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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Aliment Pharmacol Ther31, 461–476

Summary

Background  Hepatocellular carcinoma is the leading cause of death in cirrhosis. A majority of patients present at an advanced stage with poor prognosis.

Aim  To review the current screening, diagnosis and management strategies involved in hepatocellular carcinoma.

Methods  A literature search was performed using PubMed for publications with a predetermined search string to identify relevant studies.

Results  Hepatocellular carcinoma is dramatically increasing in incidence that is mostly attributed to chronic hepatitis C and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and its clinical phenotype diabetes and obesity. Cirrhosis is the major predisposing risk factor and its presence necessitates close surveillance for hepatocellular carcinoma with serial imaging studies. Hepatocellular carcinoma can be diagnosed by its unique radiological behaviour of arterial enhancement and washout on delayed images. The Barcelona Clinic Liver Cancer staging classification system is a clinically useful algorithm for the management of patients with hepatocellular carcinoma. The simultaneous presence of cirrhosis in the patients complicates their management and monitoring for cirrhosis-related complications is important.

Conclusions  Early diagnosis and definitive treatment remains the key to long-term outcome. A multidisciplinary approach is critical to the successful management of hepatocellular carcinoma. Studies combining sorafenib with locoregional or other targeted molecular therapies are likely to improve responses and outcome.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Hepatocellular carcinoma (HCC) is a highly prevalent disease worldwide with most patients presenting with advanced disease well known to carry a poor prognosis. As the sixth most common cancer worldwide with over 600 000 deaths per year, HCC represents a major health challenge with significant and increasing global impact.1, 2 HCC is the third most common cause of cancer-related death and the leading cause of death among patients with cirrhosis in Europe and in the US.3–6 Epidemiological data show that its incidence and mortality are increasing, while mortality from other cirrhosis-related complications appears to be declining.7 The most relevant risk factors for HCC which are well described include chronic hepatitis C (HCV) infection, hepatitis B (HBV) infection, alcoholic cirrhosis and non-alcoholic steatohepatitis.8 In the US and Europe, the rise in incidence is mainly related to the current HCV epidemic and the burden of HCV-related HCC is expected to continue to increase over the next two decades.9, 10 This dramatic increase in HCC is driven by the epidemic of HCV that peaked in the 1980s and the 20–30 year lag time in its natural history between the onset of infection and the development of cirrhosis. However, the overriding risk factor in 80–90% of HCC regardless of aetiology is the presence of the preneoplastic cirrhotic liver.11, 12 Furthermore, the increasing incidence in the US of obesity and diabetes, which have also been identified as independent risk factors for chronic liver disease and HCC, is likely to further augment the number of Americans afflicted with HCC.13–15 Thus, the development of new, tolerable and effective therapeutic agents are urgent and pressing issues.

The tumour biology of HCC and the co-existing cirrhosis have presented major obstacles to drug development. Over the past several years, significant progress has been made in our understanding of the molecular pathogenesis of HCC. Preclinical models of HCC have shown the importance of upregulated molecular signalling pathways and angiogenesis in the evolution of HCC.16 These advances in our understanding led to the rationale for the use of novel molecular-targeted agents such as sorafenib in clinical trials in unresectable, advanced HCC. The establishment of a survival benefit in a randomized clinical trial with the use of sorafenib in advanced HCC has provided the first proof of concept that targeting these processes with molecular therapies can be efficacious in this grim disease. While this has improved hope, it has also generated a number of questions on how best to use these novel therapies as part of our armamentarium against HCC. This has spawned a number of clinical trials that are evaluating the efficacy of other molecular-targeted therapies already approved in other malignancies and that are in clinical development. This review will summarize the current screening, diagnosis, staging and the management of HCC and discuss future therapeutic directions.

Surveillance of high-risk groups

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

The annual incidence of HCC in cirrhotic patients can run as high as 3–5% and one-third will develop HCC in their lifetime.17 Surgical resection and liver transplantation offer the best potential for cure in HCC, but are only available to those whose tumours are detected early (currently occurs in only 10–20% of cases).3 A vast majority of patients are not candidate for curative therapies as they present with advanced HCC at the time of diagnosis. Thus, screening and surveillance strategies for HCC have been developed with the goal of detection at an earlier stage when curable interventions can be offered.18 However, robust evidence in support for screening is lacking as it would be unethical to randomize at-risk patients into screened and nonscreened groups to compare outcomes. However, a single randomized study from China comparing surveillance and nonsurveillance in hepatitis B (HBV) patients using serum alpha-fetoprotein (AFP) and abdominal ultrasound at 6-month intervals demonstrated the benefit of surveillance in terms of reduced mortality.19 In addition, cohort studies have strengthened this conclusion by showing a survival advantage for patients under a surveillance programme while retrospective studies have shown it to be cost-effective.20–23 In agreement with these findings, the current American Association for the Study of Liver Diseases (AASLD) guidelines recommend HCC surveillance for high-risk groups such as all patients with cirrhosis and certain HBV-infected patients regardless of the presence of cirrhosis using an abdominal ultrasound at 6–12 month intervals (Table 1).24 Serum AFP has very poor sensitivity and specificity and thus should not be used as a screening tool unless ultrasonography (or other imaging modality) is unavailable.25 Other serum biomarkers for early detection of HCC on the horizon such as des-gamma-carboxy prothrombin, the lectin-bound AFP fraction (AFP-L3) and glypican 3 remain to be fully investigated.26 However, a recent multicentre, phase 2 biomarker study showed that AFP was more sensitive than DCP and AFP-L3 for the diagnosis of early-stage HCC at a cutoff of 10.9 ng/mL that needs further evaluation.27

Table 1.   Surveillance for hepatocellular carcinoma is recommended for the following high-risk groups
Hepatitis B carriersNonhepatitis B cirrhosis
  1. HCC, hepatocellular carcinoma; HBV, hepatitis B virus; NASH/NAFLD, non-alcoholic steatohepatitis/non-alcoholic fatty liver disease.

Asian males ≥age 40Hepatitis C
Asian females ≥age 50Alcoholic cirrhosis
Family history of HCCNASH/NAFLD
Africans over age 20Genetic haemachromatosis
Non-cirrhotic hepatitis B carriersAlpha 1 antitrypsin deficiency
All cirrhotic hepatitis B carriersAutoimmune hepatitis
High HBV DNAPrimary biliary cirrhosis

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

The standardization of diagnosing HCC by non-invasive imaging has allowed earlier HCC detection and has facilitated the implementation of surveillance programmes. When a screening ultrasound detects an abnormal lesion or nodule, HCC can be diagnosed by its unique dynamic behaviour on triple-phase contrast enhanced computerized tomography (CT) or magnetic resonance imaging (MRI). The typical vascular profile on dynamic imaging is of early arterial phase enhancement followed by loss of enhancement (washout) in the portal venous and delayed phases (Figure 1). This imaging characteristic lends itself to the non-invasive diagnosis of HCC with a sensitivity of 90% and specificity of 95%.28 Another imaging option once a hepatic nodule is detected may include contrast-enhanced ultrasound (CEUS). CEUS allows for real time imaging with microbubble contrast agents (second generation contrast media) through all vascular phases allowing diagnosis based on vascularity and enhancement similar to CT and MRI.29 There is no universal consensus on the optimal diagnostic imaging modality. There are many factors that influence the selection of imaging modality such as presence of cirrhosis, steatosis and number of nodules. Ultimately, however, the most important factors are local availability and expertise.

image

Figure 1.  Contrast enhanced (three phase) computerized tomography imaging study showing the unique dynamic behaviour in hepatocellular carcinoma of hyperenhancement on the arterial phase (left panel) and loss of enhancement (washout) on the delayed venous phase (right panel).

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Once a lesion is detected on a screening ultrasound in the setting of cirrhosis, the diagnostic approach to HCC heavily depends on the size of the nodule and can involve a sequence of events such as repeat imaging, AFP level and/or biopsy (Table 2). Nodules that are <1 cm have a low likelihood of being HCC and are followed with imaging every few months to detect growth suggestive of malignant transformation. The absence of growth during a monitoring period (1–2 years) implies low likelihood of HCC, while enlargement over this period suggests malignancy and warrants further investigation. For nodules between 1 and 2 cm, the diagnosis of HCC is established by the presence of the characteristic vascular pattern of HCC on two dynamic imaging studies. If the radiological imaging features on the 2 dynamic studies do not coincide, an image guided core biopsy can be considered. However, biopsies of small tumours <2 cm can yield false negative rates as high as 30–40% and the small size of the lesions can be difficult to target.30 Furthermore, inter-observer variability among pathologists also becomes more problematic with lesions <2 cm and 20–25% of small lesions with early enhancement show no interval growth or disappear during serial contrast-enhanced dynamic imaging and thus are not HCC.31 This suggests that a wait-and-watch approach with enhanced follow-up imaging of inconclusive lesions may be the best option.32 For lesions >2 cm, the likelihood of HCC is high and the diagnosis is made, if serum AFP >200 ng/mL and/or if one dynamic contrast enhanced imaging study displays the typical vascular profile as the positive predictive value of clinical and radiological findings exceed 95%.33 For lesions >2 cm or increasing size with atypical vascular pattern, an image-guided biopsy should be performed.

Table 2.   Radiological diagnosis of hepatocellular carcinoma in patients with cirrhosis
Imaging techniquesContrast-enhanced CT and MRI
  1. The contrast enhanced imaging studies of computed tomography (CT) and magnetic resonance imaging (MRI) can use the unique dynamic radiological behaviour of hepatocellular carcinoma (hypervascular on the arterial phase and washout on the delayed venous phase). The sequence of events needed to make the radiological diagnosis depends on the size.

Nodules < 1 cmMonitor with serial imaging
Nodules 1–2 cmTwo imaging techniques showing arterial phase enhancement and venous washout
Nodules >2 cmOne imaging technique with typical vascular pattern

Prognostic staging

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Once the diagnosis of HCC is made, the outcome is influenced by two key factors that include the stage of the HCC and the severity of the underlying liver disease. Multiple independent prognostic factors that relate to the HCC tumour burden and the degree of liver function impairment have been identified as important contributors to outcome (Table 3).34, 35 For the extent of tumour component, this includes the number (multiplicity) and size of nodules, presence or absence of macrovascular invasion and presence or absence of extra-hepatic spread. For the degree of liver function impairment, this includes the Child–Pugh classification, serum bilirubin, albumin level and presence of portal hypertension. In light of the importance of liver function, calculation of the Model for End-stage Liver Disease (MELD) score should also be considered to obtain an estimate of the 3-month mortality risk as it relates to the underlying liver disease. The general physical status of the patient as defined by the Eastern Cooperative Oncology Group (ECOG) classification and presence of symptoms also have prognostic value, while aetiology of liver disease has not been shown to be a prognostic factor. As such, the extent of tumour and the severity of liver disease have to be carefully considered to assess properly prognostic outcomes and determine the appropriate treatment modality.

Table 3.   The main established prognostic factors in hepatocellular carcinoma
  1. ECOG, Eastern Cooperative Oncology Group.

Tumour status
 Number and size of nodules
 Presence/absence of macrovascular invasion
 Presence/absence of extraheaptic spread
Liver function
 Child–Pugh class
 Serum bilirubin
 Albumin levels
 Presence/absence of portal hypertension
Physical status
 ECOG classification
 Presence of symptoms

While several HCC staging systems exists, the Barcelona Clinic Liver Cancer (BCLC) staging system has emerged as the standard classification to assist clinical management decisions and for clinical trial entry of patients with HCC (Figure 2).36 The BCLC incorporates well established independent prognostic variables related to liver function, tumour burden and physical status to stage patients and then links the stage of disease with standard treatment algorithms. The BCLC construct is a clinically useful classification in the management of patients with HCC as it defines the treatment standard of care for each tumour stage and provides an estimate of life expectancy based on response rates to the various treatments.37 This staging system has been endorsed by the European Association for the Study of the Liver,33 the AASLD,24 and has been validated in European and US cohorts.38, 39 The 5-stage classification categorizes patients into early HCC (stage 0 and A), intermediate HCC (stage B), advanced HCC (stage C) and end-stage HCC (stage D). The stage-specific treatment strategies and expected survivals are shown in Figure 2. The curative treatment modalities include resection, ablative therapies such as radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) and liver transplantation. The palliative treatment modalities include transarterial chemoembolization (TACE) and targeted systemic chemotherapy with sorafenib. Inherent in the algorithm is the clear multidisciplinary approach that is needed in the management of patients with HCC as it involves disciplines such as surgery, hepatology, diagnostic and interventional radiology, oncology and pathology.

image

Figure 2.  The Barcelona Clinic Liver Cancer (BCLC) staging classification for the management of hepatocellular carcinoma (HCC). Patients presenting with very early (stage 0) and early-stage diseases (stage A), which represent 20–30%, are suitable for curative treatments such as resection, liver transplantation, or local abalation with percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA). Patients with intermediate stage (stage B) receive a survival benefit from transarterial chemoembolization (TACE). Patients with advanced HCC that consists of macroscopic vascular invasion (portal vein invasion), extrahepatic spread (lymph nodes and metastatis) or cancer-related symptoms (performance status 1–2) have a proven first line treatment with sorafenib. Patients with terminal stage (stage D), which represents that 10–20% receive symptomatic treatment. Adapted from Llovet et al.36

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Early-stage HCC (stages 0 and A)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Resection

Before beginning a discussion on nonsurgical management of HCC, it is important to recognize that surgical resection and liver transplantation are potential curative treatment options and early referral to centres with surgical expertise in HCC management is crucial. In general, local tumour resection is the treatment of choice for solitary HCC in noncirrhotic patients because the background liver has well-preserved hepatic function. Unfortunately, this presentation is uncommon in Western countries occurring about 5%.23 Most patients with HCC have underlying cirrhosis and require careful evaluation for resection because of the potential for postresection hepatic decompensation. The minimal critical size of remnant liver after resection is 25% in presence of normal liver and 50% in patients with cirrhosis.40 When the potential size of remnant liver is too small, then preoperative, ipsilateral portal vein embolization can be considered to optimize the contralateral volume of the remnant liver and increase the safety of the resection. Patients with small subcapsular, solitary (early) HCC and Childs A cirrhosis are the best resection candidates. In these patients with a normal bilirubin and the absence of clinically significant portal hypertension (lack of oesophageal varices and splenomegaly with platelets <100 000 or a directly measured hepatic venous portal gradient <10 mmHg), there is minimal risk of post-operative liver failure and they may achieve a 5-year survival of 70%, in comparison with the <30% for those with total bilirubin >1 mg/dL and portal hypertension.41 Unfortunately, following resection, patients with cirrhosis are at risk for tumour recurrence which can exceed 70% at 5 years42 mostly because of intrahepatic dissemination of primary lesion (60–70%) and less commonly de novo (metachronous) tumours (30–40%).43, 44 Established predictors of recurrence following resection are the presence of microvascular invasion and multiplicity of tumours. More recently, in patients who underwent curative resection, a gene-expression signature was found to correlate with late recurrence (or de novo HCC) and mortality, and may be a critical advance into more personalized treatment.45 The refinement of patient selection and progress in surgical technique using intra-operative ultrasound to improve localization, staging and anatomical resection with free margins have shown that in experienced centres, treatment-related mortality can be <3% and that 5-year survival rates of 70% or more are achievable. In addition, recent data show RFA to have similar local control and survival rates to resection in those with early HCC that are candidates for resection.46, 47 Thus, RFA may be considered an alternative treatment to resection for those with central lesions with no large vessels in close proximity (reduced thermoablation volume because of ‘heat sink effect’) and more impairment in liver function considered high risk for postresection liver failure.

Transplantation

The current guidelines for liver transplantation are based on the Milan criteria, which support transplantation in the setting of one lesion ≤5 cm or up to three lesions ≤3 cm in diameter, which has an associated 5-year survival rate >70% and tumour recurrence rate <15%.48 The high risk of recurrence after resection of HCC in cirrhosis is used to argue that transplantation is superior as it treats both the HCC and the underlying liver disease (5-year recurrence rates of 70–80% for resection vs. 10–20% for transplantation). However, there has been no randomized control trial comparing resection and liver transplantation for Child A cirrhotic patients with a small HCC lesion and retrospective data suggest that the two modalities are comparable with 5-year survival rates that range between 50% and 70%.3 Resection may be the best option for patients with small lesions and Child A cirrhosis who are surgical candidates in the setting of shortage of donor organs. For patients with decompensated cirrhosis (Child B and C cirrhosis) and HCC who fall within transplantation criteria, liver transplantation is the superior treatment of choice as they cannot undergo resection because of marginal liver function. United Network for Organ Sharing (UNOS) currently assigns 22 MELD exception points on the basis of radiological diagnosis of solitary lesions >2 cm and <5 cm or for up to three lesions when each is <3 cm.49 For each 3 month period in which the patient remains on the waiting list, three additional MELD points are awarded based on the expected 10% increase in pretransplant mortality while on the waiting list. Bridging therapies such as RFA and TACE are routinely applied to slow tumour progression and prevent drop-out on the waiting list. However, it remains unclear if the benefit reported in small studies is a true oncological benefit of the interventions or improved patient selection in the absence of adequate prospective randomized studies. For those beyond the UNOS criteria, down staging the size and numbers of HCC lesions with one or a combination of TACE, RFA and/or PEI can be a successful strategy in close to half of patients, as shown by the University of California at San Francisco protocol.50 However, without prospective randomized studies directly comparing patients who receive transplants within and exceeding Milan Criteria, these encouraging results require further study. Recently, the ‘Metroticket Investigator Study Group’ report that careful extension of the Milan Criteria with the ‘Up to Seven Rule’ (seven being the sum of the size of the largest tumour in centimetres and the number of tumours) results in a 5-year survival that is ≥70%.51

PEI and RFA

Local ablative strategies are the best treatment option for patients with small tumours who are not candidates for surgical resection or liver transplantation. These local ablative modalities involve the destruction of tumour cells by modifying the temperature (RFA, cryotherapy, microwave, laser) or injection of chemical substances (PEI, acetic acid or boiling saline). PEI and RFA are the best studied and used most commonly. PEI is highly effective for small tumours causing coagulation necrosis of tumours by cellular dehydration, thereby achieving complete tumour necrosis in 90–100% of the HCC tumours <2 cm, 70–80% of the HCC tumours between 2 and 3 cm and 50% in HCC tumours between 3 and 5 cm.52, 53 Several retrospective and nonrandomized studies have shown that for early lesions in patients with mild-to-moderate liver dysfunction, PEI prolongs patient survival with rates similar to those with resection, especially for tumours <3 cm.54, 55 PEI is popular for its low rate of adverse events (AEs; major complications in 3.2%, mortality in 0.1%, tumour seeding in 0.7%) and for being an inexpensive procedure. The major drawback is its high local recurrence rate, which requires repeated injections, particularly for lesions >3 cm as the ethanol cannot access the entire tumour volume.56 RFA causes thermal necrosis to tumours by delivering electromagnetic energy through single or multiple needle electrodes inducing a wider region of complete tumour necrosis and because of this has largely replaced PEI. While the efficacy of RFA for small tumours <2 cm is similar to PEI, the efficacy of RFA is superior to PEI for tumours >2 cm. Based on multiple randomized controlled trials, RFA appears to be more efficacious than PEI in terms of tumour necrosis rates (90–96% with a mean of 1.1–2.1 sessions for RFA vs. 4.8–6.5 session for PEI), less operator variability, less local recurrence (8–14% at 2–3 years in RFA vs. 22–34% in PEI) and overall survival (OS; 100% and 98% for 1 and years with RFA vs. 96% and 88% with PEI).57 From these studies, RFA has largely supplanted other percutaneous therapies and represents the most common ablative approach to HCC. Some pitfalls of RFA that need to be considered are tumours with subcapsular location, in close proximity to large vessels that lower the level of lethal heating needed to induce tumour coagulation (so called ‘heat sink’) and poor differentiation, which have been associated with increased risk of neoplastic seeding.58

Intermediate stage HCC (stage B)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

The liver is an ideal organ for chemoembolization (targeted regional chemotherapy) because of its dual blood supply from the hepatic artery and portal vein. During the progression of HCC, its blood supply becomes increasingly arterialized (>90% arterial), while the noncancerous liver parenchyma remains supplied largely by the portal vein (80% portal venous). This dual blood supply anatomy provides the rationale in support of arterial obstruction (embolization) as an effective therapeutic option to induce ischaemic tumour necrosis given that the hepatic artery almost exclusively supplies the HCC tumours. Transarterial embolization (TAE) refers to obstruction of the hepatic artery achieved by placement of various agents such as gelfoam, polyvinyl alcohol, microspheres or metallic coils. In TACE, various chemotherapeutic agents (doxorubicin, cisplatin or epirubicin) are delivered to the lesion prior to the arterial obstruction. The chemotherapeutic agents are usually mixed with iodized poppy seed oil (lipiodol), which together form a medium that is selectively retained and concentrated within the tumour for maximal exposure.

TACE

Transarterial chemoembolization is the recommended palliative treatment for patients with large or multifocal tumours (intermediate stage B) that have progressed beyond the curative options of resection, transplantation or percutaneous ablative strategies, but with adequate liver function, absence of extrahepatic spread/vascular invasion and no significant cancer-related symptoms. Thus, the best candidates are patients with Child A cirrhosis and multifocal non-invasive HCC with an excellent performance status. The evidence that TACE has a survival benefit comes from randomized controlled trials, which show an improvement in the 3-year survival rates (from 10% to 40–50%) and the median survival (from 16 to 20 months), and has established TACE as the standard of care for asymptomatic multinodular disease.59–61 However, it remains unclear whether embolization alone (TAE) gives the same survival advantage as TACE as the study was stopped early and at the time of study termination bland embolization did not show a survival benefit. The main contraindications for TACE are decompensated Child B or C cirrhosis, portal vein invasion or thrombosis as treatment increases the risk of liver failure. However, some have found no notable increase in procedure-related complications and similar treatment-related benefits in HCC patients with portal vein thrombosis using highly selective embolizations.62 The most common complication of TACE is the postembolization syndrome that occurs in more than 50% of patients with transient fever, abdominal pain, nausea, ileus and elevated alanine aminotransferase. This is usually self-limited with supportive care, lasting between 24 and 48 h. In <10% of patients, signs of hepatic decompensation in the form of ascites and gastrointestinal bleeding may develop and treatment-related mortality is <5%.63 Other side effects of TACE related to the chemotherapy are nausea, vomiting, bone marrow suppression, alopecia and, potentially, renal failure.

It is important to recognize that there is tremendous heterogeneity in the way the TACE procedure is performed across centres. There are multiple variables that make up the TACE procedure such as the type of anticancer drugs and dose, the use of lipoidol, the choice of embolic agent, delivery, timing, selectivity and the treatment schedule (on demand based on residual tumour enhancement or fixed schedule). These have the potential to lead to different outcomes and the optimal treatment strategy with respect to all these variable remains to be determined. Furthermore, the recent advent of TACE with drug eluting beads loaded with doxorubicin (DEB; also called DC/LC beads) called Precision TACE is another chemoembolization strategy with unique properties. This novel strategy uses deformable beads to absorb chemotherapeutic agents and upon reaching the tumour vascular bed slowly release the agents. This strategy combines the local controlled release of doxorubicin ensuring high intratumoural retention of drug with minimal systemic toxicity and the simultaneous induction of ischaemia as the intra-arterially delivered beads embolize the tumour. The most recent single-arm phase II studies reported rates of objective responses that range between 66% and 85% with 1 and 2 years survivals of 92–97% and 88–91% respectively, with a sharp reduction in systemic side effects associated with chemotherapy.64–66 Furthermore, the development of biliary abscess in the initial study was not observed in the two subsequent cohort studies. The randomized phase II Precision V trial evaluating the efficacy and safety of Precision TACE compared with conventional TACE was recently published.67 The tumour response rate with Precision TACE was greater (DEB 63% vs. TACE 52%; = 0.11), but not statistically different. There was a significant reduction in doxorubicin-related side effects and serious liver toxicity with Precision TACE. In addition, patients with more advanced characteristics (Child B cirrhosis, worse performance status, bilobar disease) demonstrated significantly higher response rates with Precision TACE with improved safety. Thus, given that the current AASLD guidelines do not recommend chemoembolization for Child B cirrhosis, these findings suggest that Precision TACE can be safely used in these patients.

Combination TACE and RFA

Both TACE and RFA have well known limitations in terms of control of large tumours. The effectiveness of RFA depends on thermal necrosis and blood flow through the tumour promotes heat loss and prevents proper heating of the tumour. A strategy of combining TACE with RFA by performing TACE before RFA treatment to reduce the heat sink effect and increase the ablation volume of the tumour was recently evaluated in a randomized study.68 In this study, patients with tumours larger than 3 cm were randomized to TACE, RFA and TACE–RFA. The combination modality was superior in median survival (TACE–RFA 37 months, TACE 24 months vs. RFA 22 months) and rate of objective tumour response (TACE–RFA 54%, TACE 35% vs. RFA 36%). The positive findings in this study represent initial evidence in support for the use of combining local regional modalities to improve outcomes in patients with unresectable tumours. Despite aggressive local treatments with this combination strategy, recurrence and distant metastasis continue to have a significant effect on the OS of patients with HCC. Therefore, studies that combine effective systemic treatment such as sorafenib with either TACE or RFA have the potential of further improving treatment outcomes.

Radioembolization

Transarterial radioembolization (TARE) with intra-arterial injection of yttrium-90 microspheres (Y-90) is another form of hepatic arterial therapy that is available as glass (TheraSpheres; Theragenics Corp., Ottawa, Canada) or resin (Sirtex; Sirtex Medical, Wilmington, MA, USA) and can be delivered to single or multiple segments based on selective arterial cannulation. Their small size (20–60 μm) results in preferential trapping in the tumour capillary bed. These spheres can safely deliver up to 150 Gy of β radiation to induce tumour necrosis by radiation and microscopic embolization once they obstruct in the tumour capillary bed. This limits radiation exposure to adjacent healthy tissue, given its half-life of 62 h and radius of action of up to 1 cm.69 Patient selection requires pre-treatment procedures including an angiogram to perform prophylactic embolization if variant anatomy is identified to avoid nontarget delivery of Y-90 and a macroaggregated albumin scan to confirm that hepatic artery-to-lung shunting is <16% to prevent lung injury.70 An advantage of this treatment over TACE is its applicability in patients with portal vein thrombosis and potential complications caused by nontarget delivery of Y-90 include gastrointestinal ulcerations, pancreatitis, pneumonitis and cholecystitis.71 While Y-90 has anti-tumour activity, controlled data comparing TARE with TACE is lacking and its impact on survival is not established.

Advanced HCC (stage C)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Conventional systemic chemotherapy therapy

In patients with advanced HCC marked by vascular invasion and/or extrahepatic disease (stage C), traditional cytotoxic systemic chemotherapies have marginal anti-tumour activity and have failed to impact survival. The poor results with traditional chemotherapies may be secondary to the high expression of transporters of multidrug resistance protein family (MDR-1) in HCC, poor drug delivery and dose limitations from underlying liver dysfunction. 72 In addition, baseline leucopenia and thrombocytopenia caused by splenic sequestration and portal hypertension compromise therapy with agents that induce bone marrow suppression. A major advancement in the last 3 years in the management of HCC has been the development of molecular systemic HCC therapies. With the growing body of literature showing aberrant activation of several cellular growth signalling and angiogenic pathways critical to cancer development and progression, molecular-targeted therapies have emerged as attractive and rationale new treatment options in HCC.16 Pathways identified as potential targets in HCC with molecular therapies include the tyrosine kinase receptor EGFR, RAS/MAPK, PI3K-Akt-mTOR, angiogenesis inhibitors, enhancing apoptosis and telomerase inhibitors, which are undergoing evaluation.

Targeted systemic therapy with sorafenib

Advanced HCC represented a clinically unmet need with no viable systemic treatment until the release of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study comparing sorafenib with placebo.73 The multikinase inhibitor sorafenib targets the serine-threonine kinase Raf-1 and has antiangiogenic activity.74 Preclinical studies show that Raf-1 kinase signalling pathway and prolific tumour angiogenesis together play an important role in the evolution of HCC, lending a molecular rationale for the use of sorafenib in this malignancy.75 This knowledge along with the early signal of efficacy in phase 2 study (median OS of 9.2 months) led to the phase 3 SHARP registration study.76

The SHARP trial enrolled 602 patients with advanced HCC and preserved liver function that were randomized according to prespecified stratification factors (macroscopic vascular invasion and/or extrahepatic spread, ECOG performance status and geographical region) to receive sorafenib (= 299) or placebo (= 303) with patients continued on therapy until they experienced both radiological progression and symptomatic worsening. The primary end points were OS and time to symptomatic progression and the secondary endpoints included time to radiographic progression. The baseline patient characteristics comprised approximately 30% with HCV infection, 20% with HBV infection and 25% with alcoholic liver disease. Nearly all patients had Child A cirrhosis with good ECOG performance status 0 or 1. In general, there were no relevant differences between the sorafenib vs. the placebo group with regard to baseline demographics, severity of liver disease, BCLC stage and aetiology of liver disease.

At the planned interim analysis, the study met its primary endpoint with the OS significantly longer in the sorafenib group (10.7 months) compared with placebo (7.9 months) with a hazard ratio for sorafenib of 0.69 (< 0.001). There was no difference in time to symptomatic progression, although time to radiological progression was significantly longer in the sorafenib group (5.5 months) compared with that in placebo (2.8 months) endorsing the concept that sorafenib is extending survival by delaying tumour progression. In terms of tumour responses, the composite disease control rate (a combination of complete response, partial response and stable disease) was significantly higher in the sorafenib group (43%) than in placebo (32%), while only nine Response Evaluation Criteria in Solid Tumours (RECIST) responses were observed in the entire patient population. These findings further support the concept that targeted agents do not induce the typical tumour involution seen with cytotoxic chemotherapy, but instead promote disease stabilization and thereby prolong survival. This unique property of targeted therapies is critical to recognize when designing endpoints for clinical trials as use of the RECIST criteria as a surrogate for response may fail to capture the benefits of targeted drugs.35

The SHARP study is a major milestone in the management of advanced HCC offering hope for the more than 600 000 patients who die each year of HCC worldwide. Despite the enthusiasm surrounding the survival benefit found in the registration trial, there remains uncertainty on whether sorafenib will be efficacious and an appropriate therapy for the majority of patients with HCC and cirrhosis in clinical practice. There are several differences between the patients in the SHARP trial and the majority of patients with advanced HCC in clinical practice. In the SHARP study, HCV was the cause of liver disease in approximately 30% of patients, which is usually the cause of liver disease in more than 70% of patients in the US and Western Europe.77 While the SHARP trial was not designed to assess the efficacy of sorafenib relative to the aetiology of liver disease, a subgroup analysis of 178 patients with HCV-associated HCC in the SHARP trial showed a superior OS with sorafenib (14.0 months) vs. placebo (7.9 months.78 Many patients seen in clinical practice fall outside the enrolment criteria studied in the SHARP trial by the degree of underlying liver function impairment. As noted, 97% of the study population was classified as Child A cirrhotic patients. Can the safety and tolerability of sorafenib hold up in clinical practice in patients with more compromised cirrhosis and advanced HCC and still provide an equivalent survival benefit? Currently, there are limited data on the use of sorafenib in Child B cirrhosis. The available data from the phase II single-arm study of sorafenib in advanced HCC which has been presented showed a clear difference in OS between Child A (41 weeks) and B (14 weeks) cirrhosis.79 In general, toxicity profiles were similar regardless of Child–Pugh status in agreement with a recent uncontrolled single-arm study using sorafenib in patients with concomitant advanced cirrhosis.80 In the absence of robust data on the use of sorafenib in Child B cirrhosis, the risk–benefit in this setting needs to be individualized with close clinical monitoring. Data from ongoing trials may provide a clearer profile of risk and benefit in patients treated with sorafenib outside the clinical trial setting.

Adverse events with sorafenib

The overall incidence of treatment-related AEs was similar in both groups. The most common symptoms were fatigue, anorexia, weight loss, hand–foot skin reaction (HFSR), abdominal pain and diarrhoea. Previous studies have raised concerns about the risk of bleeding, cardiac events and hypertension in patients receiving multikinase inhibitors. This study did not identify an overall increase risk of bleeding (oesophageal variceal bleeding with sorafenib 2% vs. 4%) or cardiac ischaemia (sorafenib 3% vs. 1%). Bleeding occurred at similar rates in both groups (sorafenib 18% vs. 20%). However, hypertension was higher in the sorafenib group (9% vs. 4%). The most common lab abnormalities identified in both groups included lipase (40% vs. 37%) and amylase (34% vs. 29%) elevations and hypophosphataemia (35% vs. 11%) of unknown aetiology. One patient in the sorafenib group developed clinical pancreatitis (grade 2) suggesting that monitoring lipase levels should be routine during clinical follow-up in light of the propensity for the patients to develop abdominal pain (31% vs. 26%).

Managing adverse reactions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Hand–foot skin reaction

Generally, HFSR appears during the first 6 weeks of treatment. Management of dermatological reactions should be early in the course of therapy to decrease symptom severity and should include topical therapies [Eucerin cream (Beiersdorf, Wilton, CT, USA), Kerasal (Alterna, Whippany, NJ, USA) and Udderly Smooth (Redex, Salem, OH, USA)] pre-emptively and for symptomatic relief. Some patient management strategies include avoiding sun and heat exposure, activities associated with friction on the hands or feet, avoiding contact with strong detergents and wearing loose-fitting clothing and shoes.81 A key to a successful strategy in the management of HFSR is frequent contact with the treating physician to ensure early diagnosis and intervention that is responsive to the severity of the HFSR (Table 4). For patients who develop grade 1 (paresthesias and painless swelling) they should continue treatment with no dosing modification and daily application of topical creams/lotions. For grade 2 (painful erythema and swelling with interferes with activities of daily living), dose reduction to level 2 (400 mg daily) with close monitoring is recommended.82 If there is improvement in the grade 2, dose is increased by one dose level (level 1400 mg twice daily), but if there is no resolution, therapy is interrupted until resolution and then restarted at a lower dose level (level 2400 mg q.d.s.). For grade 3 (desquamation, ulcers, blistering), treatment is interrupted until there is resolution or improvement to grade 1 and then resumed at a lower dose level (level 2 or 3 at the discretion of the treating physician). Patients should be monitored very closely during this dosing reduction, interruption and re-escalation strategy to reassess response and severity constantly.

Table 4.   Management strategy for hand-foot-skin reaction
GradesDefinitionIntervention
  1. Topical therapies for symptomatic relief, dose modifications using the three dose levels and treatment interruptions as well as close monitoring are the keys to successful management of this dermatological reaction. Dose levels: 1–400 mg b.d.; 2–400 mg q.d.s.; 3–400 mg q.o.d.

1Paresthesias, erythemaMaintain and monitor for change. Use urea containing topical creams
2Painful erythema, interferes ADLsReduce dose to 400 mg q.d.s. × 7–28 days. If resolves, then increase. If no resolution, then stop
3Desquamation, ulcers, blisteringInterrupt treatment for 7 days and until improvement to grades 0–1. Then resume decrease by 1 dose level

Managing other AEs

When managing the common sorafenib-related AEs such as fatigue, abdominal pain and diarrhoea, a complete clinical evaluation can be very useful to exclude secondary contributing factors such as dehydration, anaemia, gastrointestinal bleeding, ascites, renal insufficiency, hypothyroidism and nutritional issues. For more severe and persisting AEs that do not respond to general measures, a dose reduction strategy can be beneficial particularly with regard to diarrhoea.83 Our own experience has been that fatigue is one of the major dose-limiting AEs in those with cirrhosis and thus we like to limit beta-blocker use and often use stimulating antidepressants or drugs like modafinil to maintain reasonable energy levels. Overall, once the AE has resolved or come under reasonable control, it is often possible to escalate back to full dosing.

Importance of close hepatology monitoring

One of the features that separate HCC from other tumours is the fact that it occurs in the background of cirrhosis and chronic liver disease. This concept of ‘two diseases in one’ adds tremendous complexity in the management of the patients as both HCC and progressive liver disease occur simultaneously. Potential complications related to cirrhosis include variceal bleeding, ascites, hepatorenal syndrome and hepatic encephalopathy (HE). Managing cirrhosis and its complications is important both during and after the treatment of the tumour to maximize outcome of our patients. An initial step in evaluating patients with HCC should include an assessment of the underlying hepatic function, using the Child–Pugh scoring system (bilirubin, albumin, prothrombin time, ascites and encephalopathy) and the MELD score (creatinine, INR, bilirubin). Stratifying the degree of hepatic function impairment with these scoring systems provides clinically useful prognostic assessment of the hepatic function, once a patient has been diagnosed with HCC. All patients with cirrhosis should undergo a screening upper endoscopy for oesophagogastric varices, which can be present in approximately 50% of patients with compensated cirrhosis and higher in those with more compromised hepatic function.84 The haemorrhage rate for varices ranges between 10% and 30% per year and a mortality rate of 30–50%. Treatment of existing large varices may include nonselective beta blockers and/or endoscopic band ligation, particularly for those varices with signs of recent bleeding. Another frequent complication from cirrhosis is ascites that can be controlled with a combination of measures such as sodium restriction, diuretic regimen and potentially a paracentesis for initial control. Treatment of ascites is important as it will improve quality of life and prevent other sequelae such as spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome.85 Patients at highest risk of SBP (hospitalized with gastrointestinal bleeding, ascites protein <1 g/dL or history of prior SBP) should receive antibiotic prophylaxis with a fluoroquinolone. HE is another common occurrence in patients with HCC and cirrhosis. Non-absorbable disaccharides such as lactulose are the current first line treatment for HE. Typically, lactulose requires an escalating treatment strategy that is associated with adverse effects leading to poor tolerance and compliance.86 One alternative agent that recently completed phase III evaluation is the non-absorbable antibiotic rifaxamin, which showed a significant reduction in the risk of breakthrough and worsening HE symptoms compared with placebo with comparable safety and tolerability profile.87 The complexity in the management of the underlying cirrhosis of the HCC patients requires close clinical monitoring, which is most successful with a multidisciplinary approach.

Future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

The identification of the molecular pathways involved in carcinogenesis has led to the clinical development of numerous molecular-targeted therapies. The SHARP trial has shown that targeting angiogenesis with the multikinase inhibitor sorafenib improves survival in HCC and supports further studies that combine sorafenib with other novel molecular-targeted therapies. The future landscape in clinical development for HCC treatments will undoubtedly include various combinations of sorafenib with locoregional therapies and with other targeted agents. Preliminary studies have shown the combination of locoregional therapies, mainly Precision TACE with sorafenib to be safe and may offer benefit in terms of survival.88, 89 However, well-designed randomized control trials are needed to determine if this approach should be the standard practice. Several targeted agents such as EGFR inhibitors (erlotinib, cetuximab, lapatinib), VEGF/VEGFR inhibitors (bevacizumab, vandetanib, AZD2171,sunitinib), Ras/Raf/MEK inhibitors (lonafarnib, AZD6244), PI3K/Akt/PTEN inhibitors (sirolimus, everolimus), apoptosis inducers (mapatumumab), proteosome inhibitors (bortezomib) and HDAC inhibitors (LBH589, vorinostat) are in different phases of clinical development (Table 5). Combinations of these systemic agents that target angiogenesis with other treatment modalities such as TACE, RFA and PEI have shown promising results in animal models and are under clinical investigation in HCC.90 However, the heterogeneous clinical behaviour of HCC will make this process challenging. As such, further research efforts need to focus on the molecular classification of HCC to develop individualized treatment strategies. The EGFR mutational status correlating with response to tyrosine kinase inhibitors demonstrates that molecular classification to personalize therapy is feasible.91 The need to identify molecular and clinical tools to guide the use of these agents will need prospective evaluation to determine if using tumour molecular profiling is efficacious in selecting treatment. As these studies evaluate the safety and efficacy of various treatments, the inclusion of molecular signatures of tumours can provide significant insights into the tumour biology and facilitate the finding of novel biomarkers of tumour response, which will improve clinical management.

Table 5.   Molecular-targeted agents in various phases of clinical development for hepatocellular carcinoma treatment.
TargetDrug (trade name)Stage of development
  1. EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet derived growth factor receptor; FLT-3, FMS-like tyrosine kinase 3; c-KIT, another member of the receptor tyrosine kinase subclass III family; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; PTEN, phosphatase with tensin homology; mTOR, mammalian target of rapamycin; TRAIL-R1, tumor necrosis factor-related apoptosis inducing ligand receptor; HDAC, histone deacetylase.

EGFR pathway inhibitors
 EGFRErlotinib (Tarceva, Roche, Switzerland)Phase II/III
 EGFRCetuximab (Erbitux, Merck/Schering, Germany)Phase II
 EGFR, HER2Lapatinib (Tykerb, GlaxoSmithKline, UK)Phase II
VEGF/VEGFR pathway inhibitors
 VEGF-ABevacizumab (Avastin, Roche, Switzerland)Phase II
 VEGFR-2, EGFRVandetanib (Zactima, AstraZeneca, UK)Phase II
 VEGFR-1-3 Phase II/IIIAZD2171 (Recentin, AstraZeneca, UK)Phase II
 VEGFR-1-3, PDGFR, c-KIT, FLT-3Sunitinib (Sutent, Pfizer, USA)Phase II/III
Ras/Raf/MEK pathway inhibitors
 RasLonafarnib (Sarasar, Merck/Schering, USA)Phase II
 Raf-1, VEGFR-2 and -3, PDGFR, c-KITSorafenib (Nexavar, Bayer, Germany)Approved for advanced HCC Phase II/III in combination
 MEKAZD6244 (AstraZeneca, UK)Phase II
PI3K/Akt/PTEN pathway inhibitors
 mTORSirolimus (Rapamune, Pfizer, USA)Phase I/II Phase III liver transplantation
 mTOREverolimus (Novartis, Switzerland)Phase I/II
Enhancing apoptosis
 TRAIL-R1Mapatumumab (Human Genome Science, USA)Phase I
Proteasome inhibitors
 ProteasomesBortezomib (Velcade, Millenium, USA)Phase I
HDAC inhibitors
 HDACLBH589 (Novartis, Switzerland)Phase I
 HDACVorinostat (Zolinza, Merck & Co., USA)Phase I

Costs of molecular-targeted therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

There are limited data on the economic consequences on the management of HCC, which is important to understand given the rising prevalence and changing treatment landscape of HCC. A recent study estimates the annual average overall cost of caring for a HCC patient to be $32 907 in 2005 with a total overall cost using the prevalence of 14 000 from 2005 of $454.5 million.92 This cost analysis probably underestimates the true economic burden of HCC as it is based on the healthcare utilization in 1999, which was vastly different from the current landscape of local ablative therapies alone or in combination, liver transplantation and the current standard palliative treatments of TACE and sorafenib.93 As molecularly targeted therapies continue to be developed and are introduced in various combinations, a discussion on cost-effectiveness is inevitable. Molecularly targeted therapies are expensive with an average cost around US$6000 per month. Financial resources for health-care services are not unlimited and the rising costs of the new cancer treatments will force difficult questions on patients and their families and the treating physicians. Should patients be guaranteed unlimited access to effective drugs regardless of the costs?94 And should physicians be encouraged to consider cost when they decide on treatment? Should, in addition to clinical benefit and toxicities, cost effectiveness be considered when recommending new treatment as the standard? Cost-effectiveness is measured by the costs of a new regimen per life year or quality-adjusted life year (QALY) gained as compared with the cost of best supportive care or another therapy.95 A set threshold then establishes whether a new treatment is considered cost-effective and the threshold, most frequently described, although debated, ranges between $50 000 and $100 000 based on the costs of 1 year of haemodyalisis for end-stage renal disease. Recent estimates of cost-effectiveness for molecularly targeted agents for renal cell carcinoma showed that all exceeded the threshold such as sunitinib (52 593-142-924/QALY), sorafenib (204 996/QALY, temsirolimus (188 770/QALY) and bevacizumab (342 602/QALY).96 Continuing this cost-efficacy debate, the National Institute for Health and Clinical Excellence (NICE) in the UK has denied covering sorafenib (Nexavar, Bayer HealthCare, Leverkusen, Germany) for the treatment of advanced HCC. This decision denies patients a modern treatment known to prolong survival and places physicians in the difficult situation of being unable to provide the best possible care for their HCC patients other than best supportive care. Discussions of cost-effectiveness will only intensify in the coming years with the addition of new targeted agents. Multiple groups are likely to be involved in future cost-effectiveness discussions and the principles of evidence-based medicine and efficacy should be the focus during the deliberations.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

The incidence of HCC continues to rise dramatically because of the epidemic of HCV and recently identified risk factors of diabetes and obesity. The standardization of radiological diagnosis of HCC and the implementation of surveillance programmes in those at risk for HCC are crucial in allowing earlier diagnosis. Once HCC is detected, the BCLC staging classification is a clinically useful construct that is helpful in guiding physicians to the appropriate care for the various tumour stages. Many highly effective and even curative therapies are available, including resection, liver transplantation and local ablative procedures. The management of HCC also requires an understanding of the underlying liver disease and needs to involve a multidisciplinary approach to maximize outcomes. Early referral to a centre with the potential to offer the various interventions to treat the tumour is extremely important. Despite the tremendous advances in our knowledge regarding diagnosis and treatment of HCC, a majority of patients get treatment well beyond the opportunity curative options. Future efforts need to focus on improving our knowledge of HCC tumourogenesis, discovering better biomarkers (diagnostic and therapeutic) and developing more effective therapies.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References

Declaration of personal and funding interests: Dr Cabrera is a speaker, consultant, and has research grants from Bayer. Dr Nelson is a consultant and has research grants from Bayer and Human Genome Science.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Surveillance of high-risk groups
  5. Diagnosis
  6. Prognostic staging
  7. Early-stage HCC (stages 0 and A)
  8. Intermediate stage HCC (stage B)
  9. Advanced HCC (stage C)
  10. Managing adverse reactions
  11. Future directions
  12. Costs of molecular-targeted therapy
  13. Conclusions
  14. Acknowledgement
  15. References