Anna Darnell

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)

Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib.

BACKGROUND & AIMS There are no clinical data/markers to predict improved survival in patients with hepatocellular carcinoma treated with sorafenib. Majority of sorafenib adverse events appear within the first 60 days of treatment and studies correlating them with outcome are needed. METHODS We prospectively studied 147 hepatocellular carcinoma patients (97% cirrhotic, 82% Child-Pugh A, BCLC-B 77, BCLC-C 69) treated with sorafenib. Follow-up included monthly clinical and laboratory monitoring and tumor staging at week 4 and every 8 weeks. RESULTS After a median follow up of 11.6 months (treatment duration 6.7 months), time to progression and overall survival were 5.1 and 12.7 months. All but one patient presented at least one adverse event (median time to appearance 56 days). Time dependent covariate analysis (HR [95% CI]) identified baseline performance status (2.86 [1.75 to 4.55], p<0.001), BCLC (1.69 [1.18 to 2.50], p = 0.005), and dermatologic adverse event requiring dose adjustment within the first 60 days (0.58 [0.36 to 0.92], p = 0.022) as independent predictors of better outcome. Other early adverse events did not have an impact in outcome. The predictive value of dermatologic adverse events for survival was confirmed by the landmark analysis (p = 0.0270). CONCLUSIONS Development of dermatologic adverse events within 60 days of sorafenib initiation is associated with better survival. Therefore, this should not to be taken as a negative event and discourage treatment maintenance. Likewise, second line clinical trials should be designed and/or evaluated considering this information to avoid significant bias.

Dual-energy CT: oncologic applications.

OBJECTIVE Dual-energy CT (DECT) is an innovative imaging technique that operates on the basic principle of application of two distinct energy settings that make the transition from CT attenuation-based imaging to material-specific or spectral imaging. The purpose of this review is to describe the use of DECT in oncology. CONCLUSION Applications of DECT in clinical practice are based on two capabilities: material differentiation and material identification and quantification. The capability of obtaining different material-specific datasets (iodine map, virtual unenhanced, and monochromatic images) in the same acquisition can improve lesion detection and characterization. This approach can also affect evaluation of the response to therapy and detection of oncology-related disorders. DECT is an innovative imaging technique that can dramatically affect the care of oncologic patients.

Liver Imaging Reporting and Data System with MR Imaging: Evaluation in Nodules 20 mm or Smaller Detected in Cirrhosis at Screening US

PURPOSE To evaluate the diagnostic accuracy of the Liver Imaging Reporting and Data System (LI-RADS) with magnetic resonance (MR) imaging for hepatic nodules 20 mm or smaller detected during ultrasonographic (US) surveillance in patients with cirrhosis. MATERIALS AND METHODS Between November 2003 and January 2010, patients with cirrhosis with a newly US-detected solitary hepatic nodule 20 mm or smaller were included in this institutional ethics committee-approved study. All patients provided written informed consent before the study; the need to obtain consent for reanalysis of the data was waived. Patients underwent MR imaging and fine-needle biopsy (the reference standard). Nodules without pathologic confirmation were followed up with MR imaging every 6 months. A LI-RADS category was retrospectively assigned to nodules seen at MR imaging. The diagnostic accuracy for each LI-RADS category was described by sensitivity, specificity, and positive and negative predictive values with 95% confidence intervals. RESULTS Final diagnoses of 133 nodules in 159 patients were as follows: 102 hepatocellular carcinomas (HCCs), three intrahepatic cholangiocarcinomas (ICCs), one neuroendocrine metastasis, and 27 benign lesions (median MR imaging follow-up, 95 months). None (0%) of five LI-RADS category 1 lesions, three (25%) of 12 category 2 lesions, 29 (69%) of 42 category 3 lesions, 24 (96%) of 25 category 4 lesions, and 44 (98%) of 45 category 5 lesions were HCCs. One category 3 lesion was ICC, one category 5 lesion was a neuroendocrine metastasis, and two (50%) of four lesions categorized as other malignancies were HCCs. In patients with nodules detected at surveillance US, LI-RADS category 4 criteria were as effective as category 5 criteria for HCC diagnosis. Combining both categories would improve sensitivity without impairing specificity or positive or negative predictive value for HCC diagnosis (42.3%, 98.2%, 97.8%, and 47.4% vs 65.4%, 96.4%, 97.1%, and 59.6%, respectively). CONCLUSION In patients with cirrhosis with US-detected nodules 20 mm or smaller, both LI-RADS category 4 and category 5 have high specificity for HCC. In addition, a relevant proportion of lesions categorized as LI-RADS category 2 or 3 or as other malignancies were HCCs. Thus, active diagnostic work-up, including biopsy to allow prompt treatment, is recommended in such patients. Online supplemental material is available for this article.

Systemic Therapy for Hepatocellular Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-Refined RECIST

Recent advancements have improved the management of patients with liver cancer. Results of studies have informed how to stage and decide the optimal treatment option for each patient with an adequate balance between risks and benefits. The Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy has been widely endorsed for this purpose. This is not a rigid system: One of the key aspects in the management of patients is the optimal timing for systemic treatment initiation and for declaring tumor progression and/or treatment failure. Some patients at intermediate or even early stage may be considered for systemic therapy as options of higher priority may have failed or may not be feasible. Sorafenib is the sole systemic agent that has shown efficacy in phase 3 trials. Other agents (sunitinib, brivanib, linifanib, everolimus, ramucirumab) have failed in terms of safety and/or survival benefit. Optimal sorafenib administration and adequate adherence of the patients are crucial requirements to obtain the benefits of the drug. Because development of adverse events has been shown to correlate with better outcome, careful dose adjustments should be in place while avoiding unnecessary treatment interruption. Furthermore, recent studies have shown that progression at imaging may not translate in poor prognosis and that treatment beyond progression may be considered if there is no option for a second-line research trial.In this review, the authors examine all of the controversial aspects that affect treatment initiation and maintenance, how response to treatment should be evaluated, and define the needs that are faced by current research.

Idiopathic portal hypertension: Natural history and long-term outcome

Idiopathic portal hypertension (IPH) is a rare cause of intrahepatic portal hypertension. Data on natural history and prognosis of IPH are limited. We sought to describe the complications and long‐tem outcome of IPH by retrospectively studying 69 biopsy‐proven cases of IPH. Mean duration of follow‐up was 6.7 ± 4.6 years. All patients had evidence of portal hypertension (PH) at diagnosis, and 42% were symptomatic. Variceal bleeding (VB) was the most common manifestation. In those without bleeding at diagnosis, 74% had varices at first endoscopy. In those with large varices, the 1‐year probability of first bleeding despite primary prophylaxis was 9%. The 1‐year probability of rebleeding was 22%. Ascites and hepatic encephalopathy was documented in 26% and 7% of patients, respectively, at least once during the clinical course. The 1‐year probability of developing portal vein thrombosis (PVT) was 9%, and 53% of patients receiving anticoagulation achieved recanalization. Human immunodeficiency virus (HIV) infection and VB at diagnosis were the independent predictors of PVT. Seven patients died (6 as a result of an IPH‐related cause) and 2 were transplanted. Probability of liver transplantation–free survival was 82% at 10 years. Presence of a severe associated disorder and ascites as a presenting symptom were associated with poor survival. Conclusion: Variceal bleeding is a major complication of IPH. Using, in IPH patients, the same management approach for PH as in cirrhosis is safe and maintains a low incidence of first bleeding and rebleeding in IPH patients. PVT is a frequent complication, particularly in those with HIV infection. Despite several complications, overall survival of patients with IPH is considerably good. (Hepatology 2014;59:2276–2285)

Imaging in clinical decision-making for portal vein thrombosis

Thrombosis of the portal venous system is a frequent and potentially life-threatening condition that can take place in a number of different clinical settings including liver cirrhosis, hepatocellular carcinoma, other solid tumours, abdominal septic foci, acute pancreatitis, haematological malignancies and congenital or acquired prothrombotic disorders. Clinical decision-making in patients with thrombosis of the portal venous system is a particularly complex process owing to the heterogeneity of the population affected by this condition and the lack of high-quality evidence from randomized controlled trials for the use of anticoagulation therapy in these patients. This Review discusses the available data regarding how imaging can provide assistance to physicians involved in this decision-making process in different clinical settings. A flowchart illustrating how to use imaging in this setting, based on current evidence and on the experience of the Vascular Liver Diseases Group of the Hospital Clinic in Barcelona, is also presented.

Nontumoral portal vein thrombosis in patients awaiting liver transplantation.

Portal vein thrombosis (PVT) occurs in approximately 2%‐26% of the patients awaiting liver transplantation (LT) and is no longer an absolute contraindication for LT. Nearly half of PVT cases are accidentally found during the LT procedure. The most important risk factor for PVT development in cirrhosis may be the severity of liver disease and reduced portal blood flow. Whether other inherited or acquired coagulation disorders also play a role is not yet clear. The development of PVT may have no effect on the liver disease progression, especially when it is nonocclusive. PVT may not increase the risk of wait‐list mortality, but it is a risk factor for poor early post‐LT mortality. Anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) are 2 major treatment strategies for patients with PVT on the waiting list. The complete recanalization rate after anticoagulation is approximately 40%. The role of TIPS to maintain PV patency for LT as the primary indication has been reported, but the safety and efficacy should be further evaluated. PVT extension and degree may determine the surgical technique to be used during LT. If a “conventional” end‐to‐end portal anastomotic technique is used, there is not a major impact on post‐LT survival. Post‐LT PVT can significantly reduce both graft and patient survival after LT and can preclude future options for re‐LT. Liver Transpl 22:352‐365, 2016.

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).

Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines

One of the key strategies to improve the prognosis of HCC, beside prevention, is to diagnose the tumor in early stages, when the patient is asymptomatic and the liver function is preserved, because in this clinical situation effective therapies with survival benefit can be applied. Imaging techniques are a key tool in the surveillance and diagnosis of HCC. Screening should be based in US every 6 months and non-invasive diagnostic criteria of HCC based on imaging findings on dynamic-MR and/or dynamic-CT have been validated and thus, accepted in clinical guidelines. The typical vascular pattern depicted by HCC on CT and or MRI consists on arterial enhancement, stronger than the surrounding liver (wash-in), and hypodensity or hyposignal intensity compared to the surrounding liver (wash-out) in the venous phase. This has a sensitivity of around 60% with a 96-100% specificity. Major improvements on liver imaging have been introduced in the latest years, adding functional information that can be quantified: the use of hepatobiliary contrast media for liver MRI, the inclusion of diffusion-weighted sequences in the standard protocols for liver MRI studies and new radiotracers for positron-emission tomography (PET). However, all them are still a matter of research prior to be incorporated in evidence based clinical decision making. This review summarizes the current knowledge about imaging techniques for the early diagnosis and staging of HCC, and it discusses the most relevant open questions.