TACE in HCC: a multi-disciplinary overview An ILCA satellite symposium sponsored by Biocompatibles - HCC: Level of clinical evidence

Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and more than 600,000 new cases of HCC are diagnosed worldwide each year. HCC is also the third leading cause of cancer-related mortality and is the leading cause of death in cirrhotic patients. Treatments for HCC include surgical treatments (resection and transplantation), loco-regional treatments (percutaneous ethanol injection, radiofrequency ablation, chemoembolisation, arterial chemotherapy and internal radiation) and systemic treatments (sorafenib, interferon and systemic chemotherapy). However, despite the array of available treatments, survival rates remain disappointing.

At the recent, inaugural meeting of the International Liver Cancer Association (ILCA), in Barcelona, Spain, Biocompatibles Ltd, hosted a symposium to discuss transarterial chemoembolisation (TACE) for the treatment of HCC. Chaired by Dr Jordi Bruix, BCLC Group Liver Unit, Hospital Clínic, University of Barcelona, Spain, multi-disciplinary speakers discussed the scientific rationale for TACE as well as the health and safety aspects that need to be considered. They also assessed the current clinical data of TACE (and other treatment options), examined issues surrounding device selection and delivery technique, and ended with an oncologist's perspective regarding the management of liver cancer.

Overview of the clinical data
The level of clinical evidence of the various treatment options for hepatocellular carcinoma (HCC) and an analysis of the staging systems, as defined by the Barcelona Clinic Liver Cancer (BCLC) Group, was presented by Professor Josep M Llovet, Professor of Research, BCLC Group Liver Unit, Hospital Clinic Barcelona, Spain, and Director of HCC Research, Associate Professor, Mount Sinai School of Medicine, NY, USA.

As has been previously stated, the prevalence of HCC is common and is increasing particularly in the US and Europe, and Llovet started his presentation by examining the sources of evidence in the treatment of HCC. He highlighted that there is a distinct lack of large randomised trials (RCTs), defined as >1,000 patients, as well as no meta-analysis of RCTs. In total, Llovet highlighted some 77 sources of evidence (Llovet, Hepatology, 2003; Lopez, Alim Pharm Ther, 2006), these included: meta-analysis of pooled data from RCTs (Embolisation/Chemoembolisation [19] and Tamoxifen [12]), small RCTs (radiofrequency ablation [11], arterial or systemic chemotherapy [21], immunotherapy, octreotide [4], internal radiation [3], anti-androgens, others [6] anti-proliferative agents [1]), and cohort studies (surgical resection [1] and liver transplantation: CLT/LDLT [0]).

Current knowledge and grey areas
Llovet then assessed the levels of evidence for the various treatments for HCC and what benefit (according to the evidence) these treatments deliver, according to the National Cancer Institute (Llovet et al. Sem Liv Dis, 2005). He stated that the evidence reveals that surgical resection, liver transplantation and percutaneous treatments all increase survival. However, these are from cohort studies (3iiiA) and therefore only suggest, but do not prove, a mortality reduction effect.

In addition, the evidence shows that radiofrequency ablation (RFA) provides better local control than percutaneous ethanol injection (PEI) from four RCTs (1iiD). However, with regard to significant survival it is unclear what benefit RFA provides compared with PEI. However, chemoembolisation does show an increase in survival in a group of selected patients from a RCT and a meta-analysis of pooled data (1iiA). In contrast, arterial chemotherapy and internal radiation (I-131, Y-90) both demonstrate good treatment response (2Diii), although its effect on survival is unknown as there are no RCTs. Lastly, 21 RCTs have demonstrated that systemic treatments such as tamoxifen + interferon (1iA), and systemic chemotherapy (1iiA) offer no benefit.

BCLC staging system
Llovet then outlined the numerous staging systems that assist in selecting the best candidates for the best therapies currently available. Of the four different classification staging systems available, he explained that only the BCLC incorporates tumour status, liver function and health status. The other three staging systems - Cancer of the Liver Italian Program (CLIP), American Joint Committee on Cancer (AJCC) and Japan Integrated Staging (JIS) only feature tumour status and/or liver function. They also do not provide treatment guidance.

The BCLC staging system defines the prevalence of the disease and treatment schedule. There are five stages of HCC: very early stage (0); early stage (A) applies to patients with asymptomatic early tumours suitable for radical therapies - resection, transplantation or percutaneous treatments; intermediate stage (B) pertains to patients with asymptomatic multi-nodular HCC; advanced stage (C) applies to patients with symptomatic tumours and/or an invasive tumoural pattern (vascular invasion/extrahepatic spread); and end-stage disease (D) includes patients with extremely grim prognosis (Okuda stage III or PST 3-4) that should merely receive symptomatic treatment. Five year survial rates for stage 0 and A is between 40-70%, three-year survival for stage B and C is between 10-40% and one-year survival for stage D is 10-20% (Llovet JM, Burroughs A, Bruix J. Lancet, 2003).

Natural history of unresectable HCC
In a RCT of 102 patients the authors were able to define stage B and C (Llovet JM. Hepatology, 1999) and subsequently identified those patients with unsectable HCC (stage B, C and D) whose natural outcome depends on cancer-related symptoms (PST/ECOG) and tumour stage (portal invasion and metastases). Furthermore, a RCT of seocalcitol versus placebo (n=746) demonstrated that over the natural history of the disease the median time of survival for stage B patients was 16 months and six months for stage C patients (Beaugrand M, et al. Hepatology, 2005ª).

Intermediate Stage (B)
Llovet then assessed the literature and the results for arterial embolisation. In a 2005 study of 96 patients, chemoembolisation (versus control) was found to have a better trend although this was not significant (Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH) N Engl J Med 1995;332:1256-1261). However, chemoembolisation was able to prevent progression. In a systematic review of RCTs for HCC between 1978 and 2002, a total of six RCTs were identified for meta-analysis. The results showed that at two-years, patient (n=503) outcomes demonstrated a significant trend in favour of chemoembolisation (p=0.14) (Llovet JM and Bruix J. Hepatology, 2003), suggesting chemoembolisation does indeed boost survival in this group of patients (stage B). Moreover, a sensitivity analysis demonstrated that patients randomised to chemoembolisation showed a consistent benefit compared to embolisation alone.

Llovet said that these results justify chemoembolisation treatment for intermediate stage (B) patients as this improves survival in selected patients with unresectable HCC and may become the standard treatment. The best candidates for chemoembolisation are patients with preserved liver function and asymptomatic multi-nodular tumours without vascular invasion and extrahepatic spread. He added that further RCTs are needed to: establish the best device and chemotherapeutic agent, combination of agents, and the optimal re-treatment strategy; and to assess other treatments such as I-131, Y-90 vs chemoembolisation.

DEB: Phase II study
Llovet then outlined his experience (BCLC Group) as part of a Phase II study with Drug-Eluting Beads (DEB) to assess the safety and efficacy of this treatment method for patients with intermediate HCC (Varela M, J Hepatology 2007). A total of 27 (Child-Pugh A cirrhotics, large/ multifocal HCC) patients received DEB-TACE (500-700µm) with doxorubicin at doses adjusted for bilirubin and body surface area (range: 47-150mg). Response was assessed by CT/MRI at six months, using European Association for the Study of the Liver (EASL) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In addition, blood samples were obtained in 13 patients of the DEB-TACE group at five, 20, 40, 60, 120 minutes and six, 24, 48 and 168 hours to determine doxorubicin Cmax and area under the plasma concentration time curve (AUC) values that were compared with seven patients treated by conventional TACE (cTACE)/doxorubicin lipiodolisation. Following the procedure, liver function tests (Bilirubin, SGPT, yGPT, alkaline phosphatase and prothrombin activity) after DEB-TACE showed no permanent impairment of liver function (baseline to one-month).

An assessment of treatment response at six months (n=27) showed 65.5% of patients had a complete (25.9%) or partial response according to RECIST-modified or WHO-EASL modified criteria. In comparison, with cTACE the partial response rate was between 35-50%. Interestingly, it was also noted that in those patients who received DEB-TACE (compared with cTACE) low levels of doxorubicin was detected demonstrating that the drug was indeed being released slowly from the beads.

The results revealed that survival at three-years is 70%, with a median follow-up 20.6 months (3.3-27.3 months). There have been four deaths with one treatment-related death (4%). Complications included post-embolisation syndrome (n=10, 37%) and liver abscess (n=2, 8%). There have been no reported instances of pulmonary embolism or doxorubicin-related complications.

Conclusion
Llovet concluded that chemoembolisation expands survival in selected candidates. However, new RCTs comparing new TACE modalities as well as comparing TACE versus new treatments (internal radiation) should be established with TACE as control arm-standard of care. Chemoembolisation using DEBs is a safe and effective procedure with a favourable pharmacokinetic profile, and that the mircospheres provide an effective mechanism in terms of delivery and drug elution.