ReviewNovel advancements in the management of hepatocellular carcinoma in 2008☆
Introduction
Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer worldwide with 626,000 new cases in 2002 [1]. The incidence of HCC is increasing in Europe and the United States [2], and is currently the leading cause of death amongst cirrhotic patients [3]. Chronic hepatitis B viral (HBV) infection is the predominant risk factor in Asia and Africa, and chronic hepatitis C viral (HCV) infection in Western countries and Japan. Hepatocellular carcinoma develops in a cirrhotic liver in 80% of cases, and this pre-neoplastic condition is the strongest predisposing factor [4]. Chronic HBV carriers have a 100-fold relative risk for developing HCC, with an annual incidence rate of 2–6% in cirrhotic patients [6]. Aflatoxin B1 intake further enhances the risk. In Western countries and Japan, hepatitis C virus (HCV) infection is the main risk factor, together with other causes of cirrhosis. Around 20–30% of the estimated 170 million HCV-infected individuals worldwide will develop cirrhosis. Once cirrhosis is established, the annual incidence of HCC is of 3–5%, and one third of them will develop a HCC over their lifetime [4].
During recent years, major advancements in the knowledge of this complex disease have been reported. We review herein these new data on surveillance and early diagnosis, the clinical and molecular classification of the disease, and the novel advancements in the management of this neoplasm. Specifically, we will analyze the advent of sorafenib as the first systemic therapy that has shown survival benefits, and pinpoint the most urgent unmet needs and how to design trials to capture benefits from efficacious drugs.
Section snippets
Early diagnosis of HCC: novel markers
Surveillance with ultrasound every 6 months for detection of early HCC is recommended in cirrhotic patients and other specific risk groups [5], [6]. The only randomised study reported so far comparing surveillance vs. non-surveillance has shown benefits in terms of higher applicability of curative therapies in Chinese patients infected with HBV regardless of the presence of cirrhosis [7]. European cohort studies and cost-effectiveness analysis further reinforce the benefits of this policy [3],
Clinical and molecular classification of HCC
Cancer classification is aimed to establish prognosis and select the adequate treatment for the best candidates. In addition, it aids researchers to exchange information and design clinical trials with comparable criteria. Clinical classifications have been proposed for most cancers. However, very few involve molecular data. Such is the case of breast cancer, where Her2/nu status discriminates subgroups of patients with different outcomes and treatment responses [24]. Similarly, EGFR mutational
New advancements and needs in clinical research
In oncology, the benefits of treatments should be assessed through randomised controlled trials and meta-analysis. Other sources of evidence, such as non-randomised clinical trials or observational studies are considered less robust. Few medical interventions have been thoroughly tested in HCC, in contrast with other cancers with a high prevalence worldwide, such as lung, breast, colo-rectal and stomach cancer [34], [47]. Unfortunately, the fact that HCC is a tumor with a low incidence in
Resection
Surgery is the mainstay of HCC treatment (Table 1). Resection and transplantation achieve the best outcomes in well-selected candidates (5-yr survival of 60–70%), and compete as the first option in patients with early tumors on an intention-to-treat perspective [4], [30], [31]. Hepatic resection is the treatment of choice for HCC in non-cirrhotic patients (5% of cases in the West, 40% in Asia) [48], [49]. Major resections can be performed with low rates of life-threatening complications. In
Liver transplantation
Liver transplantation is the first treatment choice for patients with small multinodular tumors (3 nodules <3 cm) or those with advanced liver dysfunction [4], [31] (Table 1, 3iiA). Theoretically, transplantation may simultaneously cure the tumor and the underlying cirrhosis. The broad selection criteria applied two decades ago led to poor results in terms of recurrence (32–54%) and survival (5-yr survival <40%), but allowed the identification of the best candidates for liver transplantation.
Local ablation
Percutaneous ablation achieves complete responses in more than 80% of tumors smaller than 3 cm in diameter, but in 50% of tumors of 3–5 cm in size [32] (1iiD). The best results obtained in series of HCC patients treated by percutaneous ethanol injection (PEI) or radiofrequency ablation (RF) provide 5-yr survival rates of 40–70% [91], [92]. The best outcomes have been reported in Child–Pugh A patients with small single tumors, commonly less than 2 cm in diameter [32]. Independent predictors of
Chemoembolization and other locoregional treatments
Arterial embolization is the most widely used primary treatment for unresectable HCC [4], [11], [93]. In early stages, it is not indicated as first-line option, as an outcome review from Japan reported worse results than surgery or percutaneous ablation [11], [93]. Obstruction of hepatic artery induces extensive necrosis in large vascularized HCC. Embolizing agents – usually gelatin or microspheres – may be administered together with selective intra-arterial chemotherapy mixed with lipiodol
Systemic treatments
Hormonal compounds and conventional external beam radiation have not shown survival benefits in HCC. A meta-analysis of seven RCTs comparing tamoxifen vs. conservative management, comprising 898 patients, showed neither antitumoral effect nor survival benefit of tamoxifen (1iA) [33]. Two large RCTs were reported afterwards assessing tamoxifen [106], [107] with negative results in terms of survival. Thus, this treatment is discouraged in advanced HCC.
Systemic chemotherapy has been tested in nine
Molecular therapies in HCC: the case of sorafenib
The increasing knowledge in the molecular pathogenesis of HCC as well as the introduction of molecular targeted therapies in oncology have created an encouraging trend in the management of this malignancy (see reviews on [39], [112]). Table 5 depicts the molecular therapies currently tested within phase II and III clinical trials in HCC. Most of the treatments aim to abrogate signaling pathways related to proliferation and cell survival. Alternatively, other treatments rely on the blockade of
New endpoints in the design of clinical trials in HCC
The mechanism of action of biological agents against molecular targets has raised the question of which should be the primary and secondary endpoints in controlled phase II and phase III trials. Obviously, the primary endpoint for phase III studies is survival, and for adjuvant studies time to recurrence. Objective response is a weak surrogate of activity in phase II trials, since in most cases, the predominant effect of these compounds is basically cytostatic. In fact, bevacizumab has shown a
References (125)
- et al.
Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance
Gastroenterology
(2004) - et al.
Hepatocellular carcinoma
Lancet
(2003) - et al.
Clinical management on hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference
J Hepatol
(2001) - et al.
Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study
Hepatology
(2000) - et al.
Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma
Gastroenterology
(2003) - et al.
Newer markers for hepatocellular carcinoma
Gastroenterology
(2004) - et al.
Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale real-time RT-PCR approach: determination of a molecular diagnostic index
Am J Pathol
(2003) - et al.
A molecular signature to discriminate dysplastic nodules and early hepatocellular carcinoma in HCV-cirrhosis
Gastroenterology
(2006) - et al.
Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival
Hepatology
(2003) - et al.
Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection
Lancet
(2003)
Molecular-based prediction of early recurrence in hepatocellular carcinoma
J Hepatol
Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection
J Am Coll Surg
Hepatobiliary surgery
J Hepatol
Hepatocellular carcinoma: surgical indications and results
Crit Rev Oncol Hematol
Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma
Hepatology
Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy
J Hepatol
Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure
Gastroenterology
MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation
Hepatology
Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma
Gastroenterology
Microdissection-based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma
Hepatology
Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial
Lancet
Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial
Lancet
Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma
Hepatology
Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome
Liver Transpl
Liver transplantation for hepatocellular carcinoma: expansion of tumor size limits does not adversely impact survival
Hepatology
The impact of pre-operative loco-regional therapy on outcome after liver transplantation for hepatocellular carcinoma
Am J Transplant
Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation
Gastroenterology
Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan
Hepatology
A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma
Gastroenterology
Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm
Gastroenterology
Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial
Lancet
Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma
Hepatology
Global cancer statistics 2002
CA Cancer J Clin
Rising incidence of hepatocellular carcinoma in the United States
N Engl J Med
Management of hepatocellular carcinoma
Hepatology
Randomized controlled trial of screening for hepatocellular carcinoma
J Cancer Res Clin Oncol
Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis
Gut
Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey
Cancer
Characterization of small nodules in cirrhosis by assessment of vascularity: the problem of hypovascular hepatocellular carcinoma
Hepatology
Focus on dysplastic nodules and early hepatocellular carcinoma: an Eastern point of view
Liver Transpl
Neoangiogenesis and sinusoidal “capillarization” in dysplastic nodules of the liver
Am J Surg Pathol
Diagnosis of hepatic nodules <20 mm in cirrhosis. Prospective validation of the AASLD guidelines for Hepatocellular Carcinoma (HCC)
Hepatology
Early hepatocellular carcinoma and dysplastic nodules
Semin Liver Dis
Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling
Hepatology
Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases
Hepatology
Genome-wide profiles of dysplasia and HCC in HCV-cirrhotic patients
Hepatology
Trastuzumab after adjuvant hemotherapy in HER2-positive breast cancer
N Engl J Med
EGFR mutation and resistance of non-small-cell lung cancer to gefitinib
N Engl J Med
Prognosis of hepatocellular carcinoma: the BCLC staging classification
Semin Liver Dis
Cited by (807)
Impact of radiation therapy and alpha-fetoprotein level on survival outcomes for patients with hepatocellular carcinoma: A population-based study
2023, Clinics and Research in Hepatology and GastroenterologyThe effects of vaporisation, condensation and diffusion of water inside the tissue during saline-infused radiofrequency ablation of the liver: A computational study
2022, International Journal of Heat and Mass TransferPredictors of changes in preoperative tumor stage between dynamic computed tomography and gadoxetate disodium-enhanced magnetic resonance imaging for hepatocellular carcinoma
2022, Journal of the Formosan Medical AssociationThe clinical value of heat shock protein 90α in predicting the prognosis of interventional therapy for hepatocellular carcinoma
2024, Chinese Journal of Oncology
- ☆
The authors receive consulting and lecture fees from Bayer Healthcare Pharmaceuticals; consulting fees from MDS Nordion, Bristol-Myers Squibb and Biocompatibles and Research grants from Exelixis. The authors have been supported by the following government grants: Dr. J.M. Llovet, National Institute of Health-NIDDK Grant 1R01DK076986-01, National Institute of Health, Spain (I+D Program, Grant No. SAF-2007-61898), and as Professor of Research at Institut Català de Recerca Avancada (ICREA); and from Samuel Wasman Cancer Research Foundation Dr. J. Bruix: National Institute of Health, Spain (FIS Program, Grant No. PI 05/150). We acknowledge the support of CIBERehd (Centro Investigaciones BioMedicas en Red, Instituto Carlos III).