Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents one of the most common neoplasms worldwide. Surgical resection and local ablative therapies represent the most frequent first lines therapies adopted when liver transplantation can not be offered or is not immediately accessible. Hepatic resection (HR) is currently considered the most curative strategy, but in the last decade local ablative therapies have started to obtain satisfactory results in term of efficacy and, of them, radiofrequency ablation (RFA) is considered the reference standard. An extensive literature review, from the year 2000, was performed, focusing on results coming from studies that directly compared HR and RFA. Qualities of the studies, characteristics of patients included, and patient survival and recurrence rates were analyzed. Except for three randomized controlled trials (RCT), most studies are affected by uncertain methodological approaches since surgical and ablated patients represent different populations as regards clinical and tumor features that are known to affect prognosis. Unfortunately, even the available RCTs report conflicting results. Until further evidences become available, it seems reasonable to offer RFA to very small HCC (< 2 cm) with no technical contraindications, since in this instance complete necrosis is most likely to be achieved. In larger nodules, namely > 2 cm and especially if > 3 cm, and/or in tumor locations in which ablation is not expected to be effective or safe, surgical removal is to be preferred.

Current concepts in hepatic resection for hepatocellular carcinoma in cirrhotic patients

Hepatocellular carcinoma(HCC) is one of the most frequent neoplasms worldwide and in most cases it is associated with liver cirrhosis.Liver resection is considered the most potentially curative therapy for HCC patients when liver transplantation is not an option or is not immediately accessible.This review is aimed at investigating the current concepts that drive the surgical choice in the treatment of HCC in cirrhotic patients;Eastern and Western perspectives are highlighted.An extensive literature review of the last two decades was performed,on topics covering various aspects of hepatic resection.Early post-operative and long-term outcome measures adopted were firstly analyzed in an attempt to define an optimal standardization useful for research comparison.The need to avoid the development of post-hepatectomy liver failure represents the "conditio sine qua non" of surgical choice and the role of the current tools available for the assessment of liver function reserve were investigated.Results of hepatic resection in relationship with tumor burden were compared with those of available competing strategies,namely,radiofrequency ablation for early stages,and trans-arterial chemoembolization for intermediate and advanced stages.Finally,the choice for anatomical versus non-anatomical,as well as the role of laparoscopic approach,was overviewed.The literature review suggests that partial hepatectomy for HCC should be considered in the context of multi-disciplinary evaluation of cirrhotic patients.Scientific research on HCC has moved,in recent years,from surgical therapy toward non-surgical approaches and most of the literature regarding topics debated in the present review is represented by observational studies,whereas very few well-designed randomized controlled trials are currently available;thus,no robust recommendations can be derived.

Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma(HCC) since 2007 and numerous studieshave investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.

Prognostic factors for hepatocellular carcinoma recurrence

The recurrence of hepatocellular carcinoma,the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide,represents an important clinical problem,since it may occur after both surgical and medical treatment.The recurrence rate involves 2 phases:an early phase and a late phase.The early phase usually occurs within 2 years after resection;it is mainly related to local invasion and intrahepatic metastases and,therefore,to the intrinsic biology of the tumor.On the other hand,the late phase occurs more than 2 years after surgery and is mainly related to de novo tumor formation as a consequence of the carcinogenic cirrhotic environment.Since recent studies have reported that early and late recurrences may have different risk factors,it is clinically important to recognize these factors in the individual patient as soon as possible.The aim of this review was,therefore,to identify predicting factors for the recurrence of hepatocellularcarcinoma,by means of invasive and non-invasive methods,according to the different therapeutic strategies available.In particular the role of emerging techniques(e.g.,transient elastography)and biological features of hepatocellular carcinoma in predicting recurrence have been discussed.In particular,invasive methods were differentiated from non-invasive ones for research purposes,taking into consideration the emerging role of the genetic signature of hepatocellular carcinoma in order to better allocate treatment strategies and surveillance follow-up in patients with this type of tumor.

Surveillance for early diagnosis of hepatocellular carcinoma: How best to do it?

Surveillance for hepatocellular carcinoma(HCC)is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy.Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments.Repetition of liver ultrasonography(US)every 6 mo is the recommended surveillance program to detect early HCCs,and a positive US has to entrain a well-defined recall policy based on contrast-enhanced,dynamic radiological imaging or biopsy for the diagnosis of HCC.Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance,the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure.Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC.The promotion of specific educational programs for practitioners,clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.

Liver function impairment in liver transplantation and after extended hepatectomy

Extended hepatectomy,or liver transplantation of reduced-size graft,can lead to a pattern of clinical manifestations,namely"post-hepatectomy liver failure"and"small-for-size syndrome"respectively,that can range from mild cholestasis to irreversible organ non-function and death of the patient.Many mechanisms are involved in their occurrence but in the recent past,high portal blood flow through a relatively small liver vascular bed has taken a central role.Therefore,several techniques of inflow modulation have been attempted in cases of portal hyperperfusion first in liver transplantation,such as portocaval shunt,mesocaval shunt,splenorenal shunt,splenectomy or ligation of the splenic artery.However,high portal flow is not the only factor responsible,and before major liver resections,preoperative assessment of the residual liver function is necessary.Techniques such as portal vein embolization or portal vein ligation can be adopted to increase the future liver volume,preventing posthepatectomy liver failure.More recently,a new surgical procedure,that combines in situ splitting of the liver and portal vein ligation,has gradually come to light,inducing remarkable hypertrophy of the healthy liver in just a few days.Further studies are needed to confirm this hypothesis and overcome one of the biggest issues in the field of liver surgery.

Prophylaxis for venous thromboembolism after resection of hepatocellular carcinoma on cirrhosis: Is it necessary?

AIM: To assess the safety and effectiveness of prophylaxis for venous thromboembolism (VTE) in a large population of patients with hepatocellular carcinoma (HCC) on cirrhosis.METHODS: Two hundred and twenty nine consecutive cirrhotic patients with HCC who underwent hepatic resection were retrospectively evaluated to assess whether there was any difference in the incidence of thrombotic or hemorrhagic complications between those who received and those who did not receive prophylaxis with low-molecular weight heparin.Differences and possible effects of the following parameters were investigated: age,sex,Child-Pugh and model for end-stage liver disease (MELD) score,platelet count,presence of esophageal varices,type of hepatic resection,duration of surgery,intraoperative transfusion of blood and fresh frozen plasma (FFP),body mass index,diabetes and previous cardiovascular disease.RESULTS: One hundred and fifty seven of 229 (68.5%) patients received antithromboembolic prophylaxis (group A) while the remaining 72 (31.5%) patients did not (group B).Patients in group B had higher Child-Pugh and MELD scores,lower platelet counts,a higher prevalence of esophageal varices and higher requirements for intraoperative transfusion of FFP.The incidence of VTE and postoperative hemorrhage was 0.63% and 3.18% in group A and 1.38% and 1.38% in group B,respectively;these differences were not significant.None of the variables analyzed including prophylaxis proved to be risk factors for VTE,and only the presence of esophageal varices was associated with an increased risk of bleeding.CONCLUSION: Prophylaxis is safe in cirrhotic patients without esophageal varices;the real need for prophylaxis should be better assessed.

Liver transplantation for hepatic tumors:a systematic review

Improvements in the medical and pharmacological management of liver transplantation(LT)recipients have led to a better long-term outcome and extension of the indications for this procedure.Liver tumors are relevant to LT;however,the use of LT to treat malignancies remains a debated issue because the high risk of recurrence.In this review we considered LT for hepatocellular carcinoma(HCC),cholangiocarcinoma(CCA),liver metastases(LM)and other rare tumors.We reviewed the literature,focusing on the past 10 years.The highly selected Milan criteria of LT for HCC(single nodule<5 cm or up to 3 nodules<3cm)have been recently extended by a group from the University of S.Francisco(1 lesion<6.5 cm or up to3 lesions<4.5 cm)with satisfying results in terms of recurrence-free survival and the"up-to-seven criteria".Moreover,using these criteria,other transplant groups have recently developed downstaging protocols,including surgical or loco-regional treatments of HCC,which have increased the post-operative survival of recipients.CCA may be treated by LT in patients who cannot undergo liver resection because of underlying liver disease or for anatomical technical challenges.A well-defined protocol of chemoirradiation and staging laparotomy before LT has been developed by the Mayo Clinic,which has resulted in long term diseasefree survival comparable to other indications.LT for LM has also been investigated by multicenter studies.It offers a real benefit for metastases from neuroendocrine tumors that are well differentiated and when a major extrahepatic resection is not required.If LT is an option in these selected cases,liver metastases from colorectal cancer is still a borderline indication because data concerning the disease-free survival are still lacking.Hepatoblastoma and hemangioendothelioma represent rare primary tumors for which LT is often the only possible and effective cure because of the frequent multifocal,intrahepatic nature of the disease.LT is a very promising procedure for both primary and secondary liver malignancies;however,it needs an accurate evaluation of the costs and benefits for each indication to balance the chances of cure with actual organ availability.

Liver grafts from hepatitis B surface antigen-positive donors: A review of the literature

The scarcity of available organs and the gap between supply and demand continue to be the main limitations of liver transplantation. To relieve the organ shortage, current transplant strategies have implemented extended criteria, which include the use of liver from patients with signs of past or present hepatitis B virus(HBV) infection. While the use of liver grafts from donors with evidence of past HBV infection is quite limited, some data have been collected regarding the feasibility of transplanting a liver graft from a hepatitis B surface antigen(HBs Ag) positive donor. The aim of the present work was to review the literature regarding liver transplants from HBs Ag-positive donors. A total of 17 studies were identified by a search in Medline. To date, HBs Ag positive grafts have preferentially been allocated to HBs Ag positive recipients. The large majority of these patients continue to be HBs Ag positive despite the use of immunoglobulin, and infection prevention can only be guaranteed by using antiviral prophylaxis. Although serological persistence is evident, no significant HBV-related disease has been observed, except in patients coinfected with delta virus. Consistently less data are available for HBs Ag negative recipients, although they are mostly promising. HBs Agpositive grafts could be an additional organ source for liver transplantation, provided that the risk of reinfection/reactivation is properly prevented.

Long term follow-up and outcome of liver transplantation from hepatitis B surface antigen positive donors

Liver transplant for hepatitis B virus(HBV) currently yields excellent outcomes: it allows to rescue patients with an HBV-related advanced liver disease, resulting in a demographical modification of the waiting list for liver transplant. In an age of patient-tailored treatments, in liver transplantation as well the aim is to offer the best suitable graft to the patient who can benefit from it, also expanding the criteria for organ acceptance and allocation. With the intent of developing strategies to increase the donor pool, we set-up a multicenter study involving 3 Liver Transplant Centers in Italy: patients undergoing liver transplantation between March 03, 2004, and May 21, 2010, were retrospectively evaluated. 1408 patients underwent liver transplantation during the study period, 28(2%) received the graft from hepatitis B surface antigen positive(HBs Ag)-positive deceased donors. The average follow-up after liver transplantation was 63.7 mo [range: 0.1-119.4; SD ± 35.8]. None Primary nonfunction, re-liver transplantation, early or late hepatic artery thrombosis occurred. The 1-, 3-and 5-year graft and patient survival resulted of 85.7%, 82.1%, 78.4%. Our results suggest that the use of HBs Agpositive donors liver grafts is feasible, since HBV can be controlled without affecting graft stability. However, the selection of grafts and the postoperative antiviral therapy should be managed appropriately.

The impact of extent of pancreatic and venous resection on survival for patients with pancreatic cancer

Background:Borderline resectable pancreatic cancer may require extended resections in order to achieve tumor-free margins,especially in the case of up-front resections,but it is important to know the limits of surgical therapy in this disease.This study aimed to investigate the impact of extent of pancreatic and venous resection on short-and long-term outcomes in patients with pancreatic adenocarcinoma(PDAC).Methods:This was a retrospective study from a prospectively maintained database of pancreatic resections for PDAC.Short-and long-term outcomes were analyzed in patients having borderline resectable PDAC submitted to up-front total pancreatectomy(TP)or pancreaticoduodenectomy(PD)with simultaneous portal vein(PV)and/or superior mesenteric vein(SMV)resection.Venous resections were carried out as tangential venous resection(TVR)or segmental venous resection(SVR).Patients were divided into 4 groups:(1)PD+TVR,(2)PD+SVR,(3)TP+TVR,(4)TP+SVR.Uni-and multivariate Cox regression analysis were performed to identify factors associated with survival.Results:Ninety-nine patients were submitted to simultaneous pancreatic and venous resection for PDAC.Among them,25 were submitted to PD+TVR(25.3%),12 to PD+SVR(12.1%),23 to TP+TVR(23.2%),and 39 to TP+SVR(39.4%).Overall,major morbidity(Clavien-Dindo grade≥IIIA)was 26.3%.Thirty-and 90-day mortality were 3%and 11.1%,respectively.There were no significant differences among groups in terms of short-term outcomes.Median overall survival of patients submitted to PD+TVR was significantly higher than those to TP+SVR(29.5 vs 7.9 months,P=0.001).Multivariate analysis identified TP(HR=2.11;95%CI:1.31–3.44;P=0.002)and SVR(HR=2.01;95%CI:1.27–3.15;P=0.003)as the only independent prognostic factors for overall survival.Conclusions:Up-front TP associated to SVR was predictive of worse survival in borderline resectable PDAC.Perioperative treatments in high-risk surgical groups may improve such poor outcomes.

Urea cycle disorders:A case report of a successful treatment with liver transplant and a literature review

The urea cycle is the final pathway for nitrogen metabolism. Urea cycle disorders(UCDs) include a variety of genetic defects, which lead to inefficient urea synthesis. Elevated blood ammonium level is usually dominant in the clinical pattern and the primary manifestations affect the central nervous system. Herein, we report the case of a 17-year-old girl who was diagnosed with UCD at the age of 3. Despite a controlled diet, she was hospitalized several times for acute attacks with recurrent life risk. She came to our attention for a hyperammonemic episode. We proposed an orthotopic liver transplant(OLT) as a treatment; the patient and her family were in complete agreement. On February 28, 2007, she successfully received a transplant. Following the surgery, she has remained well, and she is currently leading a normal life. Usually for UCDs diet plays the primary therapeutic role, while OLT is often considered as a last resort. Our case report and the recent literature data on the quality of life and prognosis of traditionally treated patients vs OLT patients, support OLT as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment.

Competing risk analysis on outcome after hepatic resection of hepatocellular carcinoma in cirrhotic patients

AIM To investigate death for liver failure and for tumor recurrence as competing events after hepatectomy of hepatocellular carcinoma.METHODS Data from 864 cirrhotic Child-Pugh class A consecutive patients, submitted to curative hepatectomy(1997-2013) at two tertiary referral hospitals, were used for competing-risk analysis through the Fine and Gray method, aimed at assessing in which circumstances the oncological benefit from tumour removal is greater than the risk of dying from hepatic decompensation. To accomplish this task, the average risk of these two competing events, over 5 years of follow-up, was calculated through the integral of each cumulative incidence function, and represented the main comparison parameter. RESULTS Within a median follow-up of 5.6 years, death was attributable to tumor recurrence in 63.5%, and to liver failure in 21.2% of cases. In the first 16 mo, the risk of dying due to liver failure exceeded that of dying due to tumor relapse. Tumor stage only affects death from recurrence; whereas hepatitis C infection, Model for End-stage Liver Disease score, extent of hepatectomy and portal hypertension influence death from liver failure(P < 0.05 in all cases). The combination of these clinical and tumoral features identifies those patients in whom the risk of dying from liver failure did not exceed the tumour-related mortality, representing optimal surgical candidates. It also identifies those clinical circumstances where the oncological benefit would be borderline or even where the surgery would be harmful. CONCLUSION Having knowledge of these competing events can be used to weigh the risks and benefits of hepatic resection in each clinical circumstance, separating optimal from non-optimal surgical candidates.

Efficacy of radiofrequency ablation of hepatocellular carcinoma prior to liver transplantation and the need for competing-risk analysis

Radiofrequency ablation(RFA)currently represents a potentially curative treatment for hepatocellular carcinoma(HCC)in its early stages(1,2).Providing higher rates of complete necrosis of target tumor than other loco-regional therapies(LRTs),RFA plays an important role as bridge therapy to liver transplantation(LT)(3).In the study from Lee and colleagues of the UCLA medical center,published in issue of June 2017 of Hepatology,Authors analyzed the outcome of 121 patients with 156 de-novo HCC treated with RFA as initial stand-alone therapy(4).The study is a fair attempt to analyze the efficacy of RFA as bridge therapy to LT,considering all potential outcome measures.Nevertheless,some results passed unnoticed,while instead deserve further discussion.

Treatment options for recurrence of hepatocellular carcinoma after surgical resection: review of the literature and current recommendations for management

The recurrence rate after primary resection for hepatocellular carcinoma(HCC)has been reported to be up to 80%.There is no consensus or guideline about the best treatment option for such recurrent HCC(rHCC).It is therefore of paramount importance to select patients for suitable treatment due to the high risk of associated morbidity and mortality.In this paper,we review the literature on treatment for rHCC and propose a strategy based on the best evidence available.Even in rHCC,it is still possible to achieve cure and good survival rates through careful patient selection.Repeat hepatectomy is recognized as a feasible and safe procedure even in cirrhotic patients and should be considered as the best option with curative intent when the patient is fit enough.Greater adoption of minimally-invasive liver surgery could have the potential to increase the number of candidate patients with rHCC for repeat resection in the next few years.Liver transplantation offers longer disease-free survival compared to repeat resection,curing the underlying cirrhosis,but is not widely available due to organ shortage.When surgery is not feasible,locoregional treatments such as radiofrequency ablation and transarterial chemoembolization have an important role for patients who cannot tolerate repeat hepatectomy and are not suitable for transplantation.For advanced cases,systemic therapy could be considered.

Incorporating alpha-fetoprotein within dimensional criteria for hepatocellular carcinoma transplantation

Since the adoption of Milan criteria more than 20 years ago,selection criteria for liver transplantation(LT)in patients suffering from hepatocellular carcinoma(HCC)represented a debated issue.Halazun and colleagues presented at the American Surgical Association of 2018,and published on the issue of October of Annals of Surgery,their results from an analysis aimed at including alpha-fetoprotein(AFP)in a model developed to predict long-term results after LT for HCC(1).Of 1,450 patients included between 2001 and 2013,16.2%were outside Milan criteria,61.1%were hepatitis C virus(HCV)positive and more than 80%of candidates received pre-LT locoregional therapies.Their study showed that incorporating AFP levels at diagnosis,maximum AFP(Max-AFP)at any time point,and the final immediate pre-transplant AFP(Final-AFP)to tumor number and diameter can well stratify different groups of patients at different risks of HCC recurrence after LT(NYCA model).