María Reig

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.

Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma

Evidence-based management of patients with hepatocellular carcinoma (HCC) is key to their optimal care. For individuals at risk for HCC, surveillance usually involves ultrasonography (there is controversy over use of biomarkers). A diagnosis of HCC is made based on findings from biopsy or imaging analyses. Molecular markers are not used in diagnosis or determination of prognosis and treatment for patients. The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system. Patients with single liver tumors or as many as 3 nodules ≤3 cm are classified as having very early or early-stage cancer and benefit from resection, transplantation, or ablation. Those with a greater tumor burden, confined to the liver, and who are free of symptoms are considered to have intermediate-stage cancer and can benefit from chemoembolization if they still have preserved liver function. Those with symptoms of HCC and/or vascular invasion and/or extrahepatic cancer are considered to have advanced-stage cancer and could benefit from treatment with the kinase inhibitor sorafenib. Patients with end-stage HCC have advanced liver disease that is not suitable for transplantation and/or have intense symptoms. Studies now aim to identify molecular markers and imaging techniques that can detect patients with HCC at earlier stages and better predict their survival time and response to treatment.

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

Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study

PURPOSE We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib. PATIENTS AND METHODS Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade ≥3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.

Postprogression survival of patients with advanced hepatocellular carcinoma: Rationale for second‐line trial design

Sorafenib improves overall survival (OS) of patients with hepatocellular carcinoma (HCC) in the absence of objective response. Thus, time to tumor progression (TTP) is used to capture benefits of novel molecular agents, but proof of its surrogacy with survival is lacking. Furthermore, survival predictors upon progression are not established and there is a need to characterize postprogression survival (PPS) and assess with time‐dependent covariates analysis if it is influenced by progression pattern, and not solely by simultaneous impairment of liver function and performance status. We prospectively followed HCC patients treated with sorafenib. Clinical and biochemical evaluation were done every 4 weeks. Radiologic assessment of progression was done at week 4 and then every 8 weeks using RECIST 1.1. The progression pattern was divided into: intrahepatic/extrahepatic increase in tumor size, new intrahepatic lesion, and new extrahepatic lesion (NEH). We included 147 patients (hepatitis C virus [HCV] 57.1%, performance status [PS] 0 83.6%, Child‐Pugh A 82.3%, and BCLC‐C 47.3%). The median OS was 12.7 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were: baseline BCLC 2.49 [1.66‐3.73], PS 1.86 [1.12‐3.10], registration during follow‐up of Child‐Pugh B or Child‐Pugh C scores (2.36 [1.51‐3.69] and 2.89 [1.62‐5.15], respectively), definitive sorafenib interruption 2.48 [1.54‐4.01], and TTP 3.39 [1.89‐6.1]. The presence of NEH 2.42 [1.32‐4.44] is also an independent predictor of OS and PPS in patients with radiologic progression. Conclusion: Tumor progression is a surrogate of survival but its impact varies according to progression pattern. Thus, PPS is influenced by progression pattern and this is key in prognostic prediction and second‐line trial design and analysis. (Hepatology 2013; 58:2023–2031)

Non-invasive diagnosis of hepatocellular carcinoma ⩽2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI

BACKGROUND & AIMS To prospectively assess the diagnostic accuracy of the incorporation of additional magnetic resonance imaging (MRI) parameters in those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5 and 20mm, detected during surveillance in patients with cirrhosis. METHODS Between November 2003 and January 2010, we prospectively included 159 cirrhotic patients with a newly detected solitary nodule between 5 and 20mm in diameter by screening ultrasonography (US). Hepatic MRI and fine-needle biopsy were performed in all patients. RESULTS Final diagnoses were hepatocellular carcinoma (HCC) (n=103), other malignant lesions (intrahepatic cholangiocarcinoma/metastases) (n=4), and benign lesions (n=52). The specific enhancement pattern (arterial enhancement followed by washout) yielded a sensitivity and specificity of 58.3% and 96.4%, respectively. Peritumoral capsule was present in 43 HCC and in 2 non-HCC lesions. Intralesional fat was detected in 24 nodules; 5 nodules were non-HCC. Finally, the presence of both capsule and fat was observed in 10 cases, all of them HCC (100% specificity), but all of them also displayed the specific enhancement pattern, thus adding no sensitivity or specificity. CONCLUSIONS Conclusive non-invasive diagnosis of HCC in cirrhosis should be based only on the contrast enhancement pattern, while other characteristics at MRI do not increase the diagnostic accuracy.

Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma

Background and aims Conventional pathological analysis fails to achieve sufficient sensitivity and specificity for the diagnosis of hepatocellular carcinoma (HCC) in small nodules. Immunohistochemical staining for glypican 3 (GPC3), heat shock protein 70 (HSP70) and glutamine synthetase (GS) has been suggested to allow a confident diagnosis but no prospective study has established the diagnostic accuracy of this approach. The aim of this study is to assess prospectively the diagnostic accuracy of a panel of markers (GPC3, HSP70, GS) for the diagnosis of HCC in patients with cirrhosis with a small (5–20 mm) nodule detected by ultrasound screening. Methods Sixty patients with cirrhosis with a single nodule 5–20 mm newly detected by ultrasound were included in the study. Contrast-enhanced ultrasound, magnetic resonance and fine needle biopsy of the nodule (gold standard) were performed; the biopsy was repeated in case of diagnostic failures. Three consecutive sections of the first biopsy sample with meaningful material were stained with antibodies against GPC3, HSP70 and GS. Results Forty patients were diagnosed with HCC. The sensitivity and specificity for HCC diagnosis were: GPC3 57.5% and 95%, HSP70 57.5% and 85%, GS 50% and 90%, respectively. The sensitivity and specificity of the different combinations were: GPC3+HSP70 40% and 100%; GPC3+GS 35% and 100%; HSP70+GS 35% and 100%; GPC3+HSP70+GS 25% and 100%. When at least two of the markers were positive (regardless of which), the sensitivity and specificity were 60% and 100%, respectively. Conventional pathological analysis yielded three false negative results, but the addition of this panel only correctly classified one of these cases as HCC. Conclusion These data within a prospective study establish the clinical usefulness of this panel of markers for the diagnosis of early HCC. However, the panel only slightly increases the diagnostic accuracy in an expert setting.