also be considered, and have been used, for advanced and end-stage HCC (BCLC C-D),[32], [33] but with worse outcome, in the latter case, when compared with TARE.34 Patients with portal vein thrombosis have been treated, as TARE techniques have far less embolising characteristics

TARE as adjuvant/neo-adjuvant therapy with potentially curative treatments

Potentially curative treatments are those used for the very early and early HCC. They comprise resection, percutaneous ablation and liver transplantation, which for early stage tumours result in a survival rate ranging from 55% to 70% at 5 years.2 Recurrence of HCC after such therapeutic approaches occurs in 70% after resection or following radiofrequency ablation,[55], [56] and in only 15% of cases after liver transplantation.[57], [58], [59]

Adjuvant or neo-adjuvant therapies have been used

Sorafenib and TARE

After radiation exposure of an HCC cell-line, an in vitro increase in Vascular Endothelial Growth Factor (VEGF) has been documented.70 This also happens following TACE.71 A clear relationship between serum VEGF and the patient’s prognosis has been reported.72 Thus the use of sorafenib, which acts on VEGF signalling, might be synergistic with TARE. Horgan et al. showed the feasibility of this approach reporting on two clinical cases,73 without treatment related toxicity. This experience together

Conclusion

Many issues need to be resolved in the management of HCC with cirrhosis. Liver dysfunction represents a limit for radical therapeutic approaches to both the tumour and premalignant field.

TARE appears to be an effective treatment for intermediate-advanced HCC and as an adjuvant/neo-adjuvant option for early HCC. Its use could be easily integrated into HCC treatment paradigms (Fig. 3). However, evidence-based literature on this topic is limited due to the low number of well-powered prospective

Conflict of interest

The authors declare no sources of financial support and no conflict of interest.

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