Carlos Rodríguez de Lope

Current Strategy for Staging and Treatment: The BCLC Update and Future Prospects

Staging and treatment indication are relevant topics in the management of patients with hepatocellular carcinoma (HCC) and for optimal results, they have to take into account liver function, tumor stage, and physical status. For any staging system to be meaningful it has to link staging with treatment indication; this should be based on robust scientific data. Currently, the sole proposal that serves both aims is the Barcelona Clinic Liver Cancer (BCLC) approach. It takes into account the relevant parameters of all important dimensions and divides patients into very early/early, intermediate, advanced, and end-stage. Early-stage HCC patients should be considered for potentially curative options such as resection, ablation, and transplantation. Patients at intermediate stage benefit from chemoembolization, whereas patients at an advanced stage, or who cannot benefit from options of higher priority, have sorafenib as the standard treatment. Finally, patients at end-stage should merely receive palliative care.

Management of HCC.

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia, the management of which has significantly improved during the last few years. A better knowledge of the natural history of the tumor and the development of staging systems that stratify patients according to the characteristics of the tumor, the liver disease, and the performance status, such as the BCLC (Barcelona Clinic Liver Cancer) system, have led to a better prediction of prognosis and to a most appropriate treatment approach. Today curative therapies (resection, transplantation, ablation) can improve survival in patients diagnosed at an early HCC stage and offer a potential long-term cure. Patients with intermediate stage HCC benefit from chemoembolization and those diagnosed at advanced stage benefit from sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects. In this article we review the current management in HCC and the new advances in this field.

Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?

Evaluation of response to treatment is a key aspect in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) are used in most oncology trials, but those criteria evaluate only unidimensional tumor measurements and disregard the extent of necrosis, which is the target of all effective locoregional therapies. Therefore, the European Association for the Study of the Liver (EASL) guidelines recommended that assessment of tumor response should incorporate the reduction in viable tumor burden. The current report provides an assessment of the agreement/concordance between both RECIST and the EASL guidelines for the evaluation of response to therapy.

Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study†

Epidemiology, risk factors, and clinical effect of infections by multiresistant bacteria in cirrhosis are poorly known. This work was a prospective evaluation in two series of cirrhotic patients admitted with infection or developing infection during hospitalization. The first series was studied between 2005 and 2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011 (162 bacterial infections in 110 patients). In the first series, 32% of infections were community acquired (CA), 32% healthcare associated (HCA), and 36% nosocomial. Multiresistant bacteria (92 infections; 18%) were isolated in 4%, 14%, and 35% of these infections, respectively (P < 0.001). Extended‐spectrum β‐lactamase‐producing Enterobacteriaceae (ESBL‐E; n = 43) was the main multiresistant organism identified, followed by Pseudomonas aeruginosa (n = 17), methicillin‐resistant Staphylococcus aureus (n = 14), and Enterococcus faecium (n = 14). The efficacy of currently recommended empirical antibiotic therapy was very low in nosocomial infections (40%), compared to HCA and CA episodes (73% and 83%, respectively; P < 0.0001), particularly in spontaneous bacterial peritonitis, urinary tract infection, and pneumonia (26%, 29%, and 44%, respectively). Septic shock (26% versus 10%; P < 0.0001) and mortality rate (25% versus 12%; P = 0.001) were significantly higher in infections caused by multiresistant strains. Nosocomial origin of infection (hazard ratio [HR], 4.43), long‐term norfloxacin prophylaxis (HR, 2.69), recent infection by multiresistant bacteria (HR, 2.45), and recent use of β‐lactams (HR, 2.39) were independently associated with the development of multiresistant infections. Results in the second series were similar to those observed in the first series. Conclusions: Multiresistant bacteria, especially ESBL‐producing Enterobacteriaceae, are frequently isolated in nosocomial and, to a lesser extent, HCA infections in cirrhosis, rendering third‐generation cephalosporins clinically ineffective. New antibiotic strategies tailored according to the local epidemiological patterns are needed for the empirical treatment of nosocomial infections in cirrhosis. (HEPATOLOGY 2012)

Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design.

BACKGROUND & AIMS Transarterial chemoembolisation (TACE) improves survival of properly selected patients with hepatocellular carcinoma (HCC). Drug eluting beads (DEB) provide a calibrated and homogenous procedure while increasing efficacy. Outcome data applying this technology is lacking, and this is instrumental for clinical decision-making and for trial design. We evaluated the survival of HCC patients treated with DEB-TACE following a strict selection (preserved liver function, absence of symptoms, extrahepatic spread or vascular invasion). METHODS We registered baseline characteristics, the development of treatment-related adverse events, and the overall survival of all HCC patients treated by DEB-TACE from February 2004 to June 2010. RESULTS One hundred and four patients were treated with DEB-TACE. All but one were cirrhotic, 62.5% HCV+, 95% Child-Pugh A, 41 BCLC-A and 63 BCLC-B. Causes of DEB-TACE treatment in BCLC-A patients were: 35 unfeasible ablation, and six post-treatment recurrences. After a median follow-up of 24.5 months, 38 patients had died, two patients had received transplantation and 24 had received sorafenib because of untreatable tumour progression. Median survival of the cohort was 48.6 months (95% CI: 36.9-61.2), while it was 54.2 months in BCLC stage A and 47.7 months in stage B. Median survival after censoring follow-up at time of transplant/sorafenib was 47.7 (95%CI: 37.9-57.5) months. CONCLUSIONS These data validate the safety of DEB-TACE and show that the survival expectancy applying current selection criteria and technique is better than that previously reported. A 50% survival at 4 years should be considered when suggesting treatment for patients fitting into controversial scenarios such as expanded criteria for transplantation/resection for multifocal HCC.

Cholangiocarcinoma in cirrhosis: Absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma

This study assesses the magnetic resonance (MR) features of intrahepatic cholangiocarcinoma (ICC) in patients with cirrhosis with specific analysis of the contrast enhancement pattern. Cholangiocarcinoma may show increased contrast uptake in the arterial phase, and, if washout in the delayed venous phase were to be detected, the noninvasive diagnostic criteria proposed in the American Association for the Study of Liver Diseases guidelines would be refuted. We reviewed the MR findings of 25 patients with cirrhosis with 31 histologically confirmed ICC nodules. Signal intensity on basal T1‐weighted and T2‐weighted images and characteristics of enhancement after contrast administration on arterial, portal, and delayed phase were registered. Enhancement pattern was defined according to the behavior of the lesions in each phase, and dynamic pattern was described according to the progression of enhancement throughout the different phases. The most frequent pattern displayed by ICC was a progressive contrast uptake (80.6%). Stable contrast enhancement was registered in 19.4%. None of the ICCs showed a washout pattern, a profile that is specific for hepatocellular carcinoma (HCC). The ICC dynamic behavior differed significantly according to tumor size: progressive enhancement pattern was the most frequent (20 of 25 cases) in lesions larger than 20 mm, whereas the stable pattern was mainly identified in nodules smaller than 20 mm. The most characteristic MR contrast pattern in ICC in cirrhosis is a progressive contrast uptake throughout the different phases, whereas contrast washout at delayed phases is not observed. Because stable enhancement pattern without washout also can be registered in small HCC nodules, the evaluation of delayed phase is mandatory for a proper nodule characterization. If washout is not registered, a biopsy should be mandatory for diagnosis. (HEPATOLOGY 2009.)

Intrahepatic peripheral cholangiocarcinoma in cirrhosis patients may display a vascular pattern similar to hepatocellular carcinoma on contrast-enhanced ultrasound.

The aim of this study was to describe the imaging features by contrast‐enhanced ultrasound (CEUS) of intrahepatic cholangiocarcinoma (ICC) in cirrhosis patients. We registered the CEUS images of cirrhosis patients with histologically confirmed ICC. In all cases magnetic resonance imaging (MRI) was done to confirm the diagnosis and/or staging purposes. A total of 21 patients met all the criteria to be included in the study. The median nodule size was 32 mm. All nodules showed contrast enhancement at arterial phase; in 10 cases it was homogeneous and in 11 cases peripheral (rim‐like). All nodules displayed washout during the venous phases; it appeared during the first 60 seconds in 10 nodules, between 60‐120 seconds in five cases, and in six cases after 2 minutes. Ten nodules (five larger than 2 cm) displayed homogeneous contrast uptake followed by washout and they correspond to the specific pattern of hepatocellular carcinoma according to the American Association for the Study of Liver Diseases criteria. However, none of these lesions displayed washout on MRI. Conclusion: CEUS should not be used as the sole imaging technique for conclusive hepatocellular carcinoma diagnosis and if the MRI does not display the diagnostic vascular pattern, a confirmatory biopsy is mandatory. Hepatology 2010;51:2020–2029

Treatment of early hepatocellular carcinoma: Towards personalized therapy

In recent years, the wide implementation of surveillance programs has led to diagnose HCC at earlier stages, when curative options can be applied. In order to obtain the best results, treatment indication should take into account the estimation of baseline life expectancy. Patients at an early stage are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A-B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses with potential long-term cure, as reflected by a 5 years survival superior to 50-70%. These include surgical resection, liver transplantation and ablation. We briefly reviewed therapeutic management for early HCC, taking into account that any recommendation should be delivered in the clinical setting and based on an individualised evaluation of each patient.

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child‐Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612‐622).

Tratamiento del carcinoma hepatocelular avanzado

In the last few years, much progress has been made in the diagnosis and treatment of hepatocellular carcinoma (HCC). Due to these advances, HCC is no longer regarded as a disease with an extremely poor prognosis and has become the focus of some of the most active basic and clinical research in recent years. The most important advance is possibly the demonstration that sorafenib, a multikinase inhibitor with antiproliferative and antiangiogenic properties, is an effective treatment, able to increase survival in patients with advanced-stage HCC. This increased survival has demonstrated that these drugs, which act selectively on the molecular pathways involved in tumoral progression, can be effective in the treatment of HCC and has opened the door to the evaluation of these molecular agents, alone or in combination, in HCC. The present article provides a review of the treatment of advanced-stage HCC, with special emphasis on the distinct agents that are currently under evaluation.