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Revista Española de Enfermedades Digestivas

Print version ISSN 1130-0108

Rev. esp. enferm. dig. vol.108 n.8 Madrid Aug. 2016

http://dx.doi.org/10.17235/reed.2015.4012/2015 

REVIEW

 

New challenges in clinical research on hepatocellular carcinoma

Nuevos retos en la investigación clínica del carcinoma hepatocelular

 

 

Álvaro Díaz-González1, Alejandro Forner1,2, Carlos Rodríguez-de-Lope3 and María Varela4

1 Hepatic Oncology Unit (BCLC). Hepatology Service. Hospital Clínic Barcelona. IDIBAPS. Universidad de Barcelona. Barcelona, Spain.
2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd).
3 Department of Digestive Diseases. Hospital Universitario Marqués de Valdecilla. IDIVAL. Santander, Spain.
4 Hepatology Unit. Department of Digestive Diseases. Hospital Universitario Central de Asturias (HUCA). Universidad de Oviedo. Oviedo, Spain

Correspondence

 

 


ABSTRACT

This is an updated review of screening, early diagnosis and treatment of hepatocellular carcinoma, focusing on the advancements occurred in the last years and highlighting the challenges in clinical research.
Hepatocellular carcinoma (HCC) is nowadays the sixth most frequent cancer worldwide with up to 740,000 new cases diagnosed each year, and it is the third most prevalent cause of cancer-related-death worldwide (1). This neoplasm usually appears linked to an underlying liver disease, being one of the most relevant causes of death in patients diagnosed of liver cirrhosis (2,3). In the last years, important advancements in terms of diagnosis, staging and treatment of HCC, improving the management and outcome of the disease, have been made (4-7). Despite the fact that these improvements have absolutely changed natural history of HCC, there are several areas that still need further advancements.
The aim of this document is to discuss some controversial aspects, which in our opinion constitute real challenges in clinical research of HCC.

Key words: Hepatocellular carcinoma. Hepatic oncology. Sorafenib. Transarterial chemoembolization. AFP.


RESUMEN

Esta es una revisión actualizada de los distintos aspectos de cribado, diagnóstico precoz y tratamiento del carcinoma hepatocelular destacando especialmente los cambios sucedidos en los últimos dos años y las áreas de mejora que requieren trabajos de investigación clínica.
El carcinoma hepatocelular (CHC) constituye actualmente el sexto cáncer más frecuente, con más de 740.000 casos diagnosticados anualmente, y la tercera causa de muerte por neoplasia a nivel mundial (1). Esta neoplasia aparece frecuentemente asociada a la presencia de una enfermedad hepática, siendo una de las principales causas de muerte en los pacientes afectos de cirrosis hepática (2,3). En los últimos años han aparecido novedades importantes en el diagnóstico, estadiaje y tratamiento del CHC que han permitido una mejora en el manejo de esta enfermedad (4-7). A pesar de que estos avances han cambiado completamente la historia natural del CHC, existen aún muchas áreas en las que se precisan avances para poder mejorar. El objetivo de este documento es discutir algunos aspectos controvertidos que a nuestro juicio constituyen retos en la investigación clínica del CHC.

Palabras clave: Carcinoma hepatocelular. Oncología hepática. Sorafenib. Quimioembolización transarterial. AFP.


 

Improving early diagnosis

From the basis that the only possibility to offer and apply treatments with curative intention is being able to diagnose HCC at early stages, when there are not cancer related symptoms. Since this option is only feasible if screening is performed in population at risk, scientific guidelines recommend performing abdominal ultrasonography (US) in every patient with liver cirrhosis. Despite the recommendation of HCC screening by the Spanish guidelines (4), one registry study performed in Spain which included 62 centers and 705 patients diagnosed of HCC within a period of time of 4 months showed that just 47% of HCC patients were diagnosed in the setting of surveillance and less than a half were diagnosed at early stage (8).

This data shows that early diagnosis, a key issue to be able to significantly reduce HCC-related mortality, is one of the most relevant issues that deserve further efforts from scientific community. Aiming to evaluate which were the causes of screening program fail in the United States of America, Singal et al. evaluated 1,005 patients included in the HALT-C prospective study. A third part of patients did not adhere to an adequate screening program and, in 70% of cases that were diagnosed at an advanced stage, the main reason was the absence of detection in US (9).

With the aim of improving detection rate, it is crucial to establish formative programs in order to certify the capability of being able to carry on this activity and it is necessary to use up-to-date ultrasonography scans in order to perform an optimal liver exploration. Tumor markers could be a useful tool to overcome theoretical limitations of US: its evaluation is not subjective, does not depend on the operator and it may be reproducible, as well as it is relatively cheap and a tool easy to access in areas with low monetary income. Regrettably, different tumor markers evaluated in early stage HCC scenario have shown a low diagnostic accuracy (10-13) and its association with ultrasonography does not improve its performance and increases the cost of screening programs (14). A recent study has proposed a microRNA panel detected in plasma samples for the early diagnosis, but there is a need of external validation of its efficacy (15).

Another relevant aspect is choosing an optimal population in whom the screening program is cost-effective. The decision of entering into surveillance is based on the risk of developing HCC, life expectancy and the cost that should be assumed. More than 30 years ago (and based in patients with chronic kidney disease in whom the decision was if they were entered on dialysis program) it was determined that an intervention was cost-efficient if it permitted increasing survival 100 days with a cost of $50,000/year of life gained (16). These considerations are outdated: life expectancy of patients with liver cirrhosis is difficult to predict, and nowadays it is more challenging as there is an available and effective treatment for hepatitis C virus (HCV) infection. In addition, the assumed cost is not updated, and the most important issue, the actual costs of screening programs are very difficult to determine; besides the cost of screening techniques and subsequent studies needed to confirm diagnosis, also is important to consider the social impact risen by the implementation of a screening program (for instance, days of labor absenteeism), as well as economical and emotional impact of false positives and potential complications derived from screening and confirmation techniques (17).

Based on the assumptions previously described, surveillance is cost-efficient if HCC incidence in patients with underlying liver cirrhosis exceeds 1.5% and if it is over 0.2% in patients with chronic liver disease but who have not developed cirrhosis. Accordingly, surveillance is recommended in every patient with cirrhosis whatever the etiology, as well as in non-cirrhotic patients with chronic hepatitis C and advanced liver fibrosis F3, and in those patients with chronic HBV infection who present an increased risk of HCC (incidence of HCC in Asian or African adults with an active HBV infection, with or without family history of HCC, clearly exceeds this point [18]). Nevertheless, many authors have recently showed that the risk of developing HCC is not homogeneous and have suggested different tools to predict it. Regarding patients with chronic HCV infection, liver elastography seems to be a useful tool in order to stratify patients at risk of developing HCC (19,20). It is worthy to highlight that in those cases of HCV-related cirrhosis, the achievement of sustained virological response does not rid the risk of developing HCC after treatment (21) and therefore these patients should remain under surveillance. In those patients with HBV-related chronic infection, age, male sex, an increased liver stiffness, alcohol consumption and an increased viral load are associated with an increased risk of HCC (18,22-24). Among patients with alcoholic cirrhosis, low platelets count and age older than 55 years identifies the patients at high risk of HCC development (25). Finally, information about risk of developing HCC among those patients with non-alcoholic fatty liver disease (NAFLD) is scarce, particularly in those who have not developed cirrhosis yet. In addition, screening in this population is complicated by obesity and application of potentially curative treatments may be limited by the frequently associated comorbidities. Accordingly, no recommendation can be raised about screening programs in this group of patients.

Noninvasive diagnosis by imaging technics has been progressively refined, allowing a definitive diagnosis of HCC without any biopsy in a great amount of patients. Nevertheless, in those nodules under 2 cm, sensitivity of imaging techniques is about 50-60% (26-28) so in about 40-50% of cases a biopsy is mandatory. Some new strategies have been recently evaluated in order to increase sensitivity of noninvasive criteria. The presence of intralesional fat, hypointensity in venous-phases and the presence of a pseudocapsule have been analyzed. Unfortunately, these parameters do not significantly increase the diagnostic accuracy of MRI (29). Diffusion weighted imaging have shown a potential utility for HCC, but until now there are no prospective studies showing a relevant increase of the diagnostic accuracy (30,31). Organ specific contrast media have been also investigated (32). Despite the fact that retrospective studies have described promising results (33,34), there are no prospective studies showing a better performance comparing to conventional MRI contrast media.

 

Refining prognostic assessment and therapeutic decision

Once the diagnosis is established, prognostic evaluation is a crucial step in management of HCC. Taking into account that, in most cases, HCC raises in patients with underlying cirrhosis, and the fact that the severity of liver dysfunction determines therapeutic options and survival regardless of HCC, it is mandatory to consider both liver function and tumoral extent. In addition, the presence of cancer-related symptoms evaluated in an appropriate way with validated scales such as ECOG performance status (35) have shown a very important prognostic value and, as well as liver dysfunction, determines the applicability of different therapeutic options. Success of any staging system is based on the ability of linking the disease stage with the recommended treatment option. Multiple staging systems have been suggested during last 30 years; most of them do not take into account the presence (or not) of cancer related symptoms or evaluate tumoral extent roughly (36). Among all staging systems proposed until now, the most relevant and successful one has been Barcelona Clinic Liver Cancer (BCLC) staging system. Since its former publication in 1999 (37), BCLC classification has been continuously refined to its last version in 2014 (38), it has been externally validated (39-42) and because of its very well known predictive ability and its utility for clinical decision making, this staging system is the recommended one by the most relevant scientific societies (5,6,43,44). A new staging system called Hong Kong Liver Cancer (HKLC) staging system has been recently published. It was built based in a cohort of 3,856 patients treated in Hong Kong (45). The main singularity proposed by this group is the acceptance of surgical treatment in intermediate/advanced stage patients. However, HKLC classification has several and important limitations (46). One of the most important one is the fact that it has been constructed in a retrospective way and, because of this, those patients selected for surgical resection instead of transarterial chemoembolization (TACE) present certain peculiarities, which determine good prognosis, while those patients treated with TACE lack those favorable profile, inducing an important bias towards surgical resection (47).

The intermediate stage (BCLC-B) is formed by a heterogeneous group of patients. Aimed to refine the prognostic evaluation in this stage, Bolondi et al. have proposed a sub-classification of this intermediate stage in 4 subgroups attending to tumor stage, presence or not of cancer related symptoms and severity of liver dysfunction (48).

This sub-classification includes patients with a severe liver dysfunction. These patients, as it is clearly defined in the BCLC staging system, should be evaluated for liver transplantation and in those decompensated patients, the presence of HCC may become a contraindication criterion if tumor extent exceeds the criteria accepted for enlistment. Furthermore, they suggest not taking into account the presence of cancer related symptoms measured by ECOG-Performance status, issue that is clearly contradictory and inconsistent with studies published by the same authors showing the prognostic importance of having an impaired performance status (ECOG PS 1) in patients treated with chemoembolization (49). Another drawback is that, while in the BCLC staging system those solitary tumors without cancer related symptoms and with no dissemination must be considered as BCLC A, Bolondi proposes classifying these patients as BCLC B. Finally, this sub-classification has not been externally validated in European patients (50).

Despite the advantages of the BCLC system, there is room for further prognostic evaluation refinement. In this regard, several genetic expression profiles with prognostic significance have been suggested (51-57). However, to date, it has not been shown that the presence of a specific molecular pattern allows a concrete therapeutic decision.

Furthermore, the use of genetic information is clearly limited because of tumoral heterogeneity in HCC (58,59). Similarly, although some tumoral markers (mainly AFP), have shown an indisputable prognostic power (60-64), there is no consensus in terms of determining a pathological cutoff value, and these markers do not have enough strength to evaluate patients in an individual way and in most clinical scenarios, they do not induce a change in therapeutic approach (7). Therefore, one of the current challenges in clinical research is to try to integrate gene expression data in the current evaluation systems and basing the survival prediction and treatment indication in the molecular profile of the patient.

 

Improvements in the treatment of intermediate-advanced hcc

BCLC-B and BCLC-C stages have experienced many changes in last years, and are in those stages were the research has been most active. Based on two positive randomized-controlled trials and a latter meta-analysis, chemoembolization (TACE) is considered the first-line treatment in intermediate stage (65-67). However, this treatment has been evolving during last years and there are many aspects still to be investigated (68). For instance, which is the best chemotherapeutic and/or embolic agent is still under debate. One of the greatest advances in this field was the development of polyvinyl-alcohol spheres loaded with doxorubycin; these spheres slowly and selectively release intratumoral chemotherapy, minimizing adverse events related to systemic distribution of chemotherapy (69) and allowing a homogeneous and calibrated embolization.

Despite de fact that previous studies have shown an excellent radiological response (70) and promising overall survival (71,72), randomized trials have not been able to confirm in a definitive way advantages in terms of radiological response and overall survival using these spheres comparing to conventional TACE with lipiodol (73,74). Other relevant aspects are evaluating which is the best therapeutic scheme (fixed schedule or on demand taking into account the treatment response), how response must be assessed, or the most important aspect, when treatment failure and other therapeutic approaches should be considered. Recently, intractable progression concept has arisen and it is being now suggested. This concept is defined as the progression associated to a relevant tumor load, a not so important progression but linked to liver dysfunction, worsening of performance status or a technical contraindication (75,76). Based on this concept of intractable progression, various indexes have been recently generated, aimed to objectively decide when to interrupt TACE because of inefficiency or uselessness. Most of these indexes consider radiological response and liver function worsening as the main parameters for assessing TACE failure (77,79). Unfortunately, these indexes have not been externally validated and many of them are derived from cohorts of patients who initially were bad candidates for TACE. The main inconvenient of TACE is that the majority of patients develop disease progression despite good initial response. Aimed to decrease or delay tumor progression after TACE, the association of molecular agents with antiangiogenic effects such as sorafenib or brivanib with TACE has been evaluated; regrettably, this strategy has failed in demonstrating improvement in response rate, time to progression or overall survival (80,81).

One of the most promising treatments is radioembolization using Yttrium-90 spheres (82). Many prospective studies in different stages of HCC have shown safeness and radiological response, with an overall survival comparable to those treated with TACE or sorafenib (83-87). All this promising data is the rationale for conducting randomized clinical trials comparing radioembolization in combination or not with sorafenib versus sorafenib. Table I describes those main studies that are ongoing evaluating effectiveness of radioembolization in HCC.

 

table1

 

The HCC field that has experienced the most relevant advancements is systemic treatment. Progresses in the understanding the molecular alterations associated with tumor progression (88-90) have permitted the development of multiple agents acting specifically at level of the disrupted molecular pathways. Many molecular agents have been studied, but the only one that showed efficacy in terms of overall survival and time to progression has been sorafenib, as was revealed by two phase III, randomized-controlled studies (91,92). Those results have been prospectively confirmed in different clinical trials in which sorafenib was the control arm (93-97) as well as in multiple prospective studies in real life clinical practice (98-100). Furthermore, sorafenib is able to maintain its efficacy despite the etiology of liver disease, the baseline status of neoplasm, the presence or absence of cancer related symptoms or previous therapies (101).

Despite the success of sorafenib at advanced stage, there are still many aspects to be clarified. One of the most relevant issues is to identify those patients in whom sorafenib is inefficacious, and thus, to avoid the exposure of patients to an unnecessary toxicity. Nowadays there is enough evidence to discourage the use of sorafenib in patients with an advanced liver dysfunction (classified as Child-Pugh C) (99,102,103). In those patients Child-Pugh B, pharmacokinetic profile is not substantially modified and there is no evidence about a relevant increase of adverse events, but the impact on tumor progression may not lead to survival improvement because of liver dysfunction (99,104), and that is the reason why treating patients with such liver dysfunction must be individualized (105). Furthermore, some biomarkers and clinical characteristics at baseline or during the treatment have suggested being able to predict response to sorafenib. Biomarkers such as AFP, vascular endothelial growing factor (VEGF), angiopoietin-2 (ang-2), hepatocitary growing factor or c-Kit have shown a prognostic ability in patients with advanced HCC (63). Regrettably, as previously highlighted, there are no validated cutoffs for defining pathological values and, therefore, the use of these biomarkers does not contribute to the therapeutic decision. Much more interesting is the identification of some adverse events as predictors of favorable response. In that sense, developing diarrhea (106), arterial hypertension (AHT) (107) or dermatological adverse events (108-110) are associated with better outcomes. For instance, in a recently published prospective cohort, those patients who develop early dermatological adverse events within the first 60 days under sorafenib presented a longer median overall survival comparing to those who did not develop this adverse event (18.2 versus 10.1 months respectively; p < 0.009) and the occurrence of dermatological adverse events was identified as an independent prognostic factor for survival in the multivariate analysis with time-dependent variables. This association highlights the need of a close follow up of patients with the aim of adjusting doses if adverse events appear and, thus, avoiding unnecessary interruptions. The potential basis for the relationship between side effects and treatment efficacy is the genetic polymorphisms. In that regard, the impact of genetic polymorphisms of tumor necrosis factor alpha (TNF-α), interleukin-6 and guanine nucleotide binding protein 3 (GNB3) in inflammatory/immunological syndromes is very well known. For instance, G308A of TNF-α is associated with AHT, increased risk of coronary disease and a higher predisposition for vein thrombosis; C857T TNF-α is associated with psoriatic arthritis; IL-6 and C825T of GNB3 polymorphisms play a role in development of AHT. On the other hand, it is well known that hypoxia induced by sorafenib treatment may induce a proangiogenic compensatory response. Accordingly, there are several trials aimed to identify potential polymorphisms in genes associated with angiogenic response (VEGFA, ANGPT2 and PLA2G12A) that could allow us to recognize different patient's profiles in order to adjust treatment (111-113).

Finally, in those patients with an HCC in intermediate/advanced stage treated with sorafenib, the type of radiological progression has been identified as a statistically significant independent predictor of the post-progression survival (100,114). In that regard, the development of a new extrahepatic lesion or vascular invasion is the type of progression associated with the poorest prognosis.

The positive result of sorafenib was the demonstration of the usefulness of molecular therapies in HCC and it opened the door for assessing the potential efficacy of multiple pathways blockade, in the same way as it is done in other neoplasms. Until now, no other agent evaluated in phase 3, randomized-controlled trials in first (sunitinib, linifanib, brivanib) (93,94,115) or second line (brivanib, everolimus, ramucirumab) (116-118) alone or combined with sorafenib in first line (erlotinib) (95) has shown any benefit when compared with sorafenib.

The negative results of these clinical trials must make us to speculate why these agents, efficient in other neoplasms, have failed in HCC. First lesson we have learned is that many of them are too toxic for patients with cirrhosis. Therefore, before planning phase 2-3 trials, phase 1 trials in patients with cirrhosis in order to be able to determine the maximum tolerated dose is mandatory. Another learned lesson is that results coming from phase 1-2 trials are not informative enough to be able to predict efficacy in terms of survival. For instance, the clinical trial evaluating a combination of chemotherapeutic agents (PIAF) showed objective response but without impact in survival (119), or those clinical trials with sorafenib in which, despite the absence of objective response, increase of survival was pointed out (91,92), or, recently, clinical trials with linifanib (115) or brivanib (116) in which, despite an improvement in time to radiological progression, these studies were not able to demonstrate survival benefit. In addition, these trials have several selection biases, particularly those clinical trials evaluating second line agents. In the trial design and target population selection, it is mandatory to register those events appeared during sorafenib therapy. As discussed above, the pattern of radiological progression has a statistically significant impact on post-progression survival (100,114). In addition, second-line trials recruit patients who, despite sorafenib failure, have a preserved liver function and good general condition (ECOG-PS 0-1), and in many cases had presented adverse events linked to good prognosis (110). Therefore, this population probably presents a disease with a less malignant behavior. Finally, some trials have shown a potential efficacy in a specific population according to a concrete molecular profile (120). Taking into account the preliminary data, enrichment of these trials with those patients with such molecular profile is completely justified.

Despite the dispiriting results of the last five years, nowadays there are several ongoing clinical trials evaluating different agents that have shown promising results in preliminary studies (Table II). Among the different approaches, immune checkpoints blockade has disclosed promising results, as long as treatment with these molecules has shown an objective radiological response with an acceptable security profile. The potential benefit of this approach should be confirmed in larger, randomized trials (121,122). All these efforts will allow, in an immediate future, increasing therapeutic options for our HCC patients at advanced stage.

 

table2

 

References

1. Fact Sheets by Population-Globocan-IARC (Internet). Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.         [ Links ]

2. Sangiovanni A, Del Ninno E, Fasani P, et al. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 2004;126:1005-014. DOI: 10.1053/j.gastro.2003.12.049.         [ Links ]

3. Trinchet J-C, Bourcier V, Chaffaut C, et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 Cir-Vir prospective cohort). Hepatology.2015;62:737-50. DOI: 10.1002/hep.27743.         [ Links ]

4. Forner A, Ayuso C, Isabel Real M, et al. Diagnosis and treatment of hepatocellular carcinoma. Med Clin (Barc) 2009;132:272-87. DOI: 10.1016/j.medcli.2008.11.024.         [ Links ]

5. Bruix J, Sherman M. Management of hepatocellular carcinoma: An update. Hepatology 2011;53:1020-2. DOI: 10.1002/hep.24199.         [ Links ]

6. EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908-43. DOI: 10.1016/j.jhep.2011.12.001.         [ Links ]

7. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379:1245-55. DOI: 10.1016/S0140-6736(11)61347-0.         [ Links ]

8. Varela M, Reig M, De la Mata M, et al. Treatment approach of hepatocellular carcinoma in Spain. Analysis of 705 patients from 62 centers. Med Clin 2010;134:569-76. DOI: 10.1016/j.medcli.2009. 10.042.         [ Links ]

9. Singal AG, Nehra M, Adams-Huet B, et al. Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: Where did surveillance fail? Am J Gastroenterol 2013;108:425-32.         [ Links ]

10. Trevisani F, D'Intino PE, Morselli-Labate AM, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: Influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570-5. DOI: 10.1016/S0168-8278(00)00053-2.         [ Links ]

11. Marrero JA, Feng Z, Wang Y, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009;137:110-8. DOI: 10.1053/j.gastro.2009.04.005.         [ Links ]

12. Lok AS, Sterling RK, Everhart JE, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010;138:493-502. DOI: 10.1053/j.gastro.2009.10.031.         [ Links ]

13. Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol 2012;13:817-26. DOI: 10.1016/S1470-2045(12)70233-4.         [ Links ]

14. Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen 1999;6:108-10. DOI: 10.1136/jms.6.2.108.         [ Links ]

15. Lin XJ, Chong Y, Guo ZW, et al. A serum-microRNA classifier for the early detection of hepatocellular carcinoma: A multicenter and retrospective longitudinal repository study. Lancet Oncol 2015;16:804-15. DOI: 10.1016/S1470-2045(15)00048-0.         [ Links ]

16. Neumann PJ, Cohen JT, Weinstein MC. Updating Cost-Effectiveness - The Curious Resilience of the $50,000-per-QALY Threshold. N Engl J Med 2014;371:796-7.         [ Links ]

17. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: Lessons from history and study design issues. Semin Oncol 2010;37:202-15. DOI: 10.1053/j.seminoncol.2010.05.006.         [ Links ]

18. Yang HI, Yuen MF, Chan HL, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): Development and validation of a predictive score. Lancet Oncol 2011;12:568-74. DOI: 10.1016/S1470-2045(11)70077-8.         [ Links ]

19. Masuzaki R, Tateishi R, Yoshida H, et al. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 2009;49:1954-61. DOI: 10.1002/hep.22870.         [ Links ]

20. Singh S, Fujii LL, Murad MH, et al. Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:1573-84.e1-2; quiz e88-89. DOI: 10.1016/j.cgh.2013.07.034.         [ Links ]

21. Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies. Ann Intern Med 2013;158:329-37.         [ Links ]

22. Jung KS, Kim SU, Ahn SH, et al. Risk assessment of hepatitis B virus-related hepatocellular carcinoma development using liver stiffness measurement (FibroScan). Hepatology 2011;53:88594. DOI: 10.1002/hep.24121.         [ Links ]

23. Wong GL-H, Chan HL-Y, Wong CK-Y, et al. Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B. J Hepatol 2014;60:339-45.         [ Links ]

24. Kim MN, Kim SU, Kim BK, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology 2015;61:1851-9. DOI: 10.1002/hep.27735.         [ Links ]

25. Mancebo A, Gonzalez-Dieguez ML, Cadahia V, et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol 2012;11:95-101. DOI: 10.1016/j.cgh.2012.09.007.         [ Links ]

26. Forner A, Vilana R, Ayuso C, et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 2008;47:97-104. DOI: 10.1002/hep.21966.         [ Links ]

27. Sangiovanni A, Manini MA, Iavarone M, et al. The diagnostic and economic impact of contrast imaging technique in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 2010;59:638-44. DOI: 10.1136/gut.2009.187286.         [ Links ]

28. Khalili KT, Kim TK, Jang HJ, et al. Optimization of imaging diagnosis of 1-2 cm hepatocellular carcinoma: An analysis of diagnostic performance and resource utilization. J Hepatol 2011;54:723-8. DOI: 10.1016/j.jhep.2010.07.025.         [ Links ]

29. Rimola J, Forner A, Tremosini S, et al. Non-invasive diagnosis of hepatocellular carcinoma ≤ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI. J Hepatol 2012;56:1317-23. DOI: 10.1016/j.jhep.2012.01.004.         [ Links ]

30. Piana G, Trinquart L, Meskine N, et al. New MR imaging criteria with a diffusion-weighted sequence for the diagnosis of hepatocellular carcinoma in chronic liver diseases. J Hepatol 2011;55:126-32. DOI: 10.1016/j.jhep.2010.10.023.         [ Links ]

31. Vandecaveye V, De Keyzer F, Verslype C, et al. Diffusion-weighted MRI provides additional value to conventional dynamic contrast-enhanced MRI for detection of hepatocellular carcinoma. Eur Radiol 2009;19:2456-66. DOI: 10.1007/s00330-009-1431-5.         [ Links ]

32. Van Beers BE, Pastor CM, Hussain HK. Primovist, Eovist: What to expect? J Hepatol 2012;57:421-9.         [ Links ]

33. Granito A, Galassi M, Piscaglia F, et al. Impact of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance on the non-invasive diagnosis of small hepatocellular carcinoma: A prospective study. Aliment Pharmacol Ther 2013;37:355-63.         [ Links ]

34. Golfieri R, Renzulli M, Lucidi V, et al. Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to Dynamic MRI in the detection of hypovascular small (≤ 2 cm) HCC in cirrhosis. Eur Radiol 2011;21:1233-42.         [ Links ]

35. Sorensen JB, Klee M, Palshof T, et al. Performance status assessment in cancer patients. An inter-observer variability study. Br J Cancer 1993;67:773-5. DOI: 10.1038/bjc.1993.140.         [ Links ]

36. Forner A, Reig ME, de Lope CR, et al. Current strategy for staging and treatment: The BCLC update and future prospects. Semin Liver Dis 2010;30:61-74. DOI: 10.1055/s-0030-1247133.         [ Links ]

37. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-38.         [ Links ]

38. Reig M, Darnell A, Forner A, et al. Systemic therapy for hepatocellular carcinoma: The issue of treatment stage migration and registration of progression using the BCLC-refined RECIST. Semin Liver Dis 2014;34:444-55. DOI: 10.1055/s-0034-1394143.         [ Links ]

39. Cillo U, Bassanello M, Vitale A, et al. The critical issue of hepatocellular carcinoma prognostic classification: which is the best tool available? J Hepatol 2004;40:124-31.         [ Links ]

40. Grieco A, Pompili M, Caminiti G, et al. Prognostic factors for survival in patients with early-intermediate hepatocellular carcinoma undergoing non-surgical therapy: Comparison of Okuda, CLIP, and BCLC staging systems in a single Italian centre. Gut 2005;54:411-8. DOI: 10.1136/gut.2004.048124.         [ Links ]

41. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: Comparison of 7 staging systems in an American cohort. Hepatology 2005;41:707-716. DOI: 10.1002/hep.20636.         [ Links ]

42. Cabibbo G, Enea M, Attanasio M, et al. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010;51:1274-83. DOI: 10.1002/hep.23485.         [ Links ]

43. Ferenci P, Fried M, Labrecque D, et al. Hepatocellular carcinoma (HCC): A global perspective. J Clin Gastroenterol 2010;44:239-45. DOI: 10.1097/MCG.0b013e3181d46ef2.         [ Links ]

44. Verslype C, Rosmorduc O, Rougier P. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23Suppl7:vii41-8. DOI: 10.1093/annonc/mds225.         [ Links ]

45. Yau T, Tang VY, Yao T-J, et al. Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691-700. DOI: 10.1053/j.gastro.2014.02.032.         [ Links ]

46. Sherman M. Staging for hepatocellular carcinoma: Complex and confusing. Gastroenterology 2014;146:1599-602. DOI: 10.1053/j.gastro.2014.04.026.         [ Links ]

47. Forner A, Díaz-González A, Liccioni A, et al. Prognosis prediction and staging. Best Pract Res Clin Gastroenterol 2014;28:855-65.         [ Links ]

48. Bolondi L, Burroughs A, Dufour J-F, et al. Heterogeneity of patients with intermediate (BCLC B) hepatocellular carcinoma: Proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 2012;32:348-59.         [ Links ]

49. Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs. conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014;111:255-64. DOI: 10.1038/bjc.2014.199.         [ Links ]

50. Weinmann A, Koch S, Sprinzl M, et al. Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients. Liver Int 2015;35:591-600. DOI: 10.1111/liv.12696.         [ Links ]

51. Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res 2008;68:6779-88. DOI: 10.1158/0008-5472.CAN-08-0742.         [ Links ]

52. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008;359:1995-2004. DOI: 10.1056/NEJMoa0804525.         [ Links ]

53. Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69:7385-92. DOI: 10.1158/0008-5472.CAN-09-1089.         [ Links ]

54. Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004;40:667-76. DOI: 10.1002/hep.20375.         [ Links ]

55. Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007;45:42-52. DOI: 10.1002/hep.21467.         [ Links ]

56. Nault J-C, De Reyniès A, Villanueva A, et al. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology 2013;145:176-87. DOI: 10.1053/j.gastro.2013.03.051.         [ Links ]

57. Hoshida Y, Villanueva A, Sangiovanni A, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 2013;144:1024-30. DOI: 10.1053/j.gastro.2013.01.021.         [ Links ]

58. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-92. DOI: 10.1056/NEJMoa1113205.         [ Links ]

59. Fox EJ, Loeb LA. Cancer: One cell at a time. Nature 2014;512:143-4. DOI: 10.1038/nature13650.         [ Links ]

60. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200-7. DOI: 10.1016/S0168-8278(02)00360-4.         [ Links ]

61. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004;40:1352-60. DOI: 10.1002/hep.20465.         [ Links ]

62. Merani S, Majno P, Kneteman NM, et al. The impact of waiting list alpha-fetoprotein changes on the outcome of liver transplant for hepatocellular carcinoma. J Hepatol 2011;55:814-9. DOI: 10.1016/j.jhep.2010.12.040.         [ Links ]

63. Llovet JM, Peña CEA, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012;18:2290-300.         [ Links ]

64. Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: A model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143:985-6. DOI: 10.1053/j.gastro.2012.05.052.         [ Links ]

65. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002;359:1734-9. DOI: 10.1016/S0140-6736(02)08649-X.         [ Links ]

66. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164-71. DOI: 10.1053/jhep.2002.33156.         [ Links ]

67. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003;37:429-42. DOI: 10.1053/jhep.2003.50047.         [ Links ]

68. Forner A, Gilabert M, Bruix J, et al. Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol 2014;11:525-35.         [ Links ]

69. Forner A, Real MI, Varela M, et al. Transarterial chemoembolization for patients with hepatocellular carcinoma. Hepatol Res 2007;37Suppl2:S230-7. DOI: 10.1111/j.1872-034X.2007.00190.x.         [ Links ]

70. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: Efficacy and doxorubicin pharmacokinetics. J Hepatol 2007;46:474-81. DOI: 10.1016/j.jhep.2006.10.020.         [ Links ]

71. Burrel M, Llovet JM, Reig M, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012;56:1330-5. DOI: 10.1016/j.jhep.2012.01.008.         [ Links ]

72. Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: Five-year survival analysis. Cardiovasc Interv Radiol 2012;35:1119-28.         [ Links ]

73. Lammer J, Malagari K, Vogl T, Pilleul F, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: Results of the PRECISION V study. Cardiovasc Interv Radiol 2010;33:41-52.         [ Links ]

74. Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs. conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014;111:255-64. DOI: 10.1038/bjc.2014.199.         [ Links ]

75. Raoul J, Sangro B, Forner A, et al. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: Available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011;37:212-20. DOI: 10.1016/j.ctrv.2010.07.006.         [ Links ]

76. Bruix J, Reig M, Rimola J, et al. Clinical decision making and research in hepatocellular carcinoma: Pivotal role of imaging techniques. Hepatology 2011;54:2238-44. DOI: 10.1002/hep.24670.         [ Links ]

77. Hucke F, Sieghart W, Pinter M, et al. The ART-strategy: Sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE. J Hepatol 2014;60:118-26. DOI: 10.1016/j.jhep.2013.08.022.         [ Links ]

78. Hucke F, Pinter M, Graziadei I, et al. How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma. J Hepatol 2014;61:1287-96. DOI: 10.1016/j.jhep.2014.07.002.         [ Links ]

79. Adhoute X, Penaranda G, Naude S, et al. Retreatment with TACE: The ABCR SCORE, an aid to the decision-making process. J Hepatol 2015;62:855-62. DOI: 10.1016/j.jhep.2014.11.014.         [ Links ]

80. Lencioni R, LLovet J, Han G, et al. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate-stage hepatocellular carcinoma (HCC): Phase II, randomized, double-blind SPACE trial. J Clin Oncol 2012;30:abstrLBA154.         [ Links ]

81. Kudo M, Han G, Finn RS, et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology 2014;60:1697-1707. DOI: 10.1002/hep.27290.         [ Links ]

82. Sangro B, Inarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol 2012;56:464-73. DOI: 10.1016/j.jhep.2011.07.012.         [ Links ]

83. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71-81. DOI: 10.1002/hep.21980.         [ Links ]

84. Hilgard P, Hamami M, Fouly A El, et al. Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival. Hepatology 2010;52:1741-9. DOI: 10.1002/hep.23944.         [ Links ]

85. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: A comprehensive report of long-term outcomes. Gastroenterology 2010;138:52-64. DOI: 10.1053/j.gastro.2009.09.006.         [ Links ]

86. Sangro B, Carpanese L, Cianni R, et al. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: A European evaluation. Hepatology 2011;54:868-78. DOI: 10.1002/hep.24451.         [ Links ]

87. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: A phase 2 study. Hepatology 2013;57:1826-37. DOI: 10.1002/hep.26014.         [ Links ]

88. Villanueva A, Newell P, Chiang DY, et al. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007;27:55-76. DOI: 10.1055/s-2006-960171.         [ Links ]

89. Hanahan D, Weinberg A. Hallmarks of cancer: The next generation. Cell 2011;144:646-74. DOI: 10.1016/j.cell.2011.02.013.         [ Links ]

90. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science 2013;339:1546-58. DOI: 10.1126/science.1235122.         [ Links ]

91. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.         [ Links ]

92. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. DOI: 10.1016/S1470-2045(08)70285-7.         [ Links ]

93. Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: Results of a randomized phase III trial. J Clin Oncol 2013;31:4067-75. DOI: 10.1200/JCO.2012.45.8372.         [ Links ]

94. Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31:3517-24. DOI: 10.1200/JCO.2012.48.4410.         [ Links ]

95. Zhu AX, Rosmorduc O, Evans J, et al. SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC). Ann Oncol 2012;23(Suppl9):abstract LBA2.         [ Links ]

96. Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 2013;31:3501-8.         [ Links ]

97. Cainap C, Qin S, Huang W, et al. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2013;30(Suppl 34):abstr249.         [ Links ]

98. Iavarone M, Cabibbo G, Piscaglia F, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: A prospective multicenter study in Italy. Hepatology 2011;54:2055-63. DOI: 10.1002/hep.24644.         [ Links ]

99. Lencioni R, Kudo M, Ye S-L, et al. GIDEON (Global Investigation of therapeutic Decisions in hepatocellular carcinoma and Of its treatment with sorafeNib): Second interim analysis. Int J Clin Pract 2014;68:609-17.         [ Links ]

100. Reig M, Rimola J, Torres F, et al. Post-progression survival of patients with advanced hepatocellular carcinoma. Rationale for second line trial design. Hepatology 2013;58:2023-31. DOI: 10.1002/hep.26586.         [ Links ]

101. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. J Hepatol 2012;57:821-9. DOI: 10.1016/j.jhep.2012.06.014.         [ Links ]

102. Worns MA, Weinmann A, Pfingst K, et al. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J Clin Gastroenterol 2009;43:489-95. DOI: 10.1097/MCG.0b013e31818ddfc6.         [ Links ]

103. Pinter M, Sieghart W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist 2009;14:70-6. DOI: 10.1634/theoncologist.2008-0191.         [ Links ]

104. Abou-Alfa G, Amadori D, Santoro A, et al. Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? J Clin Oncol 2008;26:Abstract4518.         [ Links ]

105. Reig M, Matilla A, Bustamante J, et al. Recommendations for the management of sorafenib in patients with hepatocellular carcinoma. Gastroenterol Hepatol 2010;33:741-52. DOI: 10.1016/j.gastrohep.2010.05.007.         [ Links ]

106. Koschny R, Gotthardt D, Koehler C, et al. Diarrhea is a positive outcome predictor for sorafenib treatment of advanced hepatocellular carcinoma. Oncology 2013;84:613. DOI: 10.1159/000342425.         [ Links ]

107. Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: Hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol 2013;36:319-24.         [ Links ]

108. Vincenzi B, Santini D, Russo A, et al. Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010;15:85-92. DOI: 10.1634/theoncologist.2009-0143.         [ Links ]

109. Otsuka T, Eguchi Y, Kawazoe S, et al. Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib. Hepatol Res 2012;42:879-86.         [ Links ]

110. Reig M, Torres F, Rodríguez-Lope C, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol 2014;61:318-24. DOI: 10.1016/j.jhep.2014.03.030.         [ Links ]

111. Pietrowski D, Tempfer C, Bettendorf H, et al. Angiopoietin-2 polymorphism in women with idiopathic recurrent miscarriage. Fertil Steril 2003;80:1026-9. DOI: 10.1016/S0015-0282(03)01011-2.         [ Links ]

112. Samli H, Demir B, Ozgoz A, et al. Vascular endothelial growth factor gene 1154 G/A, 2578 C/A, 460 C/T, 936 C/T polymorphisms and association with recurrent pregnancy losses. Genet Mol Res 2012;11:4739-45. DOI: 10.4238/2012.December.17.6.         [ Links ]

113. Wang V, Rosen R, Meyerle C, et al. Suggestive association between PLA2G12A singlenucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age related macular degeneration. Mol Vis 2012;18: 2578-85.         [ Links ]

114. Iavarone M, Cabibbo G, Biolato M, et al. Predictors of survival of patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 2015;62:784-91. DOI: 10.1002/hep.27729.         [ Links ]

115. Cainap C, Qin S, Huang W-T, et al. Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-9.         [ Links ]

116. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: Results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31:3509-16. DOI: 10.1200/JCO.2012.47.3009.         [ Links ]

117. Zhu AX, Kudo M, Assenat E, et al. EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib. J Clin Oncol 2014;32:abstr172.         [ Links ]

118. Zhu AX, Park JO, Ryoo B-Y, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015;16:859-70. DOI: 10.1016/S1470-2045(15)00050-9.         [ Links ]

119. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005;97:1532-8. DOI: 10.1093/jnci/dji315.         [ Links ]

120. Santoro A, Rimassa L, Borbath I, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: A randomised, placebo-controlled phase 2 study. Lancet Oncol 2013;14:55-63.         [ Links ]

121. Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81-8. DOI: 10.1016/j.jhep.2013.02.022.         [ Links ]

122. Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009;49:124-32. DOI: 10.1002/hep.22626.         [ Links ]

 

 

Correspondence:
María Varela.
Hepatology Unit. Department of Digestive Diseases.
Hospital Universitario Central de Asturias.
Avda. de Roma, s/n. 33011 Oviedo, Asturias. Spain
e-mail: maria.varela.calvo@gmail.com

Received: 21-09-2015
Accepted: 24-10-2015