Treatment of Hepatocellular Carcinoma – Integrating Loco-regional and Molecular-targeted Therapies
Transcatheter Treatment
Transarterial Chemo-embolisation
HCC exhibits intense neo-angiogenic activity during its progression. The rationale for TACE is that the intra-arterial infusion of a drug such as doxorubicin or cisplatin with a viscous emulsion (e.g. lipiodol), followed by embolisation of the blood vessel with gelatine sponge particles or other embolic agents, will result in a strong cytotoxic effect combined with ischaemia. Cumulative meta-analysis of all published randomised trials indicates that survival of patients with HCC not suitable for radical therapies treated with TACE is improved compared with best supportive care.26
However, the outcome of TACE depends on careful
patient selection. In a randomised trial that recruited patients with compensated cirrhosis (70% in Child-Pugh A), absence of cancer-related symptoms (81% with ECOG performance status of 0) and large or multinodular HCC with neither vascular invasion nor extrahepatic spread, two-year survival reached 63% compared with 27% in the untreated control arm (p=0.009).27
In another randomised study, the use
of broader enrolment criteria with inclusion of patients with symptoms or limited portal vein invasion resulted in a two-year survival of 31%. This figure was still superior to that of the untreated control group (two-year survival 11%); however, no survival benefit was identified in the subgroup analysis restricted to patients presenting with portal vein invasion.28
As a result of these investigations, TACE has been established
as the standard of care for patients with intermediate-stage HCC as defined by the BCLC classification, i.e. asymptomatic multinodular tumour with neither vascular invasion nor extrahepatic spread.4,5
The ideal TACE scheme should allow for the maximum and sustained concentration of the chemotherapeutic drug within the tumour with minimal systemic exposure combined with tumoral vessel obstruction. The recent introduction of an embolic microsphere composed of a polyvinyl l alcohol macromer (DC Bead, Biocompatibles), which has the ability to actively sequester doxorubicin hydrochloride from solution and release it in a controlled and sustained fashion, has been shown to substantially diminish the amount of chemotherapy that reaches the systemic circulation, thus significantly increasing the antitumoral efficacy and reducing drug-related adverse events with respect to conventional regimens.29,30
In a phase II randomised trial, DC Bead–TACE
with doxorubicin showed a higher rate of objective response and disease control compared with conventional TACE with doxorubicin, lipiodol and gelatin sponge particles, although the observed difference was not statistically significant.30
There was also a marked reduction in
serious liver toxicity in patients treated with DC Bead–TACE, and the rate of doxorubicin-related side effects was significantly lower in the DC Bead–TACE group compared with the conventional TACE group (12 versus 26%).
Transarterial Radio-embolisation
The use of external beam radiation therapy in HCC treatment has been limited by the low radiation tolerance of the non-tumoral cirrhotic liver. Internal radiation therapy, also called radio-embolisation, consists of delivering implantable microspheres labelled with 90Y into the tumour- feeding artery. This allows the delivery of a high radioactive dose to the tumour with reduced toxicity to the non-tumoral parenchyma. Radio- embolisation has been used in the treatment of HCC not suitable for curative treatment, including patients presenting with portal vein invasion. Data collected in phase I–II studies are interesting and may warrant future investigation. No randomised trials are available so far. Clinical research combining the cytotoxic effect of 90Y with the cytostatic mechanism of targeted therapies is currently in progress.
EUROPEAN ONCOLOGY
Integrating Loco-regional and Molecular-targeted Therapies
Despite the advances in loco-regional treatments,
long-term
outcomes of patients with early- or intermediate-stage HCC remain unsatisfactory because of the high rate of tumour recurrence. After local ablation of early-stage HCC, the tumour recurrence rate exceeds 80% at five years, similar to post-resection figures.31
Molecular studies
have shown that early recurrences, occurring within the first two years after curative treatment, are mainly due to the spread of the original tumour, while late recurrences are more frequently due to the development of metachronous tumours independent of the previous cancer. On the other hand, in patients with a large or multinodular tumour at intermediate-stage HCC who received TACE, tumour recurrence or progression is almost inevitable, leading to an overall survival rate of less than 30% at three years.27,28
Increased understanding of the molecular signalling pathways involved in HCC has led to the development of molecular-targeted therapies aimed at inhibiting tumour cell proliferation and angiogenesis. Sorafenib, a multikinase inhibitor with anti-angiogenic and antiproliferative properties, is the only targeted agent approved for the treatment of HCC and currently recommended for the treatment of patients with advanced-stage tumours not suitable for surgical or interventional therapies.5
This approval was based on data
from SHARP, a randomised, placebo-controlled, double-blind phase III trial.32
In SHARP, 602 patients with advanced HCC received either
oral sorafenib 400mg twice daily or placebo. Compared with placebo, sorafenib significantly prolonged median overall survival (OS 10.7 versus 7.9 months; p<0.001) and median time to radiological progression (TTP 5.5 versus 2.8 months; p<0.001). Sorafenib-related adverse events were mostly mild to moderate. A similar phase III study was conducted in 226 patients from the Asia–Pacific region. Consistent with results obtained in SHARP, sorafenib prolonged OS and TTP compared with placebo, despite patients from the Asia- Pacific region having more advanced disease.33
To date, studies of sorafenib have demonstrated its efficacy in advanced HCC; however, there may also be a role for this agent, or other molecular-targeted drugs, in earlier stages of disease, either as adjuvant treatment after curative therapy or in combination with TACE. Sorafenib will be studied in early-stage HCC in the phase III STORM trial. STORM is a phase III randomised, double-blind, placebo-controlled trial of adjuvant sorafenib in HCC patients who have undergone successful surgical resection or local ablation. Following curative treatment, patients (target enrolment 1,100) are randomised to receive either sorafenib 400mg twice daily or placebo, with the primary aim to investigate the differences in recurrence-free survival.
Tumour recurrence following TACE is characterised by increased vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In one study, changes in the biological behaviour of residual viable HCC tissue after TACE were evaluated. Tumour specimens from 42 patients treated by surgery alone (control group) and 21 patients who received TACE one to two times prior to surgical resection were analysed. The number of VEGF-positive cells in the TACE group was significantly higher than that in the control group, suggesting that TACE increases VEGF expression in the residual surviving cancerous tissue.34
Other experimental investigations suggest that TACE induces expression of other pro-angiogenic
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