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Mathieu Boulin, PhD
Pharmacist, University Hospital,
Boris Guiu, MD
Interventional Radiologist, University Hospital, Dijon, France
With approximately 750,000 new cases and 695,000 deaths in 2008 worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide.1 In 80% of patients, HCC is a complication of cirrhosis, mainly due to hepatitis B and C virus infections, excessive alcohol intake, non-alcoholic steatohepatitis or haemochromatosis. Only 30% of the patients are diagnosed at the early A stage,2 when potentially curative treatments (surgical resection, liver transplantation, percutaneous ablation) can be given. In patients with unresectable HCC, two randomised trials and two meta-analyses have shown statistically significant survival gains with transarterial chemoembolisation (TACE) compared with supportive care or systemic chemotherapy.3–6
The procedure has been used worldwide for several years and is considered to have a favourable long-term toxicity profile. However, the TACE procedure varies widely from centre to centre and from one interventional radiologist to another, especially as regards indications, anticancer drugs, doses, embolic agents, methods of delivery and schedules.7 Recently, drug-eluting beads have been developed but the optimal TACE regimen is still a matter of debate.
Rationale and definition
In 1954, it was demonstrated that HCC – in contrast to dual portal and arterial vascularisation of the liver parenchyma – was mostly dependent on the hepatic artery for its blood supply.8 This feature provided the rationale for the development of TACE and other intra-arterial procedures in the treatment of HCC. Thus, acute obstruction of the feeding arteries performed during the angiographic procedure of TACE induces selective ischaemic tumour necrosis with a high rate of objective response. Conventional TACE (cTACE) is an interventional radiology procedure that consists of injecting a chemotherapeutic agent emulsified with ethiodised oil into the hepatic artery followed by the administration of embolising agents (Figures 1 and 2). The most frequently used embolising agents are gelatin prepared as 1mm cubes or polyvinyl alcohol (PVA) particles. Gelatin powder should not be used as it may cause biliary damage. Without the injection of a chemotherapeutic agent, the procedure is called transarterial embolisation. Transarterial oily chemoembolisation (TOCE), lipiodolisation and transarterial chemotherapy infusion are names for the technique that consists of the intra-arterial administration of a mixture of a chemotherapeutic agent and ethiodised oil without embolisation. Although often considered a TACE technique, this method uses the ethiodised oil as a carrier for release of the drug and does not result in arterial occlusion.
In 1983, Konno demonstrated that ethiodised oil was retained in the microvascularisation of HCC for several weeks after injection of the lipophilic contrast medium into the hepatic artery.9 Since then, ethiodised oil has been used as the common carrier for the targeted delivery of chemotherapy agents for TACE.
Efficacy and toxicity
The first clinical study of TACE for HCC was published in 1983. Konno demonstrated a decrease in both alfafetoprotein and tumour size in patients treated with TACE using an emulsion of styrene maleic acid neocarzinostatin (SMANCS) and lipiodol for unresectable HCC.9
Since this study, over 100 cohort and randomised TACE studies for HCC have been published. Although all the patients included in these studies were considered to have unresectable HCC according to the 2000 Barcelona European Association for the Study of the Liver (EASL) criteria,10 there were considerable differences in the patients’ characteristics and in the TACE modalities between studies and sometimes in the same study.
The heterogeneous nature of the patients and treatments may partly explain the discordant results of TACE and the wide variations in term of survival rates between studies. In 2002–2003, two randomised trials and two meta-analyses showed statistically significant survival gains of cTACE compared with supportive care or systemic chemotherapy in patients with unresectable HCC.3–6
In 2011, the Barcelona Clinic Liver Cancer (BCLC) treatment algorithm – endorsed by the EASL and the American Association for the Study of Liver Disease (AASLD) – should be considered the best tool for indications of TACE in HCC.11 Since all positive TACE studies have been conducted in highly-selected patients, the procedure is indicated in patients with intermediate B-stage HCC, that is preserved liver function (Child-Pugh A or B7) with a large or multifocal tumour without vascular invasion or extrahepatic spread and the absence of symptoms).11 In these patients, TACE leads to median survival exceeding two years.11
In terms of toxicity, median TACE-related mortality defined as death within three weeks of the treatment was estimated at 2.4% (range 0–9.5%) in 37 trials of 2858 patients.
The causes of death were acute liver failure (the most frequent), tumour rupture (large HCC), upper gastrointestinal bleeding or sepsis.
Post-embolisation syndrome, consisting of transient abdominal pain and fever, occurs in >50% of patients. This syndrome, which is frequently associated with an elevation of transaminases, rarely persists for longer than 72 hours. However, the patient needs monitoring and pain control, and the syndrome can prolong hospitalisation. The severe side-effects of TACE are mainly due to procedure-induced ischaemia of the non-tumoural liver that causes or exacerbates liver failure in cirrhotic patients; they include encephalopathy, ascites, an increase in prothrombin time, an increase in serum bilirubin and a deterioration in the Child status.
The frequency of TACE-related liver failure is difficult to evaluate because of the heterogeneity in the definitions used in the studies, but it is commonly <10%. Ischaemic complications of TACE lead to hepatic abscess, acute cholecystitis, and necrosis or stenosis of the biliary tract and other rare but severe side-effects include bile duct injuries, gastrointestinal bleeding and renal dysfunction. The haematological toxicity of TACE is commonly mild, as the chemotherapeutic doses are lower than those injected intravenously in oncology.
Finding the optimal procedure
In 2007, a systematic review that evaluated the chemotherapeutic regimens used in 52 TACE or TOCE studies failed to demonstrate that one drug was better than any other.7 The most commonly used drugs for TACE are doxorubicin (36%), followed by cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin C (8%) and SMANCS (5%).7 The use of these drugs is based mainly on the results of intravenous chemotherapy trials in the 1970s and 1980s, which showed some objective responses in patients with unresectable HCC. In a recent preclinical study, we demonstrated that idarubicin – an anthracycline currently used in the treatment of leukaemia – was more cytotoxic on three HCC cell lines than were ten other anticancer drugs, including all the chemotherapeutic agents currently used for TACE.12
In the 2000s, new TACE techniques using embolisation microspheres (DEB-TACE) loaded with chemotherapeutic agents were developed. Microspheres are embolisation drug-delivery systems composed of biocompatible, non-resorbable, deformable hydrogel beads. The beads are composed of a negatively charged polyvinyl alcohol (PVA) polymer that may be loaded with positively charged anticancer drugs. As an example, the positive protonated amine group of doxorubicin hydrochloride interacts with negative sulfonate (DC Bead™) or carboxylate (Hepasphere™) microspheres. The theoretical advantage of loaded microspheres is that they combine in one step local ischaemia and local action with minimal release of the chemotherapeutic agent into the bloodstream
The first animal studies were interesting, and the pharmacokinetic advantage of the drug-eluting beads over lipiodol was demonstrated in 2007. The authors showed that, when injected into patients, doxorubicin was released more slowly from beads than when it was mixed with lipiodol.13 The first clinical results with drug-eluting beads were encouraging, even if the only phase II trial that compared patients treated with DEB-TACE vs cTACE did not show a significantly different response rate between the two techniques.14 In this trial, the anticancer drug was doxorubicin and the response rate at six months according to the EASL criteria was 52% in the DEB-TACE arm and 44% in the cTACE arm (p=0.11).
Number and frequency of sessions
The optimal number and frequency of TACE sessions for HCC has not yet been established. A panel of experts on HCC recently recommended ‘on demand’ cTACE.15 In this strategy, the response evaluated by MRI at two months determines whether or not a patient will receive a further session of treatment. At the moment, there are no recommendations about the interval between two DEB-TACE sessions. In current practice, the most frequent interval between two sessions (cTACE or DEB-TACE) is two months with a maximum of three to four sessions.
TACE is the standard treatment for patients with intermediate B-stage HCC. Although a survival benefit of TACE over symptomatic treatment or systemic chemotherapy has been demonstrated, the median survival of patients rarely exceeds two years and the optimal treatment regimen is unknown. There is, therefore, a need for TACE regimens that improve survival without increasing toxicity to the patient.
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