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Keywords:

  • advanced;
  • hepatocellular carcinoma;
  • molecular pathways;
  • molecular targeted therapy

Abstract

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Treatment of hepatocellular carcinoma has dramatically changed in the last years. The better knowledge of the molecular mechanisms responsible of tumor initiation and progression has allowed the development of molecular targeted therapies that specifically block the disrupted pathways. Among all these new agents, Sorafenib is the only one that has shown efficacy in terms of survival in advanced stage in two randomized, double-blind, controlled trials. The positive result of these two trials are the proof of the efficacy of molecular targeted therapies in hepatocellular carcinoma and opens the door to multipathway blockade and the use of these targeted therapies in the adjuvant setting. Other agents have shown promising results in phase 1-2 trials but further studies are needed to demonstrate their efficacy. In the next years, efforts should be directed to identifying genomic and proteomic profiling that will help us to assess the prognosis and to define what treatment benefits whom, ultimately giving way to personalized medicine.


Epidemiology of hepatocellular carcinoma

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Hepatocellular carcinoma (HCC) is the sixth causes of death and one of the major causes of cancer cause death worldwide (1). The incidence of HCC is increasing in Europe and the US and is currently the leading cause of death among cirrhotic patients (2). Its incidence is expected to increase until 2020 because of HVC post-transfusion hepatitis and it will then, hopefully, begin to decrease (3). Chronic hepatitis B (HBV) infection is the predominant risk factor in Asia and Africa, and chronic hepatitis C (HCV) infection, alcohol abuse and non-alcoholic steatohepatitis in Western countries and Japan. HCC develops in a cirrhotic liver in more than 90% of cases, and this condition is the strongest predisposing factor (4). Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic HBV carrier or an alcoholic patient, and there were no known effective palliative or therapeutic options. The rising incidence of HCC in several regions around the world, coupled with the capacity to achieve early diagnosis and apply effective therapy, has raised major interest in all aspects related to the research and clinical management of HCC.

Diagnosis and staging

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Diagnosis of HCC in a cirrhotic liver can be established by biopsy or by non-invasive criteria taking into account the prominent arterial blood supply to the tumour (5). Intense arterial uptake, followed by washout of contrast in the venous phase, permits to set the diagnosis: in nodules larger than 2 cm, one single technique is enough, but in tumours between 1 and 2 cm, two coincidental techniques among contrast-enhanced ultrasound, computed tomography and magnetic resonance, are required (6). Unfortunately, α-fetoprotein does not possess adequate sensitivity or specificity as it may increase during viral flares and also in other malignancies such as cholangiocarcinoma (7).

In all types of cancer, it is important to establish the stage of the disease as this is closely related to treatment proposal and prognosis. For HCC, various prognostic factors of overall survival (OS) have then been explored and several classifications have been proposed. Those that solely capture the degree of liver function impairment (Child–Pugh, model for end-stage liver disease) or tumour burden (TNM) will not be able to define the prognosis accurately and hence, most systems incorporate parameters of both dimensions. Surprisingly, some systems do not take into account the presence of cancer-related symptoms (performance status, Karnofsky index) and this impairs their capacity. Recently, some studies have assessed the value of quality-of-life indexes and this deserves further evaluation and validation. Sure refinement will arise from the better knowledge of molecular abnormalities, and this may allow a molecular classification of HCC as proposed recently (8–10).

The Barcelona Clinic Liver Cancer (BCLC) system takes into account these three aspects and at the same time links staging with both prognosis and treatment indication (11). The BCLC system has been validated extensively and this explains its success and endorsement by several associations such as the American Association for the Study of Liver Diseases (5) (Fig. 1).

image

Figure 1.  Strategy for staging and treatment assignment in patients diagnosed with hepatocellular carcinoma (HCC) according to the BCLC proposal. Adapted with permission from Llovet et al. (11).

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Treatment algorithm and current challenges

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Patients with HCC can be roughly divided into three main groups: (i) Those who can benefit from a surgical procedure or a loco regional therapy and whose main problem will be the prevention and management of recurrence. (ii) Those who are not candidates for curative options and nevertheless may benefit from medical treatment. (iii) Those with heavily impaired liver function or severe deterioration of their physical status (performance status >2) so that they are only amenable to symptomatic palliation. Patients in the first group form the so-called stage A of the BCLC classification, patients in the last category correspond to stage D and patients in the intermediate status include those with a wide range of liver function impairment (Child–Pugh A or B), tumour burden (vascular invasion, extrahepatic spread) and presence/absence of symptoms. Accordingly, these patients are divided into the intermediate BCLC B stage (no vascular invasion/spread/no symptoms) and the advanced BCLC C stage (any adverse profile) (11).

Patients into stage A can be treated with resection, transplantation or ablation and the main challenge there is how to manage patients in the waiting list for transplantation and how to prevent recurrence after initial successful therapy. Patients in BCLC B stage can benefit from transarterial chemoembolization (12) and in them the main issue is how to enhance the treatment response and maintain it for longer. Those patients in stage C had no effective treatment option and were candidates for a research trial to evaluate new agents (5). Several studies had shown that chemotherapy had no efficacy and this has also been the case for interferon, anti-androgens, oestrogen blockade and seocalcitol administration.

In the past decade, the molecular biology of hepatic carcinogenesis and tumour progression has been increasingly understood (13, 14). Although it is a complex and multistep procedure, several important intracellular signalling pathways such as Ras/Raf-MEK/ERK and PI3K/Akt/mTOR have been recognized and explored. The role of several growth factors and anti-angiogenic factors – epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) – has been confirmed. Agents targeting one or more molecular abnormalities are under development, and some of them have entered clinical trials (15). Recent data confirmed the efficacy of sorafenib, a multikinase inhibitor targeting Ras/Raf/VEGFR2/c-kit/PDGFR, on survival (16).

Entering the era of molecular targeted therapy

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

The different drugs (available or under development) are classified according to their putative targets (Table 1): drugs targeting the signal transduction via blockade of one or more growth factor receptors and/or intracellular signalling, and agents targeting angiogenesis, apoptosis, cell cycle, cell migration or protein turnover. This classification is arbitrary as most drugs are not specific for only one target or pathway but overlap several. These targeted drugs are mainly ligands specific to cell surface receptors (antibodies) and protein kinase inhibitors.

Table 1.   Targeted drugs in cancer therapy
FunctionTargetDrugs (type of drug)
  1. EGFR, epidermal growth factor receptor; HDAC, histone deacetylase; HGF, hepatocyte growth factor; IGF, insulin growth factor; MAb, monoclonal antibody; MEK, mitogen-activated protein extracellular kinase; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; TKI, tyrosine kinase inhibitor.

Signal transduction
 Growth factor receptorEGFR1(TKI)=gefitinib, erlotinib, lapatinib, (MAb)=cetuximab, panitumumab
EGFR2(TKI)=lapatinib/(MAb)=trastuzumab
PDGFR(TKI)=lestaurtinib, PKC 412, sunitinib, imatinib
FLT3(TKI)=imatinib, sunitinib, sorafenib
IGF-1R(MAb)=IMC-A12
c-Met/HGF(TKI)=SU11274, JNJ38877605, ARQ197
c-kit(TKI)=dasatinib, imatinib, sorafenib
 Intracellular signallingRas(TKI)=tipifarnib – farnesyl transferase inhibitor
Raf(TKI)=sorafenib
MEK(TKI)=vandetanib, AZD6244
ERKNo
P13k(TKI)=wortmannin, LY294002
Akt(TKI)=alkylphospholid perifosine
mTOR(TKI)=temsirolimus, everolimus, rapamicin,
 Other receptorWnt-β cateninUnder investigation
Angiogenesis
 Growth factor receptorVEGFR (1–3)(TKI)=brivanib, sunitinib, sorafenib, TSU 68, cediranib, valatanib, thalidomid analog.
PDGFR(TKI)=sunitinib, sorafenib, imatinib, TSU-68
 Growth factorVEGF(MAb)=bevacizumab, IMC1121B
 Vascular permeabilityAminopeptidaseN/CD13NGR-hTNF
Apoptosis
 Intrinsic pathwayBCL2(TKI)=imatinib, oblimersen, GX15-070
 Extrinsic pathwayApo2L/TRAIL(MAb)=mapatumumab, apomab, rhApo/TRAIL, (TKI)=AMG-655
Protein turnoverProteasome(TKI)=bortezomib – other target also-
Cell cycleCDKs(CDKI)=flavopiridol
Histone deacetylase(HDAC inhibitor)=belinostat (PXD101)
Microtubule functionEpothilone patipilone
Migration and invasionSRC(TKI)=dasatinib, XL558
Cell differentiationHedgehogNot yet

Targeting the epidermal growth factor receptor/mitogen-activated protein kinases pathway

One of the best-characterized signalling pathways is the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK) pathway, which includes receptor EGFR and a cascade of phosphorylations involving at least four kinases: Ras, Raf, mitogen-activated protein extracellular kinase (MEK) and extracellular signal-regulated kinase (ERK) (17). The ligands EGF, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and VEGF, among others, can activate the Ras/MAPK signalling pathway, which is a focal point for cell proliferation and differentiation signal transduction. Upregulated activity of the MAPK pathway has been well documented in HCC cell lines, in in vivo HCC models and in human HCC specimens (13). A recent study showed that the HCV core protein could directly activate the Raf/MEK/ERK pathway, raising the potential of a major role of this pathway in virus C-induced hepatocarcinogenesis (18). Loss of Raf kinase inhibitor protein promotes HCC proliferation and migration. Different approaches have been developed to inhibit the EGFR/Ras/Raf/MAPK pathway at different levels.

Antagonization EGFR function can be carried out using a neutralizing monoclonal antibody such as cetuximab and panitumumab, or using a tyrosine kinase inhibitor (TKI) of EGFR activity, such as gefitinib, erlotinib and lapatinib. Phase II trials with erlotinb (19), gefitinib (20), lapatinib (21) and cetuximab (22, 23) are available. In all of them, the stage of the patients is difficult to understand and hence, data about survival are not highly informative for deriving a valuable signal in terms of benefit. In most cases, the main end-point is progression-free survival (PFS) at 6 months (median PFS ranging from 1.7 to 4.7 months) and it is impossible to rule out a confounding effect of cirrhotic death in all the studies. Disease control rate (partial response+stable disease rates) ranges from 20 to 60%. The association of cetuximab with chemotherapy (gemcitabin, oxaliplatine and capecitabine) has reported a low response rate but a high rate of stable disease, leading to a time to disease progression of about 5 months (22). Results of a phase II trial with the erlotinib–bevacizumab association (a powerful anti-anagiogenic) are described later (24).

The inhibition of the Ras/Raf/MAPK pathway may have a huge potential.

(a) Targeting Ras with inhibitors of farnesyl transferase is of interest as overexpression of Ras has been demonstrated in HCC and dysplasic liver nodules. To be competent for signal transduction, Ras proteins require post-translational modification by incorporation of prenyl moieties (farnesyl and geranyl groups). One of these inhibitors, ABT-100 (prevents prenylation of Ras proteins), has shown efficacy in preventing the development of chemically induced HCC in rats.

(b) Targeting Raf with Raf kinase inhibitor Bay-439006 (sorafenib). Sorafenib is a multikinase inhibitor targeting the Raf serine/threonine kinases and the VEGFR 1/2/3, PDGFb, c-kit, Flt3 and p38 tyrosine kinases (25). In vitro, sorafenib has been shown to stop tumour cells growth and induce apoptosis of HCC cell lines through inhibition of Raf/MEK/ERK signalling (26). It has also been shown to inhibit the growth of human HCC xenografts in nude mice (27). Finally, sorafenib has successfully undergone phase I (28), II (29) and III trials (16, 30). The results of the main trials are summarized in Table 2 and Fig. 2. The median survival of patients is increased from 7.9 to 10.7 months (hazard ratio 0.69, P<0.0001). The positive data obtained in the phase 3 trial have been validated in a recent Asian trial (30) and hence, currently, there is no doubt that sorafenib is now the standard of care for patients with advanced HCC (15, 31). It increases the life expectancy in more than 40% of patients compared with placebo and has a safe profile in terms of side effects. All strata of patients and clinical profiles appear to benefit from sorafenib (Table 3 and Fig. 3). The magnitude of the benefit obtained by sorafenib is equal to that offered by targeted therapies in patients with advanced colorectal (32), lung (33), breast (34) and head and neck cancers (35), among others, both in terms of likelihood of death and in terms of absolute values. Hence, the treatment of advanced HCC deserves the same positive evaluation as that in other cancers.

Table 2.   Randomized controlled trials of sorafenib in advanced hepatocellular carcinoma
 Llovet et al. (16)Cheng et al. (30)
  1. AFP, α-foetoprotein; BCLC, Barcelona Clinic Liver Cancer; TTP, time to progression.

RegimenSorafenib 800 mg/daySorafenib 800 mg/day
Number of patients299 treated (303 placebo)150 treated (76 placebo)
Median age65 years51 years
Primary end pointSurvivalSurvival
Classification BCLC B/C(%)18%/82%4%/96%
Metastasis/vascular invasion/AFP51%/36%/median 44 ng/ml68%/34%/NA
PS 0–1/292%/8%95%/5%
Previous treatment67%NA
Etiology of cirrhosis HCV/HBV/alcohol/other29%/19%/26%/29%11%/71%/18%
Response rateDCR 43%DCR 35%
CR/PR/SD/PD0%/2%/71%/23%0%/6%/54%/31%
TTP (control)5.5 months (2.8 months)2.8 months (1.4 months)
HR (95% CI)0.58 (0.45–74)0.57 (0.42–0.79)
Median survival (control)10.7 months (7.9 months)6.5 months (4.2 months)
HR (95% CI)0.68 (0.55–0.87)0.68 (0.50–0.93)
Toxicity grade 3/430%24%
image

Figure 2.  Survival (a) and time to progression curves (b) of patients randomized to sorafenib or placebo. Adapted from Llovet (16).

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Table 3.   Sorafenib therapy in patients with advanced hepatocellular carcinoma, subgroup analysis of SHARP trial
 Alcohol related cirrhosis (58)Presence of vascular invasion (MVI) and or extrahepatic spread (EHS) (59)Absence (PS 0) or presence of symptoms (PS 1–2) (60)Prior antitumour therapyBaseline transaminases (61)HCV cirrhosis (62)
  1. ALT, alanine aminotransferase; AST, aspartate aminotransferase; TACE, transarterial chemoembolization.

Number of patients79/80MVI-EHS: 209/212PS 0: 161/164Prior curative treatment: 81/77AST/ALT normal: 143/14993/85
Sorafenib/placebo No MVI-EHS: 90/91PS 1–2: 138/139Prior TACE: 86/90AST/ALT mild: 85/75 
    AST/ALT moderate: 68/78 
TTP median (months)5.5/3.9MVI-EHS: 4.1/2.7PS 0: 5.5/2.9 (s)Prior curative treatment: 5.5/2.7AST/ALT normal: 5.5/3.37.5/2.7
Sorafenib/placebo No MVI-EHS: 9.6/4.3PS 1–2: 5.3/2.8 (s)Prior TACE: 5.8/4AST/ALT mild: 5.5/2.8 
    AST/ALT moderate 5.5/2.7 
Median survival10.3/7.9 monthsMVI-EHS: 8.9/6.7 monthsPS 0: 13.3/8.8 monthsPrior curative treatment: 11.9/8.8AST/ALT normal: 13/914/7.9
Sorafenib/placebo No MVI-EHS: 14.5/10.2 monthsPS 1–2: 8.9/5.6 monthsPrior TACE: 11.9/9.9AST/ALT mild: 11/8 
    AST/ALT moderate: 8/5.5 
image

Figure 3.  Overall survival of selected subgroups according to baseline prognostic factors. Adapted from Llovet (16).

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It is important to stress that the impact of sorafenib has been achieved without a significant effect in terms of the response rate. A minority of patients experience tumour reduction according to the RECIST criteria (36), and the effect was captured when assessing time to progression (TTP). This was significantly delayed and shows that the conventional oncology definitions will have to be modified because the activity of some of the new agents is not captured by the usual tools merely based on size reduction (31).

The phase 3 trials mostly included patients in Child–Pugh A stage. Pharmacokinetic data are similar in patients in Child–Pugh B, and on comparison with the data of phase 2 investigations, it appears that the efficacy and safety is maintained (37). Obviously, Child–Pugh B is a very wide group in terms of liver function impairment and life expectancy. Thus, it appears that at Child–Pugh B 7 points, treatment effectiveness would be maintained, while data in more evolved liver disease are unknown, and indication of sorafenib should be based on an individualized medical evaluation.

It is very appealing to combine sorafenib with other agents, either chemotherapy and/or other targeted therapy. A recent review summarized the efficacy, safety and pharmacokinetics of sorafenib with other targeted agents or cytotoxic drugs from a series or phase I/II trials in 600 patients with various solid tumours (38). Common dose-limiting toxicities were the hand foot syndrome, diarrhoea and fatigue. The maximum tolerated dose (MTD) was not reached in most trials, except with bevacizumab association. Sorafenib had little effect on the pharmacokinetics of the co-administred agent, and vice versa, except with doxorubicin, irinotecan and docetaxel. These alterations were not associated with increased clinical toxicity. There are no robust data to establish the efficacy of the combinations, but clearly a careful approach is mandatory to not lose the benefit in survival because of major toxicity because of the combination.

A recent phase II randomized study included 96 patients treated with sorafenib plus doxorubicin or doxorubicin plus placebo. The response rate was weak but similar (4%). Results for TTP and OS favour the sorafenib–doxorubicin association vs. doxorubicin–placebo (TTP 8.6 vs. 4.8 months; OS 13.7 vs. 6.5 months). An increased risk of grade 3/4 neutropenia was noted in the association group (53 vs. 46%) (39). Obviously, a more convenient study would have been the comparison of sorafenib with the sorafenib/doxorubicin association, as, in its current format, the sole conclusion is that sorafenib retains its efficacy in the presence of doxorubicin, while there is no proof that doxorubicin is of any help.

(c) Targeting MEK kinase. A recent study has shown that a MEK inhibitor could stop HCC proliferation and growth of a human HCC xenograft (40). However, long-term administration of the MEK inhibitor led to the development of resistance and loss of drug efficacy.

Targeting the PI3K/Akt/mTOR pathway

The second well-defined pathway is the PI3K/AKT/mTOR. Akt can be activated by different ways: through a tyrosine kinase receptor [EGF or insulin growth factor (IGF)], through a constitutive activation of PI3K or through the loss of function of the tumour suppressor gene PTEN (mutational acquired). PI3K activates serine/threonine kinase Akt, causing FOXO3a phosphorylation, and its nuclear translocation, promoting apoptosis. There is a strong relationship between a low level of FOXO3a evaluated by reverse transcriptase polymerase chain reaction or immunoblotting and survival (a two-fold decrease in expression vs. normal) (41). An important mediator of this pathway is mammalian target of rapamycin (mTOR). mTOR is a central regulator of cell growth and proliferation and is activated in a subset of HCCs (42).

Mammalian target of rapamycin inhibitors: rapamycin and analogues everolimus and temsirolimus are used as immunosuppressive therapies after liver transplantation, and for advanced renal cell cancer (43). Treatment of HCC xenograft mice with mTOR inhibitors caused significant tumour shrinkage and a reduced level of FOXO3a (44).

Perifosine is a novel oral alkylphosphocholine with effects on multiple signal transduction pathways including Akt, MAPK and Jun. The drug was given to 13 patients with HCC at a daily dose of 50 mg: one partial response and four stable diseases over 6 months were noted with no severe side effects (45).

Targeting other growth factor receptors

  • (a)
    C-Met/HGF signalling. HGF is a critical molecule for hepatocyte regeneration after injury, although the exact role of c-Met/HGF deregulation in the pathogenesis of HCC is not yet clear. A study conducted on 18 resected patients found a correlation with overexpression of mRNA c-Met and early stage, with no association with survival (46). Antibodies and specific inhibitors are under development.
  • (b)
    IGF. Interaction between IGF and EGF signalling may be a mechanism of resistance for some tumours. Molecules blocking IGF-1R and c-Met are under early clinical investigation.
  • (c)
    Wnt-β catenin pathway. Wnt regulates specific oncogens such as c-myc, cyclin D and survivin. Activation of Wnt occurs in 1/3 of virus C-induced HCC (13). Drugs targeting these pathways are under development.
  • (d)
    PDGFR/c-kit. PDGF and PDGFR are involved in multiple tumour-associated processes, including autocrine growth stimulation of tumour cells, stimulation of tumour angiogenesis, recruitment and regulation of tumour fibroblast, and overexpression of c-kit has been described as a prognostic factor in HCC. Imatinib mesylate is a TKI targeting PDGFR, the stem-cell factor receptor c-kit and the fusion protein Bcr-Abl. For now, it is the standard treatment of gastrointestinal stromal tumour (gain-of-function mutation of c-kit) (47) and of chronic myelogenous leukaemia (constitutively active Bcr-Abl fusion product from the Philadelphia chromosome) (48). In a small phase II study, imatinib (400 mg/day) was given to 17 HCC patients with advanced disease. All the patients were PDGFR and c-kit negative in immunohistochemical staining. There was no objective response and only 5/17 patients had a stable disease after 8 weeks of treatment. The median OS was only 3 months (49). Perhaps treatment should have focused on PDGFR/c-kit-positive tumour, but this seems to be uncommon with HCC (0–25%). These results make PDGFR and c-kit questionable targets in the treatment of patients with HCC.

Targeting angiogenesis

Angiogenesis is a fundamental process for tumour growth. Cells of the growing tumour tissue are exposed to physiological stresses connected with insufficient delivery of oxygen (hypoxia) and accumulation of acidic products of the glycolytic metabolism (acidosis). Adaptation to these micro-environmental stresses leads to an increased secretion of the hypoxia-inducible factor (HIF), which activates a broad array of genes functionally involved in angiogenesis such as VEGF and PDGF. Transmembrane carbonic anhydrase isoform IX (CA IX) is a direct target of HIF and serves as a surrogate marker of hypoxia. Tumour and stromal cells can also secrete VEGF; thus, VEGF acts as a stimulating growth factor for endothelial cells (paracrine stimulation), tumoral and stromal cells (autocrine stimulation). VEGF is also inducible via other pathways such as Ras/Raf/MAPK, Akt/PI3K/mTOR and PTEN. An increased level of VEGF and microvessel density is a common pattern in many cancers, and also in HCC. Targeting angiogenesis is of particular interest in HCC, because of its hypervascular profile.

Bevacizumab is a VEGF monoclonal antibody with some available data in HCC treatment as a single agent or in association. Bevacizumab seems to give more tumoral responses than sorafenib according to RECIST; however, the impact on survival remains unknown. Bevacizumab also has more contra-indications than EGFR inhibitors (vascular and cardiovascular), and has to be avoided in patients with vascular or renal impairment. In addition to these limitations, the data available on bevacizumab indicate a high risk of bleeding, in some cases leading to death (50).

TSU-68 is an oral multikinase inhibitor (VEGFR, PDGFR and FGFR). In a phase II study, TSU-68 was given at a daily dose of 400 mg to 35 Child-Pugh A/B HCC patients. Three patients demonstrated a partial response and six showed a stable disease for more than 6 months, and only one discontinuation for toxicity (51).

Thalidomide was originally developed as a treatment for insomnia and is highly effective in myeloma. Its precise mechanism of action is unknown. It appears to have multiple actions: inhibition of angiogenesis (anti-FGFR, VEGFR), inhibition of growth and survival of stromal cells, alteration of production/activity of cytokines [cyclooxygenase 2, tumour necrosis factor α (TNFα) – role in cancer-induced cachexia – interleukins 4, 5, 6, 8, 10 and 12], alteration of the expression of adhesion molecules and stimulation of T cell. Thalidomide has been given to HCC patients, but its efficacy appears to be weak, and annoying side effects such as fatigue and somnolence limit its administration in cancer patients (52).

Sunitinib is a molecule that inhibits multiple tyrosine kinase of receptors: VEGFR1-2, FLK, PDGFR, FLT3 and c-kit. The anti-angiogenic effect of sunitinib is mainly mediated through VEGFR and PDGFR protein kinase inhibition, and also via the direct antiproliferative effect through blockage of FLT3 and c-kit receptors. Sunitinib is already approved for the treatment of gastrointestinal stromal tumour and renal cell carcinoma. The results of the available phase II trials indicate a more intense antitumoral effect than sorafenib when assessing the appearance of tumour necrosis rather than the tumour size. A 50 mg/day dosage is associated with major side effects such as bleeding and death (53), and a lower dose seems to reduce this incidence but does not really eliminate it (54). The positive data with sorafenib have prevented a comparison vs. placebo and major, strong data regarding safety and efficacy as measured by TTP and survival in phase 2 should be available before running a head-to-head comparison can be made. Indeed, if sorafenib is the standard of care, with the available data, the expected trial would take place in second line.

NGR-hTNF is a novel agent that selectively binds to aminopeptidase N/CD13, highly expressed on tumour blood vessels. A phase II trial enrolled 16 patients with progressive HCC. NGR-hTNF was given at 0.8 mcg/m2 for 1 h via an intravenous infusion every 3 weeks. Thirty-six per cent of patients showed disease stabilization for more than 4 months. The median PFS was 2.4 months, and no grade 3–4-related toxicities were noted (55).

Drugs targeting other pathways and other putative hepatocellular carcinoma treatments

Microtubule inhibitors, patupilone and vinflunine, have yielded poor results in phase II studies (56). Bortezomib, an inhibitor of protein turnover, has also yielded disappointing data in a phase II study in association with doxorubicin (57). A putative efficacy of ADI-PEG20 demonstrated in a phase I study needs to be explored in a phase II study.

Belinostat (PXD101), an inhibitor of histone deacetylase, was given to 12 HCC patients. The phase I trial indicated a very good tolerance, with a MTD not being reached at a dose level of 1200 mg/m2/day; a phase II trial is ongoing.

Future perspectives

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Treatment of advanced HCC has become a very active area of research. The better knowledge of the mechanisms leading to tumour progression has allowed the development of novel agents that have been included for human testing. Only sorafenib has been shown to be able to significantly improve survival in a double-blind randomized phase 3 trial, and now we face a huge competition to add other agents to the therapeutic armamentarium. However, the evaluation of novel agents will also require novel tools as we have learned that well-established concepts in oncology are no longer valid (31). Sorafenib improves survival without inducing tumour shrinkage. Hence, TTP is a better end-point, but at the same time, we need to develop tools to verify the achievement of biological impact. New radiology techniques based on diffusion and perfusion assessment may show some promise but clearly, there is an urgent need to develop and validate biomarkers to identify the best candidates for therapy and also to promptly detect the failure of treatment and, hence, we need to apply second-line therapies. Genomic profiling and proteomics will definitely play an instrumental role in this setting. Recent studies have shown how genomics may identify patients at a high risk of recurrence after surgery, and we will definitely see data able to define what treatment benefits whom, ultimately giving way to personalised medicine.

In addition to the search for efficacy, major attention will have to be paid to the emergence and management of toxicity related to the usage of new agents. After the demonstration of benefits in an advanced stage, the evaluation of sorafenib will be performed at earlier stages of the disease. Trials are underway to prevent recurrence, after achieving successful ablation or tumour resection and to enhance the benefits of transarterial chemoembolization through sorafenib administration. Life expectancy is larger and thus, long-term side effects may emerge, and may require specific investigations to control them. Needless to say, the fact that cirrhosis underlies HCC in most of the cases adds complexity to the picture and makes HCC clinical research a special area where expertise in different fields is required. Biologists, hepatologists, surgeons, radiologists and oncologists will have to generously convene in teams to raise and run research proposals with the proper background and expertise. If this is not done negative results will ensue, and this will not benefit patients and researchers. Hence, the sole valid approach is to create multidisciplinary teams and develop good-quality proposals. A recent document produced by a panel of experts in different disciplines highlights the benefit of this collaborative approach and, in the next years, we will definitely see how the management of HCC has changed from an absence of effective therapy, but surgery, to a scenario where we have an array of effective therapies at all evolutionary stages that ultimately translate into a major life expectancy after the initial diagnosis (31). Thus, HCC is no longer seen as a cancer with no treatment and with a very dismal prognosis in the short term, but rather the contrary. Active research during the last decades has been fruitful and more will come in the next few years.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References

Alejandro Forner is partially supported by a grant from the Instituto de Salud Carlos III (PI 05/645) and from the BBVA foundation. Maria Reig is supported by a grant from the BBVA foundation. CIBEREHD is funded by the Instituto de Salud Carlos III. The remaining authors have not declared any conflicts of interests.

References

  1. Top of page
  2. Abstract
  3. Epidemiology of hepatocellular carcinoma
  4. Diagnosis and staging
  5. Treatment algorithm and current challenges
  6. Entering the era of molecular targeted therapy
  7. Future perspectives
  8. Acknowledgements
  9. Conflicts of interest
  10. References
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