Hepatology Hepatocellular Carcinoma


New Treatments for Hepatocellular Carcinoma Cornelia Pfrepper1


and Jean-François Dufour1,2


1. University Clinic of Visceral Surgery and Medicine, Bern University Hospital; 2. Hepatology Department of Clinical Research, University of Bern


Abstract


As a consequence of rising incidence, rapid pharmacological advances and promising future trends for local therapies, clinical research for hepatocellular carcinoma has become very active. The kinase inhibitor sorafenib is the first of a class of drugs that has been shown to prolong survival of patients with advanced stages of the disease. The experience with sorafenib also underscores the side effects of these new systemic targeted drugs and the challenge of identifying patients who will benefit the most from specific inhibitors. Transarterial chemoembolisation is a well-established local therapy. Fortunately, the procedure is becoming more standardised by using embolic microspheres loaded with drugs, for example, doxorubicin. Internal radiotherapy by radioembolisation with yttrium-90 microspheres shows promising results, particularly for patients affected with a large tumour. Concerning surgical treatment, different concepts have been tried to extend the transplantation criteria outside the Milan criteria. Owing to the heterogeneous nature of hepatocellular carcinoma, biomarkers are needed to better understand the tumour in order to choose the most appropriate therapy.


Keywords


Hepatocellular carcinoma, sorafenib, side effects, brivanib, everolimus, transarterial chemoembolisation, radiotherapy, transplantation, Metroticket, yttrium-90 microspheres, biomarkers


Disclosure: Cornelia Pfrepper has no conflicts of interest to declare. Jean-François Dufour has received research grants and/or consultancy fees from Bayer, BMS, Gilead, Merck, Novartis and Roche. Received: 17 January 2011 Accepted: 12 April 2011 Citation: European Gastroenterology & Hepatology Review, 2011;7(2):74–6 Correspondence: Jean-François Dufour, University Clinic of Visceral Surgery and Medicine, Freiburgstrasse, CH-3010 Bern, Switzerland. E: jf.dufour@insel.ch


As of 1 January 2011, 249 interventional trials are listed on the site www.clinicaltrial.gov enrolling patients with hepatocellular carcinoma (HCC). This is a testimony to the tremendous vitality of this field. This is new and due to a combination of three factors: the rising incidence of HCC, which is capturing the attention of the investigators as well as the attention of the pharmaceutical industry, the success of sorafenib as the first drug able to increase the survival of patients with advanced HCC and the rich pipeline of new drugs targeting key enzymes in signalling pathways. Based on these premises, the past few years have brought new hope to patients with HCC, which is expected to be reflected in significant prolongation of survival of patients diagnosed with this dreadful disease.


Systemic Targeted Therapy


With sorafenib a systemic targeted therapy has been shown for the first time to prolong the survival of patients that are not eligible for other treatments. This group of patients still represents a large proportion of the patients diagnosed with HCC. Until now no drug has been proved to change the dismal natural history of the disease at this stage. Sorafenib belongs to a large new class of drugs inhibiting kinases. Kinase activity is the most prevalent enzymatic activity propagating signals along the signalling cascade. By inhibiting key enzymes these drugs act, depending on their inhibition profile, at the same time on different cascades. Sorafenib inhibits the kinase activity of Raf, an enzyme in the mitogen-activated protein kinase pathway and frequently active in HCC.1


Sorafenib also inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor 74


kinase activity. This implies a complex mechanism of action with simultaneous effects on the tumour cells, the endothelial cells and the pericytes.2


It is important that these


This specific, but at the same time multimodal mechanism of action turns out to be essential for the efficacy of sorafenib against HCC. Two randomised control trials reported that sorafenib improves time to progression and overall survival.3,4


positive results were possible due to careful selection of patients. These studies included only patients with Child A, with conserved liver function and a survival limited by the tumour and not by cirrhosis. As we are treating more patients with sorafenib two factors appear more clearly. The first one is that for some patients the side effects are too severe to continue the treatment. Diarrhoea affects about 40% of the patients. Typically this is a side effect that the patients can control with loperamide and learn to live with. Abdominal pain affects about 10% of the patients and can be more problematic because there is no strategy to decrease this side effect. The most relevant side effect in terms of treatment discontinuation is the hand-foot syndrome, which manifests by a redness of the skin of the palms and the soles. It is painful and leads to desquamation. Partly, it could be prevented by avoiding beginning the treatment with a dry skin and perhaps also by introducing the full dosage progressively. Unfortunately about a quarter of the patients have to discontinue sorafenib therapy due to side effects. The effects of such discontinuation on the tumour are currently unknown, but there is experimental work suggesting that it might be harmful.5


The second issue that becomes apparent is that not all patients respond to sorafenib. Some have a long pause in the progression of their tumour, whereas tumour progression in other


© TOUCH BRIEFINGS 2011


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