EASL Clinical Practice Guidelines

Systemic therapies

Molecular pathogenesis and targets for therapies

Molecular targeted therapies have changed the landscape of cancer management. Around 20 molecular targeted therapies have been approved during recent years for patients with breast, colorectal, non-small cell lung, renal cancer and HCC, among other malignancies [[164], [303]]. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC [168]. This advancement represents a breakthrough in the treatment of this complex disease, and proves that molecular therapies can be effective in this cancer. A better understanding of the molecular hepatocarcinogenesis is critical for identifying novel targets and oncogenic addition loops [[304], [305], [306]]. No pathognomonic molecular mechanism or single dominant pathway exists in hepatocarcinogenesis and this explains why a single-targeted agent will not achieve sustained complete response in HCC. Consequently, it is conceivable to inhibit signals at different levels of one of the main pathways, or to inhibit two or three different pathways at the same time.

Hepatocarcinogenesis is a complex multistep process where multiple signaling cascades are altered leading to a heterogeneous biological portrait of the disease [[304], [305], [306]]. Although no oncogenic addition loop defining growth dependence for any subclass of HCC has been defined, several signaling pathways have been implicated in tumor progression and dissemination:


  1. Vascular growth factor (VEGF) signaling is the cornerstone of angiogenesis in HCC, and high level amplifications have been identified [[175], [307]]. VEGFR signaling can be targeted either by the monoclonal antibody bevacizumab directed against VEGF, or by inhibiting the intracellular tyrosine kinase by small molecules such as sorafenib, sunitinib, brivanib, linifanib, vatalinib, cediranib, and others. Other activated angiogenic pathways are Ang2 and FGF signaling.
  2. Epidermal growth factor (EGF) signaling is frequently overexpressed in HCC [308]. EGFR can be targeted either by the monoclonal antibody cetuximab or by small molecules that inhibit the intracellular tyrosine kinase such as erlotinib, gefitinib, or lapatinib.
  3. Ras MAPK signaling has been shown to be activated in half of early and almost all advanced HCCs [[305], [309]]. Activation of this pathway is dependant upon overexpression of ligands and hypermethylation of promoters of tumor suppressors inducing transcription of genes of the AP-1 family, such as c-Fos and c-Jun involved in proliferation and differentiation [310]. Mutations of K-Ras are infrequent in HCC (<5%). No selective Ras/ERK/MAPK inhibitor has been approved, but sorafenib and regorafenib have shown partial cascade blockage [311].
  4. The PI3K/PTEN/Akt/mTOR pathway. This pathway controls cell proliferation, cell cycle and apoptosis, and is activated by various RTKs such as EGFR or IGFR and by inactivation of the tumor suppressor PTEN. It is activated in 40–50% of HCCs [[312], [313]]. Several compounds inhibiting mTOR (rapamycin, temsirolimus and everolimus) are tested in phase II and III studies.
  5. HGF/c-MET pathway. Dysregulation of the c-MET receptor and its ligand HGF, critical for hepatocyte regeneration after liver injury, is a common event in HCC [314]. However, their role in targeted therapy needs further investigation.
  6. Insulin-like growth factor receptor (IGFR) signaling. IGF-1R and IGF-II expression is increased in HCC, whereas IGFR-II is downregulated in a subgroup of HCCs [[315], [316]]. Several IGF-1R inhibitors are now under early clinical investigation in HCC.
  7. Wnt/ß-Catenin pathway is crucial for hepatocarcinogenesis [[304], [305], [306], [317], [318], [319]]. Around one third of HCCs have activation of the Wnt signaling pathway (particularly HCV-related HCCs), as a result of activating mutations in the transcription factor ß-catenin [[175], [317], [318]], overexpression of Frizzled receptors or inactivation of E-cadherin or members of the degradation complex (GSK3B, AXIN, adenomatosis polyposis coli (APC)) [319]. New compounds to block this so-called undrugable pathway are under early clinical investigation.
Additional pathways and their role in targeted therapy such as the extrinsic/intrinsic apoptotic pathway, Hedgehog signaling, JAK/STAT signaling, TGF-ß signaling, Notch pathway, ubiquitin–proteasome pathway, nuclear factor-κB signaling, cell cycle control, and the role of the tumor microenvironment have to be further defined. Similarly, the potential role of recently described oncoMIRs relevant to hepatocarcinogenesis as molecular targets should be confirmed by clinical investigations [[135], [320]].

Molecular targeted therapies

Hepatocellular carcinoma is recognized as among the most chemo-resistant tumor types, and until 2007 no systemic drug was recommended for patients with advanced tumors, an unparalleled situation in oncology. Sorafenib emerged as the first effective systemic treatment in HCC after 30 years of research, and is currently the standard-of-care for patients with advanced tumors [168]. After this study, around 56 molecular agents are being tested in phase II and phase III clinical trials [321] (Table 4), the final results of which might lead to updated treatment recommendations. A summary of the evidence-based data is set out below. The panel recommends that drug development of novel molecules in HCC should be based on the identification of oncogenic biomarkers to guide a more personalized and stratified therapy.


Table 4
Ongoing randomized phase II–III trials aimed to change the standard of care in HCC management during the period 2012–13.



∗Halted 2010 for futility/toxicity.
∗∗See addendum at the end of the Guidelines.
Sorafenib

Sorafenib, an oral multi-tyrosine kinase inhibitor, was the first and remains the only drug that has demonstrated survival benefits in patients with advanced HCC. Following an initial phase II study showing a signal of efficacy [322], a large double-blinded placebo controlled phase III investigation was conducted, leading to positive survival results [168]. In this trial, the benefit of sorafenib was to increase the median overall survival from 7.9 months in the placebo group to 10.7 months in the sorafenib group (HR = 0.69; 95% CI, 0.55–0.87; p = 0.00058), which represents a 31% decrease in the relative risk of death. In addition, sorafenib showed a significant benefit in terms of time to progression (TTP) assessed by independent radiological review with a median TTP of 5.5 months for sorafenib and 2.8 months for placebo. The magnitude of survival benefit was similar to that demonstrated in a parallel phase III trial conducted in the Asian-Pacific population, in which hepatitis B was the main cause of HCC [323]. In this later trial, the median overall survival was 6.5 months in the sorafenib group versus 4.2 months in the placebo group (HR = 0.68; 95% CI, 0.50–0.93; p = 0.014). The worse outcome of patients included in this trial, regardless of treatment allocation, compared with the SHARP investigation, is due to the fact that the patients had more advanced diseases (ECOG 1–2 or metastatic disease). From these trials, sorafenib emerged as well tolerated; the most common grade 3 drug-related adverse events observed in these studies included diarrhea and hand-foot skin reaction, which occurred in 8–9%, and 8–16% of patients, respectively. Drug discontinuation due to adverse events was 15% in the sorafenib arm and 7% in the placebo arm. Drug-related adverse events were considered manageable, and no death related with toxicity was described. As a result, sorafenib received the European Medicines Agency (EMEA) authorization in October 2007 and was approved by the USA United Food and Drug Administration (FDA) in November 2007.

The panel of experts recommends using sorafenib as the standard systemic therapy for HCC. It is indicated for patients with well-preserved liver function (Child–Pugh A class) and with advanced tumors – BCLC C – or those tumors progressing on loco-regional therapies (concept of treatment migration). No clear recommendation can be made in Child–Pugh B patients, although cohort studies have reported a similar safety profile in patients of this class with no decompensation [[324], [325]]. It is recommended to maintain sorafenib at least until progression, and beyond that point second-line studies can be considered. Sorafenib is currently being tested in the adjuvant setting after resection or complete local ablation for early stages, in combination with chemoembolization for intermediate stages [326], in combination with erlotinib or systemic doxorubicin in advanced stages and as first-line treatment in Child–Pugh B patients. Preliminary data from a randomized phase II study suggest a potential additive effect in combination with doxorubicin, although a significant increase in cardiotoxicity was reported [327].

Other targeted molecules under clinical development
Growth factors and proliferative pathway inhibitors
mTOR inhibitors

Rapamycin (sirolimus) and its analogs (temsirolimus and everolimus) are agents blocking the mTOR signaling cascade and have been tested in preclinical and early clinical investigations [328]. Everolimus, an mTOR blocker approved for kidney cancer therapy, is being tested in phase III for a second-line indication.

EGFR inhibitors. Five EGFR inhibitors have been tested: erlotinib, gefitinib, cetuximab, lapatinib and vandetanib. Erlotinib showed activity in a phase II study with mixed HCC populations with median survival of 13 months [329], and is currently being tested in combination with sorafenib in phase III. The other drugs either have not shown meaningful signals of efficacy in phase II, such as gefitinib and lapatinib [330], or are still in early stages of investigation.

Anti-angiogenic agents

Sunitinib. Sunitinib is an oral multi-tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. Three reported phase II studies have shown potential signals of activity, but with conflictive adverse events and treatment-related deaths due to severe liver dysfunction in 5–10% of patients [[331], [332], [333]]. A recent multicenter, open-label sorafenib-controlled randomized phase III trial was prematurely discontinued for safety issues and futility reasons [334]. This drug is presently not recommended for treatment of HCC.

Brivanib alaninate. Brivanib, an oral VEGFR and FGFR tyrosine kinase inhibitor, was evaluated in two phase II studies in first and second-line patients with an advanced tumor. The median overall survival was 10 months in the first-line treated group and 9.8 months in the second-line treated group, with manageable adverse events [335]. Brivanib is currently tested in three phases III trials in HCC patients: in first-line blinded to sorafenib, in second-line blinded to placebo and in combination with chemoembolization.

Bevacizumab. Bevacizumab, a recombinant, humanized monoclonal antibody directed against VEGF, has emerged as an important therapeutic agent in several malignancies and has been approved in the treatment of colorectal cancer, non-small-cell lung cancer and breast carcinoma. Bevacizumab has been evaluated as single agent [336], or in combination with erlotinib [337] or chemotherapy [338]. As a standalone agent, it showed objective responses of 10% with median time to progression of 6.5 months [336]. Combination treatment of bevacizumab with EGFR targeting agents reported a median survival of 15 months for mixed HCC patient populations [337]. Combinations of bevacizumab with chemotherapy, such as gemcitabine and oxaliplatin or capecitabine-based regimes, obtain objective responses of 10–20% with median survivals of 9–10 months [338]. No phase III investigations with this agent are ongoing.

Linifanib. Linifanib, an oral tyrosine kinase inhibitor targeting VEGF and PDGF, and ramucirumab, a monoclonal antibody against VEGFR2 [339] are currently being tested in phase III studies in first-line and second-line indication, respectively. Other new anti-angiogenic agents, such as vatalanib, axitinib and cediranib are at very early stages of investigation. Other molecules such as c-MET inhibitors, MEK inhibitors, TGF-beta and JAK2 inhibitors are being tested in early clinical investigations [321].

Other systemic therapies

Several systemic therapies, including chemotherapy, hormonal compounds, immunotherapy and others showed inconclusive or negative results. These agents are not currently recommended for management of HCC.

Chemotherapy

The problem of using chemotherapy in HCC stems from the co-existence of two diseases. Cirrhosis can perturb the metabolism of chemotherapeutic drugs and enhance their toxicity. In addition, some chemotherapy-related complications, such as systemic infections, are particularly severe in inmmunocompromised patients, like cirrhotics. On the other hand, HCC has been shown to be chemoresistant to the most common chemotherapies, which as single agents have reported modest anti-tumoral response [[139], [340], [341], [342]]. Systemic doxorubicin has been evaluated in more than 1000 patients in clinical trials with an objective response rate of around 10%. In a 446-patient trial, nolatrexed, an inhibitor of thymidylate synthase, was compared to systemic doxorubicin with negative results (median survival 5 months versus 7.5 months, respectively) and response rates for the doxorubicin arm of 4%. Other systemic therapies such as gemcitabine, oxaliplatin, cisplatin and capecitabine used as single agents or in combinations have reported heterogeneous responses ranging from 0% to 18% in uncontrolled investigations [340].

Systemic chemotherapy using combinations of two or more agents has been tested in recent RCT. A large RCT which compared combination chemotherapy (Cisplatin/Interferon α2b/Doxorubicin/Fluorouracil-PIAF regime) versus doxorubicin chemotherapy showed objective response rates of 20.9% and 10.5%, respectively [342]. The median survival of the PIAF and doxorubicin groups was 8.67 months and 6.83 months, respectively, without differences between groups. PIAF was associated with a significantly higher rate of myelotoxicity compared with doxorubicin. Treatment-related mortality was 9% in the PIAF regimen arm as a result of HBV reactivation and liver failure. A second RCT conducted in Asia compared the efficacy of the Folfox regimen combining 5-fluorouracil, folinic acid and oxaliplatin against doxorubicin alone. This study included 371 patients with Child–Pugh A/B advanced non-operable or metastatic HCC (BCLC B/C). There was a non-significant trend favoring the Folfox group (median survival 6.4 mo versus 4.9 mo; p = 0.07) associated to a better time to progression (2.9 mo versus 1.7 mo) [343]. Chemotherapy for HCC in non-cirrhotic patients is an underexplored area [344]. Thus, considering the available evidence, systemic chemotherapy is not recommended for the treatment of HCC, nor as a control regime for any trial due to the well-known toxic effects. Phase III investigations combining chemotherapy and sorafenib are ongoing.

Hormonal compounds

Hormonal compounds have not shown survival benefits in HCC. A meta-analysis of seven RCT comparing tamoxifen versus conservative management, comprising 898 patients, showed neither anti-tumoral effects nor survival benefits for tamoxifen [139]. Two large RCT were reported afterwards assessing tamoxifen [[345], [346]] with negative results in terms of survival. Thus, this treatment is discouraged in advanced HCC. Antiandrogen therapy is not recommended [347].

Immunotherapy

HCC is a typical inflammation associated cancer. A number of different studies have demonstrated a correlation between immune responses to tumors and patient outcome [348]. Immune-based therapy phase I–II trials have been performed at centers with the appropriate expertise but results have not been confirmed by independent investigators [349]. The concept of immunotherapy requires further investigations from phase II and III studies.

Other treatments

A large RCT compared seocalcitol – a vitamin D like antiproliferative molecule – versus placebo in 746 patients and showed no differences in overall survival (9.6 months seocalcitol versus 9.2 months placebo) [350]. Finally, negative results were also reported with a tubulin inhibitor (T-67) in a large multicenter RCT [351].