Progress in the diagnostic imaging and treatment of hepatocellular carcinoma

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1 REVIEW ARTICLE Progress in the diagnostic imaging and treatment of hepatocellular carcinoma Jörg Trojan, Renate Hammerstingl, Christoph W. Strey, Thomas J. Vogl, Wolf-Otto Bechstein, Stefan Zeuzem SUMMARY Introduction: Liver cirrhosis due to chronic hepatitis C virus infection and alcoholism are currently the most common reasons for hepatocellular carcinoma (HCC) in Western countries, but diabetes and obesity are further important risk factors with rising prevalence. Methods: Selective review of the literature on the diagnosis and therapy of HCC. Results: Appropriate diagnostic imaging is needed for differential diagnosis, staging and treatment. The diagnosis of HCC is made by sonography, dynamic contrast-enhanced imaging (multiphased computed tomography and/or magnetic resonance tomography), and/or histology. Unfortunately, potential curative treatment such as resection or liver transplantation can only be offered to few patients. Patients with smaller tumors unsuitable for surgery can benefit from regional treatments, for example, thermal ablation or percutaneous alcohol injection. Transarterial chemoembolization is usually offered to patients with larger and multiple tumors. If the tumor shows a diffuse intrahepatic growth, infiltration of the hepatic portal vein, or metastatic spread, therapeutic options are restricted. Recently, the growth inhibiting and angiostatic tyrosinkinase inhibitor sorafenib has been shown to prolong survival in this population, as published in a meeting report. Dtsch Arztebl 2007; 104(48): A Key words: hepatocellular cancer, hepatic tumor, cancer diagnostic, cancer therapy, surgery H epatocellular carcinoma (HCC) is one of the most common tumors worldwide, with more than 30 cases/ population/year in Southeast Asia and central Africa. Incidence rates of the disease are increasing globally. In the United States, the incidence has doubled over the past 20 years (1). No corresponding figures are available for Germany, but in individual federal states, a similar trend has been observed, with a current incidence of 5.7 cases/ population/year in men and of 2.0/ /year in women (2). The risk of developing HCC is influenced by the etiology, activity, and stage of liver disease. Patients with cirrhosis of the liver due to chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) have the highest risk. The rising incidence in Western countries is mainly due to the rising prevalence of patients with HCV associated liver cirrhosis. Another common cause for the development of HCC in Western countries is alcohol toxic cirrhosis of the liver. Furthermore, in recent years, an increase in HCC has been observed on the background of steatohepatosis in overweight and diabetes (3). The rapid increase in overweight and diabetes in newly industrialized countries (4) can be expected to contribute to a further rise in the incidence of HCC in the near future. At the molecular level, hepatocellular cancers show many genetic variations with heterogeneous patterns. Of diagnostic relevance in this context is the often increased vascularization of the tumor, caused by an activation of angiogenesis for example, due to increased expression of vascular endothelial growth factor (VEGF). Activation of growth promoting signal cascades might be a target for molecular therapies (5). These include epithelial growth factor receptor (EGF-R) and the activation of the RAF-MEK-ERK signal cascade (RAF, "ras-activated factor"; MEK, "mitogen-activated protein kinase"; ERK, "extracellular signal-regulated kinase"). This review summarizes Leberzentrum, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main; Medizinische Klinik I: PD Dr. med. Trojan, Prof. Dr. med. Zeuzem; Institut für Diagnostische und interventionelle Radiologie: Dr. med. Hammerstingl, Prof. Dr. med. Vogl; Klinik für Allgemeinchirurgie: Dr. med. Strey, Prof. Dr. med. Bechstein Dtsch Arztebl 2007; 104(48): A

2 current diagnostic and therapeutic options in the interdisciplinary care of patients with HCC on the basis of a selective literature review and provides a short outlook on future developments. Early detection The importance of early detection programs in patients with chronic liver disorders is controversially discussed in the literature, but they are the only method by which HCC can be diagnosed at an early stage (6). In populations at high risk for example, the native population of Alaska with chronic HBV infection 6 monthly alpha-fetoprotein (AFP) measurements have proved effective in the early detection. Compared with historical controls, the prognosis of patients with HCC identified in such a manner was improved (7). Many centers have therefore introduced a 6 monthly monitoring program comprising ultrasonography and AFP measurement (6). If a pathologically raised AFP measurement and/or a new space occupying lesion in the liver are noticed, further diagnostic tests are required. More recently, elastography has become available as a non-invasive procedure to estimate the extent of fibrosis and cirrhosis (8, 9). Further investigations will show whether using elastography is suitable for an early detection program. Diagnostic tests Basic diagnostic tests The symptoms of HCC are often non-characteristic and mostly cannot be distinguished from those of patients with liver cirrhosis without HCC. Occasionally a raised transaminase value or a c b Image 1: Diagnostic tests in patients with hepatocellular carcinoma (HCC) a) Contrast enhanced ultrasonography finding of early arterial hypervascularized HCC. b) Contrast enhanced multidetector computed tomography (late arterial phase). c) Dynamic contrast enhanced magnetic resonance imaging (T1 weighted sequence, arterial phase). d) Histology of a moderately differentiated HCC (HE staining, 40 times enlarged). With permission from Dr Susanne Kriener, Senckenbergisches Institut für Pathologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt/Main. d Dtsch Arztebl 2007; 104(48): A

3 DIAGRAM Barcelona Clinic Liver Cancer (BCLC) staging classification and therapeutic recommendations in patients with hepatocellular carcinoma. ECOG, Eastern Cooperative Oncology Group performance status; RFA, radiofrequency ablation; PEI, percutaneous alcohol injection; TACE, transarterial chemoembolization. liver capsule pain (pain in the upper right quadrant) results in further diagnostic tests. Primary diagnostics include a medical history, physical examination, determining the Child-Pugh stage, measurement of AFP, and abdominal ultrasonography, including color and power Doppler sonography, to detect an HCC and to exclude a thrombosis of the portal vein. In patients with nodular cirrhosis, sonographic differentiation of HCC from regenerating nodules may be difficult. The specificity of ultrasonography can, however, be improved by intravenous administration of a contrast medium and imaging of typical early arterial hypervascularization of an HCC nodule (image 1a) (6). If treatment is an option, contrast enhanced scanning is done by multiphase computed tomography (CT) or magnetic resonance imaging (MRI) (10). Computed tomography CT scanning has advanced notably, from spiral CT to multiphase CT. It offers high spatial resolution, which may be superior to that offered by MRI. The temporal resolution allows data capture in selective perfusion phases of the liver. Four phase protocols with early and late arterial phases, imaging of the portal vein, and late phase imaging have high diagnostic precision (11). Owing to the higher irradiation load, the standard in clinical practice is an investigation of the native, late arterial phase (image 1b) and portal venous phase and a non-contrast enhanced protocol in postinterventional controls. Magnetic resonance imaging To enable improved detection and characterization of focal hepatic lesions, different native and dynamic MRI sequences are taken. HCC nodules typically show arterial hypervascularization (image 1c), followed by a reduction in signal intensity in the portal venous phase and the late phase ("wash-out") (6, 12). By using liver specific MRI contrast mediums, small lesions can be imaged and categorized more proficiently. Small, superparamagnetic iron oxides, applied as an intravenous bolus injection, enable further dynamic protocols. Hepatobiliary MRI contrast mediums that are absorbed by the hepatocytes allow conducting dynamic sequence protocols to demonstrate HCC vascularization and imaging in the late phase (13). Invasive diagnostic tests and identification of extrahepatic manifestations If a space occupying lesion in the liver shows untypical vascularization patterns and the AFP value is < 200 ng/ml, an ultrasonographically guided or, in individual cases, CT guided-fine needle biopsy of the lesion is required to confirm the diagnosis histologically (image 1d). If the finding on the image is typical of HCC and the AFP measurement is pathologically raised then histological confirmation is not necessary (6). In individual cases, the investigation can be done by lipiodol angiography with subsequent CT, to confirm Dtsch Arztebl 2007; 104(48): A

4 a c b Image 2: Surgical treatment of patient with isolated hepatocellular carcinoma (HCC) a) Contrast enhanced computed tomography confirming solitary HCC in segment VI. b) Intraoperative ultrasonography illustrating the same finding. c) Intraoperative status and d) Macroscopic image of the resected mass in the same patient. d deposits in potential HCC nodules. The investigation of extrahepatic tumor manifestations is done by using thoracic radiography and, if skeletal metastases are clinically suspected, by skeletal szintigraphy. Suspect foci are then confirmed in the scanning procedure. Staging HCC can be staged using different staging classifications. The Barcelona-Clinic-Liver- Cancer (BCLC) scale (figure) is recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver Diseases (EASL) and is a staging system that is in use in many centers (6). Distinction is made between early stage (5 year survival 50 to 70%), intermediate and advanced stage (3 year survival 20 to 40%), and end stage (1 year survival 10%). Further classifications include the Cancer of the Liver Italian Program (CLIP), the Okuda classification, and the American Joint Committee on Cancer's TNM (tumor, nodes, metastasis) classification. The main advantage of the BCLC scale, which has been prospectively evaluated in different patient cohorts, is the therapeutic algorithm, which results from tumor spread, liver function disruption, and patient's general condition. The BCLC system does, however, have problems in the context of an indication for liver transplantation and resection in HCC without associated cirrhosis. Surgical treatment Resection In patients with HCC without liver cirrhosis, surgical resection is the treatment of choice. In patients who have cirrhosis, normal measurements of bilirubin and the absence of portal Dtsch Arztebl 2007; 104(48): A

5 TABLE 1 Radiofrequency ablation in patients with hepatocellular carcinoma * 1 Author Study design Complete Local recurrence Recurrence Survival (citation) tumor necrosis (%) rate (%) free survival (%) rate (%) Lencioni (17) Randomized 2 years: 2 years: 2 years: RFA (n = 52) PEI (n = 50) Li (18) Randomized 3 years: 3 years: 3 years: RFA (n = 62) * PEI (n = 62) * PAI (n = 63) * Lin (e1) Randomized 3 years: 3 years: 3 years: RFA (n = 52) PEI (n = 52) Modifizierte PEI (n = 53) Shiina (e2) Randomized 4 years: 4 years: 4 years: RFA (n = 118) * PEI (n = 114) * Tateishi (e3) Retrospective 3 years: 3 years: RFA cohort study 93 * (n = 319)* 3 4 years: 5 years: Choi (e4) Retrospective 3 years: 3 years: 3 years: RFA (n = 570) cohort study % 70 5 years: 5 years: 21 % 58 * 1 The selection included randomized studies published in English (RFA versus PEI) and the two largest cohort studies of RFA; * 2 No author data; * 3 Patient cohort not previously treated RFA, radiofrequency ablation; PEI, percutaneous alcohol injection; PAI, percutaneous injection of acetic acid hypertension have been found to be good predictors for a sufficient functional hepatic reserve after the resection (6). Assessing the functional capacity of the remaining liver volume after resection can present difficulties in the individual case. As a rule, only patients with hepatic cirrhosis of Child-Pugh stage A can undergo resection. To plan the resection with precision while taking into consideration anatomical structures in place, intraoperative ultrasonography has become established (image 2). A safety margin is desirable especially in view of existing satellite foci, but in most cases, only limited resections are possible where the functional hepatic reserve is impaired. The 5 year survival rate after partial liver resection in Western countries is 20 to 50%. The risk of a tumor recurrence and/or dissemination is biggest in the first 3 years after the operation (6). Centers sometimes perform transarterial chemoembolization (TACE) in borderline resectable tumors, by way of a neoadjuvant intention. The benefits of this procedure have not been confirmed reliably. Adjuvant therapy after R0 resection has not become established. A complication associated with surgical treatment in addition to the usual risks associated with hepatobiliary procedures is hepatic decompensation in a scenario of low functional hepatic reserve. Liver transplantation In liver cirrhosis, liver transplantation is the best therapeutic option, because by removing the entire organ the tumor and precancerous lesions are also removed, and the impaired liver function is restored. Early experiences with liver transplants date back to the 1980s and were mostly disappointing, with 5 year survival rates of less than 40%. After the Milan criteria were introduced, the results of liver transplantation in this indication improved notably (14). This means that a transplantation can be done only in patients with a solitary HCC node 5 cm diameter, or 3 nodes 3 cm diameter, and no infiltration of the portal vein Dtsch Arztebl 2007; 104(48): A

6 a c b Image 3: Interventional and drug therapy in patients with hepatocellular carcinoma (HCC). a) Angiogram of HCC with pathological vascularization and b) progress monitoring to show depositing of embolizate by computed tomography 24 hours after arterial chemoembolization (lipiodol, mitomycin C, and microspheres) in the same patient. c) Dynamic magnetic resonance imaging after bolus administration of chelated gadolinium with imaging of hypervascularized advanced HCC before start of therapy with the tyrosine kinase inhibitor sorafenib. d) Progress monitoring in the same patient after 12 weeks' treatment with reduced vascularization (stable course of disease). d and extrahepatic manifestations. By selecting patients carefully, 5 year survival rates of more than 70% can now be achieved in HCC patients who receive a liver transplant (15). The criteria cannot currently be extended to include to larger tumors because of the shortage of organs. Until recently, the main problem for many waiting list patients with HCC has been the long time period they have to wait for a transplant. Because of the progression of the tumor during this time, a transplantation was not possible once patients had reached the top of the waiting list. The Eurotransplant organ allocation criteria have been changed since December 2006, and transplant waiting times for patients with HCC will be shortened drastically in the future. Another option is living liver donation, which has thus far hardly been practiced in Germany. Yet another option is using suitable bridging therapies to limit/stop tumor growth during the waiting time or even achieve a reduction in size. Most experience with regard to this option has been gained for transarterial chemoembolization (TACE). Locoregional therapeutic approaches Ablative procedures Often, HCC is diagnosed only at an advanced stage. The most common reasons for nonresectability are existing liver cirrhosis with impaired functional hepatic reserve, the size of the lesion or lesions, multifocality, and vascular invasion. For patients with a single HCC 5 cm diameter or a maximum of 3 nodes 3 cm diameter each, in whom transplantation is contraindicated, an ablative procedure is a potentially curative therapeutic option. The Dtsch Arztebl 2007; 104(48): A

7 TABLE 2 Summary of current studies of systemic therapy in patients with hepatocellular carcinoma * 1 Author Study type Drug No of Responsiveness Progression free Median survival (citation) patients (%) survival (months) (months) Yeo (21) Phase 3 PIAF versus doxorubicin Becker (22) Phase 3 Octreotide DEPOT versus placebo Llovet* 2 Phase 3 Sorafenib versus placebo Abou-Alfa (24) Phase 2 Sorafenib Philip (e5) Phase 2 Erlotinib Zhu (e6) Phase 2 Gemcitabine/ oxaliplatin/ bevacizumab Faivre* 3 Phase 2 Sunitinib Grünwald* 4 Phase 2 Cetuximab Thomas* 5 Phase 2 Bevacizumab/ erlotinib * 1 The study selection includes English language randomized studies of cytotoxic or hormonal therapy and Phase 2 studies with molecular targeted substances from 2005 to Additionally, we included conference abstracts from the most recent annual congress of the American Society of Clinical Oncology (ASCO) if they dealt with molecular targeted substances; * 2 Llovet J et al.: Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): Results of a phase II randomized placebo-controlled trial (SHARP trial). J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25 (June 20 Supplement) Abstract: LBA 1; * 3 Faivre SJ et al.: Assessment of safety and drug-induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25 (June 20 Supplement): 3546; * 4 Gruenwald V, Wilkens L, Gebel M et al.: A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: Final results. J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25 (June 20 Supplement): 4598; * 5 Thomas MB et al.: The combination of bevacizumab (B) and erlotinib (E) shows significant biological activity in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25 (June 20 Supplement): 4567; PIAF, Cisplatin, Interferon-a2b, Doxorubicin und 5-Fluorouracil. risk of a secondary tumor or tumor dissemination is not influenced by local ablative procedures. Further to percutaneous alcohol injection (PEI), radiofrequency ablation (RFA) is most commonly used nowadays (6). Other, thermal ablation procedures for example, laser induced thermotherapy (LITT) are used more rarely (16). In PEI, which is the most cost effective procedure, several sessions are required; with RFA or LITT, complete ablation may be achieved in a single session. Two randomized studies have shown that RFA results in a higher rate of recurrence free survival than PEI (17, 18, e1, e2) (table 1). The complication rate for RFA is about 5% higher than that of PEI. In suitable patients with good liver function, a 5 year survival rate of up to 50% may be achieved (6). The complications of local ablative procedures include liver abscess, bilioma, and right sided pleural effusion. Arterial embolization For large or multifocal tumors, many centers use transarterial chemoembolization (TACE) as palliative therapy. After angiographic imaging of one or more vessels supplying the tumor, the ideal case scenario is one of selective embolization with the oily contrast medium lipiodol, a chemotherapy drug (mostly an anthracyclin, mitomycin C, or cisplatin), and microspheres (images 3a and 3b). Randomized studies have shown a survival advantage for TACE. Repeated TACE increases 3 year survival in up to 29% and 5 year survival in up to 20% of patients with advanced HCC (6, 19). A large prospective study from Japan has confirmed that the procedure is safe, while showing a median survival of 34 months (20). Because of the risk of hepatic decompensation after TACE, the selection of patients is the crucial factor: only patients with Child-Pugh stage A should be treated with TACE. Rarely, extravasation of embolizate results in ischemic ulceration of the mucosa or pancreatitis. A problem associated with TACE is the often rapid washout of the chemotherapy drug, resulting in a low intensity dose. By linking the chemotherapy drug to drug eluting beads, Dtsch Arztebl 2007; 104(48): A

8 a notably higher local concentration can be sustained for a greater length of time. A recently published phase 2 study has documented a partial tumor response in 44% of patients with advanced HCC (21). Brachytherapy by arterial embolization using 90yttrium microspheres is sparsely documented. Control of tumor growth and regression of the tumor seem possible. There are currently no results from randomized studies. Systemic therapeutic approaches The effectiveness of systemic treatment with cytotoxic, hormonal, or immunomodulating substances is low (5, 6). Cytotoxic treatment with doxorubicin or doxorubicin based combination therapy for example, the PIAF protocol (cisplatin, interferon-α2b, doxorubicin, and 5-fluorouracil) is toxic on a background of liver cirrhosis which, in contrast to Asian patients, is present in more than 95% of west European patients with HCC and is only moderately effective, with responsiveness rates of 11% or 21% and less than 9 months' survival (22). Treatment with octreotide is ineffective (23). The results of a controversial study into the use of the HMG-CoA reductase inhibitor pravastatin have not been confirmed (24). Patients with advanced HCC thus do not have any systemic therapeutic options outside clinical studies. Therapies that target molecular structures are therefore of particular interest. Most advanced in terms of its clinical development is the use of the tyrosine kinase inhibitor sorafenib, which has been available in Germany for the treatment of patients with metastatic renal carcinoma since December Sorafenib's effective mechanisms lie in growth inhibition and angiostatic effects thanks to inhibition of different kinases (such as RAF, VEGF receptor 2/3, platelet derived growth factor receptor). The results of a phase 2 study with 137 patients with advanced HCC who were given sorafenib (400 mg b.d.) were promising (25). Meanwhile, the subsequent phase 3 study (relevant for licensing purposes) of 602 patients with advanced HCC and Child-Pugh stage A liver cirrhosis (> 95% of patients) was stopped prematurely. Although objective tumor regression was confirmed in only few patients, the group treated with sorafenib showed a significant survival advantages compared with the placebo group (10.7 months versus 7.9 months). However, this study is available only in the form of conference proceedings (Llovet J et al.: Sorafenib improves survival in advanced hepatocellular carcinoma [HCC]: Results of a phase III randomized placebo-controlled trial [SHARP trial]. J Clin Oncol 2007 ASCO annual meeting proceedings; 25 [June 20 supplement], abstract number: LBA1). The time to disease progression in the sorafenib group was almost double that in the placebo group (5.5 months versus 2.8 months). The treatment was well tolerated. Diarrhea and changes to skin and nails were common during treatment with sorafenib (8 % of patients). No increased tendency to bleed was observed. The future use of sorafenib in patients with cirrhosis of the liver will yield further data relating to its tolerability. If the increased vascularization that was noted before treatment reduces during treatment with a tyrosine kinase inhibitor, this seems of great importance in the assessment of responsiveness to therapy (images 3c and 3d). Promising phase 2 studies have been published of other drugs that target certain proteins (table 2). These include the tyrosine kinase inhibitors erlotinib (EGF receptor) and sunitinib (c-kit, VEGF- and PDGF receptor) and the monoclonal antibodies bevacizumab (anti-vegf) and cetuximab (anti-egf receptor). Comparative data about the effectiveness of cytotoxic and molecular targeted treatments are lacking. Study results on the combination of molecular targeted drugs with interventional approaches are keenly awaited. Conclusions Treating patients with HCC in a manner that is appropriate for their stage of disease requires precise diagnostics. In clinical practice, the BCLC staging classification is most commonly used. However, this is only of limited usefulness when considering the indication of liver transplantation. Surgical therapy such as resection or transplantation is currently appropriate for only few patients. Interventional therapeutic procedures are of definite value for most patients. In patients with advanced tumor disease, therapeutic options are limited. Sorafenib is the first systemic therapy whose effectiveness at an advanced tumor stage in patients with HCC has been confirmed in the setting of a placebo controlled phase 3 study. The European Dtsch Arztebl 2007; 104(48): A

9 Agency for the Evaluation of Medicinal Products (EMEA) granted a license for sorafenib in the treatment of patients with HCC on 30 October The results of further studies of the use of molecular targeted drugs are eagerly anticipated. Conflict of Interest Statement PD Trojan, Dr Hammerstingl, Professor Vogel, and Professor Zeuzem participated in Bayer Healthcare's phase 3 (relevant for licensing) study of sorafenib.pd Trojan received honoraria for presentations from Bayer Healthcare and Merck Serono. Dr Strey and Professor Bechstein declare that no conflict of interest exists according to the Guidelines of the International Committee of Medical Journal Editors. Manuscript received on 2 March 2007, final version accepted on 14 August Translated from the original German by Dr Birte Twisselmann. LITERATUR For e-references please refer to the additional references listed below. 1. 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10 25. Abou-Alfa GK, Schwartz L, Ricci S et al.: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: ADDITIONAL REFERENCES e1. Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC: Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology 2004; 127: e2. Shiina S, Teratani T, Obi S et al.: A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005; 129: e3. Tateishi R, Shiina S, Teratani T et al.: Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 2005; 103: e4. Choi D, Lim HK, Rhim H et al.: Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-institution series. Eur Radiol 2007; 17: e5. Philip PA, Mahoney MR, Allmer C et al.: Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005; 23: e6. Zhu AX, Blaszkowsky LS, Ryan DP et al.: Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: Corresponding author PD Dr. med. Jörg Trojan Medizinische Klinik I Klinikum der Johann Wolfgang Goethe-Universität Theodor-Stern-Kai Frankfurt, Germany trojan@em.uni-frankfurt.de Dtsch Arztebl 2007; 104(48): A