Novel advancements in the management of hepatocellular carcinoma in 2008

doi:10.1016/j.jhep.2008.01.022

Journal of Hepatology

Volume 48, Supplement 1, 2008, Pages S20-S37

https://doi.org/10.1016/j.jhep.2008.01.022 Get rights and content

New advancements have emerged in the field of hepatocellular carcinoma (HCC) in recent years. There has been a switch in the type of presentation of HCC in developed countries, with a clear increase of tumors <2 cm in diameter as a result of the wide implementation of surveillance programs. Non-invasive radiological techniques have been developed and validated for the diagnosis of small and tiny HCCs. Simultaneously, diagnostic criteria based on molecular profiling of early tumors have been proposed. The current clinical classification of HCC divides patients into 5 stages with a specific treatment-oriented schedule. There is no established molecular classification of HCC, although preliminary proposals have already been published. Advancements in the treatment arena have come from well designed trials. Radiofrequency ablation is currently consolidated as providing better local control of the disease compared with percutaneous ethanol injection. New devices are available to improve the anti-tumoral efficacy of conventional chemoembolization. Sorafenib, a multikinase inhibitor, has shown survival benefits in patients at advanced stages of the disease. This advancement represents a breakthrough in the management of this complex disease, and proves that molecular targeted therapies can be effective in this otherwise chemo-resistant tumor. Consequently, sorafenib will become the standard of care in advanced cases, and the control arm for future trials. Now, the research effort faces other areas of unmet need, such as the adjuvant setting of resection/local ablation and combination therapies.

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

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Impact of radiation therapy and alpha-fetoprotein level on survival outcomes for patients with hepatocellular carcinoma: A population-based study
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The use of radiation therapy (RT) in hepatocellular carcinoma (HCC) remains a matter for debate. Recently published research indicate that advanced RT techniques may improve survival in patients with HCC. This study aimed to evaluate this hypothesis in a large-scale retrospective cohort. The effect of alpha-fetoprotein (AFP) was taken into account because of its important role in the prognosis of HCC.
The Surveillance, Epidemiology, and End Results (SEER) database was queried for adults patients diagnosed 2010–2019 with HCC (≥ 18 years). The study population was divided into four groups: Non-radiation & AFP-positive (reference), Non-radiation & AF-negative, Radiation & AFP-positive, Radiation & AFP-negative. Distant metastasis (DM) was used as a stratification factor. Differences in 5-year overall survival (OS) of the four groups were assessed using the Kaplan–Meier method. Univariate and multivariable Cox proportional hazards model were used to estimate unadjusted and adjusted hazard ratios (HR).
A total of 34,656 patients were eligible for this analysis, including 21,084 (60.8%), 8,449 (24.4%), 3,810 (11.0%) and 1,313 (3.8%) in the Non-radiation & AFP-positive, Non-radiation & AF-negative, Radiation & AFP-positive and Radiation & AFP-negative groups, respectively. Median OSs of the four groups were 3, 4, 5 and 11 months in the DM cohort, and 12, 28, 15, and 28 months in the Non-DM cohort. Patients in the Radiation & AFP - group had the best OS and patients in the Non-radiation & AFP + group had the worst OS (adjusted HR [95% confidence interval (CI)]: 0.497 [0.399–0.619] in the DM cohort, and 0.405 [0.372–0.441] in the Non-DM cohort). Radiation & AFP + also showed improved survival compared with the reference group (adjusted HR [95%CI]: 0.725 [0.657–0.801] in the DM cohort, and 0.630 [0.600–0.661] in the Non-DM cohort).
This population-based cohort study confirmed a significant improvement in overall survival with radiation therapy in HCC. AFP-negative patients benefit the most from RT. Superior OS of radiation therapy and AFP-negative status persisted even in patients with complex metastasis patterns. Our data suggest that radiation may provide an alternative modality for unresectable HCC.
Heme oxygenase-1 mitigates liver injury and fibrosis via modulation of LNX1/Notch1 pathway in myeloid cells
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Activation of resident macrophages (Mϕ) and hepatic stellate cells is a key event in chronic liver injury. Mice with heme oxygenase-1 (HO-1; Hmox1)-deficient Mϕ (LysM-Cre:Hmox1^flfl) exhibit increased inflammation, periportal ductular reaction, and liver fibrosis following bile duct ligation (BDL)-induced liver injury and increased pericellular fibrosis in NASH model. RiboTag-based RNA-sequencing profiling of hepatic HO-1-deficient Mϕ revealed dysregulation of multiple genes involved in lipid and amino acid metabolism, regulation of oxidative stress, and extracellular matrix turnover. Among these genes, ligand of numb-protein X1 (LNX1) expression is strongly suppressed in HO-1-deficient Mϕ. Importantly, HO-1 and LNX1 were expressed by hepatic Mϕ in human biliary and nonbiliary end-stage cirrhosis. We found that Notch1 expression, a downstream target of LNX1, was increased in LysM-Cre:Hmox1^flfl mice. In HO-1-deficient Mϕ treated with heme, transient overexpression of LNX1 drives M2-like Mϕ polarization. In summary, we identified LNX1/Notch1 pathway as a downstream target of HO-1 in liver fibrosis.
The effects of vaporisation, condensation and diffusion of water inside the tissue during saline-infused radiofrequency ablation of the liver: A computational study
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Saline-infused radiofrequency ablation (RFA) is a thermal ablation technique that combines saline infusion and Joule heating to destroy cancer tissues. During treatment, the intense heat generated can cause water from the infused saline and inside the tissue to vaporise. Conventionally, the effects of vaporisation have been modelled by adopting the apparent heat capacity method. However, this approach does not account for the loss of water content during vaporisation, which raises questions on its accuracy, primarily because of the large water content present during saline-infused RFA. To address this, the present study proposes an alternative approach to model vaporisation effects during saline-infused RFA. The approach adopts and modifies the water fraction method to account for the effects of vaporisation, condensation and diffusion of water inside the tissue during saline-infused RFA. The framework was compared against the commonly used apparent heat capacity method through numerical simulations carried out on 3D finite element models of the liver. Results indicated that unlike condensation, the role of diffusion of water during saline-infused RFA was not as significant as condensation, where the latter was found to affect the ablation process. With the water fraction method, there was a trend of exponential decrease in tissue electrical conductivity with time, which ultimately led to the prediction of smaller coagulation volume than that of the apparent heat capacity method.
Predictors 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 Association
Gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI) has a higher diagnostic accuracy for hepatocellular carcinoma (HCC) than computed tomography (CT). However, indications for performing EOB-MRI after dynamic CT are not well defined. Therefore, we investigated the clinical factors associated with changes in the preoperative tumor stage between dynamic CT and EOB-MRI.
A prospective cohort was conducted from January 2014 to December 2017. 156 adult patients with clinical suspicion of HCC before liver resection were enrolled and we retrospectively reviewed the images. The tumor staging was evaluated by dynamic CT and then EOB-MRI subsequently according to the TNM staging system. The changes in tumor stage between two modalities were identified, and the associated clinical factors were analyzed.
A total of 99 patients were analyzed after excluding 57 patients. 20 patients (20.2%) had changes in tumor stage between dynamic CT and EOB-MRI. The change occurred only in early stage (T1 and T2 lesions) based on dynamic CT initially. Furthermore, in univariate and multivariate analyses, albumin–bilirubin (ALBI) grade 2 and log alpha-fetoprotein (AFP) levels were associated with changes in tumor staging by EOB-MRI than those without (50% vs. 9.9%, p < 0.001 and 2.04 ± 1.35 vs. 1.40 ± 1.16, p = 0.038, respectively). Patients with changes in tumor stage also exhibited higher 1-year recurrence rate and shorter recurrence-free survival.
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^☆: 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).

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ReviewNovel advancements in the management of hepatocellular carcinoma in 2008☆

Introduction

Section snippets

Early diagnosis of HCC: novel markers

Clinical and molecular classification of HCC

New advancements and needs in clinical research

Resection

Liver transplantation

Local ablation

Chemoembolization and other locoregional treatments

Systemic treatments

Molecular therapies in HCC: the case of sorafenib

New endpoints in the design of clinical trials in HCC

Gastroenterology

Lancet

J Hepatol

Hepatology

Gastroenterology

Gastroenterology

Am J Pathol

Gastroenterology

Hepatology

Lancet

J Hepatol

J Am Coll Surg

J Hepatol

Crit Rev Oncol Hematol

Hepatology

J Hepatol

Gastroenterology

Hepatology

Gastroenterology

Hepatology

Lancet

Lancet

Hepatology

Liver Transpl

Hepatology

Am J Transplant

Gastroenterology

Hepatology

Gastroenterology

Gastroenterology

Lancet

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

Review
Novel advancements in the management of hepatocellular carcinoma in 2008☆