Transcatheter Arterial Chemoembolisation (TACE) for HCC - Classic Concepts and Future Evolution
Eleni Liapi , Jean-Francois H Geschwind Russell H. Morgan Department of Radiology and Radiological Sciences, Division of Cardiovascular and
Interventional Radiology, Johns Hopkins Hospital
Overall results with TACE in Western and Eastern studies have been difficult to interpret, partly due to variable criteria for patient selection and the intent to treat for cure versus palliation. The only recent prospective randomised trials evaluating patient survival after TACE for HCC were published in 2002. Both trials demonstrated significantly longer survival with chemoembolisation. The first, by Lo et al., compared survival outcomes with chemoembolisation versus symptomatic management, with 40 patients in each group. One-, two-, and threeyear survival rates in the study group were 57%, 31%, and 26%, respectively, compared with 32%, 11%, and 3% in the control group (p=0.02). In the included univariate analysis, chemoembolisation was found to be a significant predictor of survival (OR=0.49; p=0.006).
The second study, by Llovet et al., included 112 patients in three arms and compared outcomes with chemoembolisation versus embolisation alone versus symptomatic treatment. The trial was prematurely terminated when a significant survival benefit was demonstrated with chemoembolisation (survival rates, 82% at one year and 63% at two years) over symptomatic treatment (63% at one year and 27% at two years; p=0.009). At the time the trial was halted, there was not a survival benefit identified with embolisation alone (75% at one year and 50% at two years) versus symptomatic treatment. The only variable associated with prolonged survival was assignment to the chemoembolisation group (OR= 0.45; p=0.02). A meta-analysis that included seven randomised trials of arterial embolisation for unresectable HCC provided further support of the efficacy of TACE. TACE showed a median survival of more than two years and in a few cases converted some patients into operable candidates.
Several challenges regarding the interpretation of the efficacy of TACE, as well as such as obstacles regarding the development of multi-drug resistance mechanisms and tumour revascularisation, are yet to be solved. Variations on the technique, as well as different drug regimens, hinder a more systematic approach and implementation of meta-analyses. Moreover, it is highly unlikely that there will be any prospective randomised controlled trials of chemoembolisation for HCC in the future. The lack of randomised controlled trials for HCC in the US reflects the reality that patients are not willing to be randomised to receive no therapy, mainly because TACE is a widely accessible treatment with a 20-year track record for this disease. Decisions regarding the merits of this therapy must be made based on the best available data and should not be withheld based on the absence of randomised controlled trial data that is highly unlikely to be published.
Future Evolution of TACE
Anti-VEGF Antibodies in Combination with TACE
HCCs are vascular tumours, and increased levels of vascular endothelial growth factor (VEGF) and microvessel density have been observed. High VEGF expression has been associated with inferior survival. Therefore, inhibition of angiogenesis represents a potential therapeutic target in HCC. Interestingly, and in contrast to the traditional belief that tumour ischaemia is favourable, several recent studies have shown that tumour ischaemia and hypoxia upregulate several molecular factors, including VEGF, provide resistance to cell apoptosis and stimulate the growth of HCC. Moreover, the degree of VEGF expression is reported to be associated with HCC tumour size and histologic grade.
Bevacizumab (Avastin™, Genentech Inc., San Francisco, CA), a humanised monoclonal antibody that binds VEGF and prevents its interaction to receptors on the surface of endothelial cells, has recently emerged as an important therapeutic agent in colorectal cancer and has been added to the triple chemoembolisation cocktail for patients with primary and metastatic liver cancer. In addition to its direct anti-angiogenic effects, bevacizumab may enhance chemotherapy administration by normalising tumour vasculature and decreasing the elevated interstitial pressure in tumours. A recent pilot study suggested that bevacizumab can be given safely at both 5mg/kg and 10mg/kg in HCC patients with localised unresectable HCC, preserved liver function and no significant oesophageal varices. In another pilot study, selected HCC patients undergoing TACE additionally received intravenous bevacizumab, which was well tolerated and prolonged disease control. Currently, there are two US National Cancer Institute (NCI) phase II trials evaluating the safety and efficacy of bevacizumab in patients with primary unresectable liver cancer. In the authors’ institution, a phase II trial of bevacizumab with TACE for HCC has just started enrolling patients. TACE is designed to be performed on day one of a 42-day therapy cycle and intravenous (IV) administration of bevacizumab (10mg/kg) will be administered on days seven, eight and 22. Data from these trials may guide to the development of novel anti-angiogenic liver cancer regimens. It is important to note that successful execution of these trials depends not only on the transfer of expertise from the bench to the bedside, but also on the productive collaboration of clinicians in a multidisciplinary oncologic setting.
