New Treatments for Hepatocellular Carcinoma
patients does not stop despite treatment. Clear markers are needed to identify patients who will benefit from sorafenib and even more importantly those who will not.
These two factors define the current agenda of clinical research for patients with advanced hepatocellular carcinoma. Other systemic targeted therapies are being tested in randomised controlled trials either in first-line therapy with the goal of showing non-inferiority at least with fewer side effects, or as second-line therapy for patients failing sorafenib treatment. Two drugs are in advanced stages of evaluation: brivanib and everolimus. Brivanib has a slightly different inhibitory profile from sorafenib because it also inhibits fibroblast growth factor receptor kinase activity.6
Everolimus works differently by
Many other drugs are in development and sorafenib can be considered as lamivudine for the treatment of hepatitis B, as a precursor drug that will probably be much less used in the future.
Transarterial Chemoembolisation
Transarterial chemoembolisation (TACE) has been a heterogeneous treatment for years with delivery of different drugs (doxorubicin, cisplatin, epirubicin, mitoxantrone, mitomycin) with different embolising agents (gelatine sponge particles, polyvinyl alcohol particles, starch microspheres, embospheres, etc.) with or without lipiodol and with variable times between the drug injection and the embolisation.9
disrupting the complex of mammalian target of rapamycin (mTOR) with raptor and thereby inhibiting the mTOR complex I. Pre-clinical data show important antitumoural and anti-angiogenic effects with inhibitor of mTOR.7,8
Based on these results several phase II studies have been launched that aim to show an effect on time to progression and overall survival.
Radiotherapy
HCC is a radiosensitive tumour but radiotherapy has been limited due to technical difficulties. The main challenge is to deliver a sufficient dose to the tumour while avoiding damage to the adjacent hepatic parenchyma with an external beam technique.14
Several technological
improvements have occurred over the past few years such as 3D conformal radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy, image-guided radiotherapy and respiration-gated radiotherapy. They permit the delivery of an adequate therapeutic dose while reducing the risk of radiotherapy-induced liver disease. Results of relatively small studies with 3D conformal radiotherapy,15 radiotherapy16
or with patients with portal vein thrombosis17
stereotactic show
multiple cases with objective response with acceptable side effects. However, external radiotherapy will need much more data from properly designed trials to establish itself as a treatment for HCC. Another approach that has rapidly gained the attention of the international research community is internal radiotherapy by radioembolisation of yttrium-90 microspheres. This seems a particularly attractive option for Child A patients with a large tumour burden and portal vein thrombosis.18
Before the radioembolisation a mesenteric
angiography and a technetium-99m macroaggregated albumin scanning is required to assess gastrointestinal flow and lung shunting.
Curative Treatments
TACE profited enormously from the PRECISION V trial.10 This trial tested the delivery of embolic microspheres loaded with doxorubicin. With this device the embolisation and the drug delivery occurs at the same time and the procedure gains in uniformity. This trial missed its primary end-points because there was a lack of effect on tumour response at six months. Subgroup analysis revealed that patients with negative prognostic factors such as Child B, an Eastern Cooperative Oncology Group (ECOG) performance status of 1, bilobar HCC and recurrent disease profited more from this device than from conventional TACE. Importantly there were significantly fewer side effects with the beads loaded with doxorubicin. These results led to the wide use of these beads to perform TACE and to more uniformity in the procedure. The availability of beads with different diameters still leaves some room for heterogeneity but also permits better individualisation of the treatment.
Based on these encouraging results with sorafenib and with TACE, it makes good sense to try to combine them. The best combination, leading to a maximal benefit, is to give systemic targeted therapy before, during and after the TACE sessions.11
Giving systemic targeted
therapy after TACE sessions basically means using them as an adjuvant. To stop sorafenib therapy for the TACE session could be counterproductive given that experimental work has suggested that interruption of sorafenib treatment may promote tumour growth.5
Only
by prescribing sorafenib at the same time with TACE can it efficiently block the effect of growth factors released in response to TACE.12 date, only one phase I study has used this scheme.13
To In this small study,
21 patients were included to receive sorafenib starting a week before TACE and to continue it without discontinuation. The incidence of side effects was similar to those reported with TACE alone and with sorafenib monotherapy, with the exception of thrombocytopenia, which was observed in 21% of the patients treated with sorafenib and TACE and in only 4% of the patients treated with sorafenib alone.
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
Concerning surgical treatment of HCC, the clinical research activity is less visible, but still present. After resection, more than half of the patients redevelop an HCC in the following five years. Sorafenib is being tested as an adjuvant therapy after curative treatment in patients with a significant risk of relapse. This trial is randomising patients to receive either sorafenib or placebo and is designed to run for four years. It is cleverly designed to maximise the probability of capturing an effect of sorafenib. Nevertheless, time will show whether asymptomatic patients will be ready to endure significant side effects for such a long period to prevent a hypothetical relapse.
Concerning transplantation, it is well-known that the widely applied Milan criteria are too conservative and that a substantial fraction of patients outside them could benefit from transplantation. Yao et al. proposed an extension of the criteria based on larger tumour diameters.19
Mazzaferro recently propagated the Metroticket concept,
which admits that with tumour burden the risk of relapse increases and post-transplantation survival decreases.20
This led his team to
formulate the up-to-seven criteria, i.e. patients are eligible if the sum of the number of tumours and the diameter of the largest in centimetres is less than seven. These patients achieved a five-year overall survival of 71%. Toso elegantly took the essence of the concept, proposing a maximal total tumour volume.21,22
This gives different weight to the
tumours according to their size: small tumours are less relevant than large tumours. This is particularly appropriate for the following reasons: radiological criteria for the diagnosis of HCC are less sensitive and specific for small tumours and the probability of vascular invasion, which is a strong predictor of relapse, is linked directly to tumour size.
Necessity of Biomarkers
There is a clear demand for new and effective treatments. New agents such as sorafenib have shown good effects but are limited in therapeutic range because HCC is a heterogeneous entity. There are
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