Current surgical treatment strategies for hepatocellular carcinoma in North America

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease. Many patients do not initially manifest any symptoms of HCC and present late when cure with surgical resection or transplantation is no longer possible. For this reason, patients at high risk for developing HCC are subjected to frequent screening processes. The surgical management of HCC is complex and requires an inter-disciplinary approach. Hepatic resection is the treatment of choice for HCC in patients without cirrhosis and is indicated in some patients with early cirrhosis (Child-Pugh A). Liver transplantation has emerged in the past decade as the standard of care for patients with cirrhosis and HCC meeting Milan criteria and in select patients with HCC beyond Milan criteria. Loco-regional therapy with transarterial chemoembolization, transarterial embolization, radiofrequency ablation and other similar local treatments can be used as neo-adjuvant therapy to downstage HCC to within Milan criteria or as a bridge to transplantation in patients on transplant wait list.     

Transarterial chemoembolization: Evidences from the literature and applications in hepatocellular carcinoma patients

Transarterial chemoembolization (TACE) is the current standard of care for patients with large or multinodular hepatocellular carcinoma (HCC), preserved liver function, absence of cancer-related symptoms and no evidence of vascular invasion or extrahepatic spread (i.e., those classified as intermediate stage according to the Barcelona Clinic Liver Cancer staging system). The rationale for TACE is that the intra-arterial injection of a chemotherapeutic drug such as doxorubicin or cisplatin followed by embolization of the blood vessel will result in a strong cytotoxic effect enhanced by ischemia. However, TACE is a very heterogeneous operative technique and varies in terms of chemotherapeutic agents, treatment devices and schedule. In order to overcome the major drawbacks of conventional TACE (cTACE), non-resorbable drug-eluting beads (DEBs) loaded with cytotoxic drugs have been developed. DEBs are able to slowly release the drug upon injection and increase the intensity and duration of ischemia while enhancing the drug delivery to the tumor. Unfortunately, despite the theoretical advantages of this new device and the promising results of the pivotal studies, definitive data in favor of its superiority over cTACE are still lacking. The recommendation for TACE as the standard-of-care for intermediate-stage HCC is based on the demonstration of improved survival compared with best supportive care or suboptimal therapies in a meta-analysis of six randomized controlled trials, but other therapeutic options (namely, surgery and radioembolization) proved competitive in selected subsets of intermediate HCC patients. Other potential fields of application of TACE in hepato-oncology are the pre-transplant setting (as downstaging/bridging treatment) and the early stage (in patients unsuitable to curative therapy). The potential of TACE in selected advanced patients with segmental portal vein thrombosis and preserved liver function deserves further reports.     

Outcome of transarterial chemoembolization in patients with inoperable hepatocellular carcinoma eligible for radiofrequency ablation

AIM: To evaluate the outcome of transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC)<5 cm in diameter eligible for radiofrequency ablation (RFA). METHODS: The treatment-related mortality, morbidity, long-term survival, and prognostic factors of HCC patients who had TACE and fulfilled the present inclusion criteria for RFA were evaluated. RESULTS: Of the 748 patients treated with TACE between January 1990 and December 2002,114 patients were also eligible for RFA. The treatment-related mortality and morbidity were 1% and 19%, respectively. Survival at 1, 3, and 5 years was 80%, 43%, and 23%, respectively. Older age and a high albumin level were associated with a better survival, whereas a high a-fetoprotein level (AFP) and the size of the largest tumor >3 cm in diameter were adverse prognostic factors in multivariate analysis. CONCLUSION: The morbidity, mortality, and survival data after TACE for small HCCs eligible for RFA are comparable to those reported after RFA in the literature. Our data suggest the need for a randomized comparison of the two treatment modalities for small HCCs.     

Transarterial chemoembolization as initial treatment for unresectable hepatocellular carcinoma in southern China

AIM:To identify prognostic factors from pretreatment variables of the initial transarterial chemoembolization(TACE)procedure in unresectable hepatocellular carcinoma(HCC). METHODS:One thousand and five hundred and sixtynine patients with unresectable HCC underwent TACE as initial treatment were retrospectively studied.Pretreatment variables of the initial TACE procedure with a P value less than 0.05 by univariate analysis were subjected to Cox proportional hazards model. RESULTS:The median overall survival ...     

Comparison of hepatic resection and transarterial chemoembolization for solitary hepatocellular carcinoma

AIM: To compare the outcomes of hepatic resection and transarterial chemoembolization (TACE) for solitary hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer (BCLC) staging system.METHODS: A consecutive sample of 540 patients with solitary HCC who underwent liver resection (n = 312) or TACE (n = 128) were included in the present study. Baseline characteristics, tumor characteristics, and post-operative complications were compared between the two groups. The Kaplan-Meier method was used for long-term survival analysis. Independent prognostic predictors were identified using the Cox proportional hazards model (univariate and multivariate analyses).RESULTS: The TACE and liver resection groups had similar baseline demographic and clinicopathological characteristics. The TACE group showed a significantly lower rate of major complications than the liver resection group (3.9% vs 17.4%, P < 0.001). Univariate and multivariate analyses indicated that TACE did not contribute to poor overall survival compared with liver resection; however, a solitary tumor diameter of greater than 6 cm should be considered a risk factor for poor overall survival (HR = 1.328, 95%CI: 1.002-1.783, P = 0.048). The liver resection and TACE groups had comparable overall survival rates at 1 year, 3 years, and 5 years (86.2%, 62.8%, and 44.0% vs 88.3%, 59.8%, and 40.6%, respectively, P = 0.419). In cases with tumor diameters equal to or less than 6 cm, the liver resection group showed a survival benefit compared with the TACE group at 1 year, 3 years, and 5 years (P = 0.030). The 1-, 3-, and 5-year overall survival rates of HCC cases with tumor diameters of more than 6 cm were similar among the liver resection and TACE groups (P = 0.467).CONCLUSION: A tumor diameter of 6 cm should be the cutoff for deciding between liver resection and TACE.     

Transarterial chemoembolization in patients with hepatocellular carcinoma: predictors of survival

BACKGROUND:

Transarterial chemoembolization (TACE) is the mainstay of management for patients with hepatocellular carcinoma who are not suitable for curative treatments.

OBJECTIVE:

To determine factors associated with mortality after the first TACE procedure.

METHODS:

From January 2004 to May 2008, 60 patients underwent TACE as treatment for hepatocellular carcinoma. Clinical and biochemical parameters before TACE, and response after TACE, were evaluated with conventional classifications (WHO, Response Evaluation Criteria in Solid Tumors [RECIST], and European Association for the Study of the Liver [EASL] criteria) and with one-, two- and three-dimensional assessment.

RESULTS:

Overall median survival after the first TACE procedure was 17.1±3.4 months. According to Cox regression analysis, having an alpha-fetoprotein level of greater than 200 ng/mL (HR 2.35 [P=0.02]) and a Model for End-stage Liver Disease (MELD) score of greater than 10 (HR 4.19 [P=0.001]) were associated with higher risk of mortality; whereas reduction in tumour size measured in one dimension (HR 0.96 [P=0.005]), two dimensions (HR 0.98 [P=0.004]) and three dimensions (HR 0.98 [P=0.001]) was associated with lower risk of mortality. Moreover, reduction in tumour size by 3% or more assessed in one, two or three dimensions was associated with lower risk of mortality (HR 0.48 [P=0.04]; HR 0.36 [P=0.01]; HR 0.31 [P=0.003], respectively). The three conventional classifications were not useful for predicting mortality (WHO: HR 1.07 [P=0.9]; RECIST: HR 0.94 [P=0.9]; EASL: HR 0.94 [P=0.9]).

CONCLUSIONS:

Having an alpha-fetoprotein level of greater than 200 ng/mL and a MELD score of greater than 10 before undergoing TACE was associated with a greater risk of mortality. Conventional classifications of response were not useful for predicting mortality. Reduction in tumour size after the first TACE procedure was associated with better survival, primarily if patients had more than a 3% reduction in tumour size assessed by three-dimensional measurement.     

经肝动脉化疗栓塞后联合索拉非尼治疗肝癌患者临床观察

目的探讨索拉非尼联合经肝动脉化疗栓塞术（TACE）治疗肝癌患者的效果。方法选取142例肝癌患者,其中57例接受TACE治疗,47例接受索拉非尼治疗,38例接受索拉非尼联合TACE治疗。在治疗后12 w,评估治疗效果、总生存期（OS）和疾病进展时间（TTP）。结果联合治疗组有效率为26.32%,显著高于TACE组的17.54%或索拉非尼组的19.15%（P<0.05）;联合治疗组疾病控制率为71.05%,显著高于TACE组的57.89%或索拉非尼组的53.19%（P<0.01）;联合治疗组患者OS为8.6 m,显著高于索拉非尼组的6.2 m或TACE组的7.3 m（P<0.05）;联合治疗组TTP为6.7 m,显著高于索拉非尼组的5.1m或TACE组的 5.6 m（P<0.01）。结论索拉非尼联合TACE治疗肝癌患者具有较好的临床效果。     

Transarterial chemoembolization and bland embolization for hepatocellular carcinoma

Transarterial chemoembolization(TACE)is the first line treatment for patients with intermediate stage hepatocellular carcinoma but is also increasingly being used for patients on the transplant waiting list to prevent further tumor growth.Despite its widespread use,TACE remains an unstandardized procedure,with variation in type and size of embolizing particles,type and dose of chemotherapy and interval between therapies.Existing evidence from randomized controlled trials suggest that bland transarterial embolization(TAE)has the same efficacy with TACE.In the current article,we review the use of TACE and TAE for hepatocellular carcinoma and we focus on the evidence for their use.     

A prediction model for liver abscess developing after transarterial chemoembolization in patients with hepatocellular carcinoma

BackgroundLiver abscess is a rare but potentially fatal complication of transarterial chemoembolization. Other than for biliary abnormalities, risk factors for liver abscess formation after transarterial chemoembolization have rarely been discussed.AimsTo identify other risk factors of liver abscess after transarterial chemoembolization in patients with hepatocellular carcinoma.MethodsData for 5299 patients with hepatocellular carcinoma who underwent transarterial chemoembolization from July 1999 to December 2009 were retrospectively reviewed. 72 patients who experienced liver abscess after transarterial chemoembolization were enrolled as a case group, which was compared with a randomly selected control group (n = 1009) of patients who did not develop liver abscess after transarterial chemoembolization.ResultsPneumobilia, type 2 biliary abnormality, type 1 biliary abnormality, diabetes mellitus, tumour number (≥3), tumour size (≥3 cm), and tumour necrosis on the pre-transarterial chemoembolization computed tomography, and gelfoam embolization and vessel injury during transarterial chemoembolization were all significant predisposing factors for liver abscess after transarterial chemoembolization. A prediction model for postembolization liver abscess was developed from these risk factors.ConclusionThe group of patients with risk scores greater than 71 showed a significantly increased risk of liver abscess after transarterial chemoembolization. These high-risk patients should be monitored carefully after transarterial chemoembolization.     

Milan criteria are useful predictors for favorable outcomes in hepatocellular carcinoma patients undergoing liver transplantation after transarterial chemoembolization

INTRODUCTION Hepatocellular carcinoma (HCC) is a major global health problem involving more than 500 000 new cases a year. Several treatment modalities, such as liver transplantation (LT), surgical resection, radiofrequency ablation (RFA), and percutaneou…     

Role of liver resection in the management of multinodular hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide. Various treatment modalities have been applied to HCC depending on the tumor load, functional capacity of the liver and the general condition of the patient. According to Barcelona Clinic Liver Cancer staging strategy and The American Association for the Study of Liver Disease guidelines, surgical resection is not advocated in the tretment of multinodular HCC. Despite this, many recent clinical studies show that, resection can achieve good results in patients with multinodular HCC and 5-year survival rate around 40% can be reached. If resection or transplantation is not performed, these patients are usually managed with palliative procedures such as transarterial chemoembolization, radioembolization and cytotoxic chemotherapy and 5-year survival of this group of patients will be extremely low. Although survival rates are lower and complications may be increased in this group of patients, liver resection can safely be performed in selected patients in experienced centers for the management of multinodular HCC.     

Transarterial chemoembolization with drug-eluting beads in hepatocellular carcinoma

Transarterial chemoembolization (TACE) is a widely used standard treatment for patients with hepatocellular carcinoma (HCC) who are not suitable candidates for curative treatments. The rationale for TACE is that intra-arterial chemotherapy using lipiodol and chemotherapeutic agents, followed by selective vascular embolization, results in a strong cytotoxic effect as well as ischemia (conventional TACE). Recently, drug-eluting beads (DC Beads^®) have been developed for transcatheter treatment of HCC to deliver higher doses of the chemotherapeutic agent and to prolong contact time with the tumor. DC Beads^® can actively sequester doxorubicin hydrochloride from solution and release it in a controlled sustained fashion. Treatment with DC Beads^® substantially reduced the amount of chemotherapeutic agent that reached the systemic circulation compared with conventional, lipiodol-based regimens, significantly reducing drug-related adverse events. In this article, we describe the treatment response, survival, and safety of TACE used with drug-eluting beads for the treatment of HCC and discuss future therapeutic possibilities.     

Transarterial chemoembolization with hepatic arterial infusion chemotherapy plus S-1 for hepatocellular carcinoma

BACKGROUND Transarterial chemoembolization(TACE) and hepatic arterial infusion chemotherapy(HAIC) have shown promising local benefits for advanced hepatocellular carcinoma(HCC). S-1, a composite preparation of a 5-fluorouracil prodrug, has proven to be a convenient oral chemotherapeutic agent with definite efficacy against advanced HCC.AIM To evaluate the efficacy and safety of TACE followed by HAIC with or without oral S-1 for treating advanced HCC.METHODS In this single-center, open-label, prospective, randomized controlled trial, 117 participants with advanced HCC were randomized to receive TACE followed by oxaliplatin-based HAIC either with(TACE/HAIC + S-1, n = 56) or without(TACE/HAIC, n = 61) oral S-1 between December 2013 and September 2017. Two participants were excluded from final analysis for withdrawing consent. The primary endpoint was progression-free survival(PFS) and secondary endpoints included overall survival(OS), objective response rate, disease control rate and safety.RESULTS In total, 115 participants(100 males and 15 females; mean age, 57.7 years ± 11.9) were analyzed. The median PFS and OS were 5.0 mo(0.4–58.6 mo)(95% confidence interval(CI): 3.82 to 6.18) vs 4.4 mo(1.1–54.4 mo)(95%CI: 2.54 to 6.26; P = 0.585) and 8.4 mo(0.4–58.6 mo)(95%CI: 6.88 to 9.92) vs 8.3 mo(1.4–54.4 m)(95%CI: 5.71 to 10.96; P = 0.985) in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. The objective response rate and disease control rate were 30.9% vs 18.4% and 72.7% vs 56.7% in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. Grade 3/4 adverse events had a similar frequency in both treatment groups.CONCLUSION No improvements in tumor response rates, PFS or OS were observed with the addition of S-1 to TACE/HAIC in advanced HCC. Both treatment regimens had a similar safety profile.     

Anti-angiogenesis in hepatocellular carcinoma treatment: current evidence and future perspectives

Hepatocellular carcinoma(HCC) is among the most common cancer diseases worldwide.Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization(TACE).This interventional method is the standard treatment for patients with intermediate stage HCC,but is also applied as bridging therapy for patients awaiting liver transplantation in many centers worldwide.Usually the devascularization effect induced by TACE is transient,consequently resulting in r...     

Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial

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Early prediction of survival in hepatocellular carcinoma patients treated with transarterial chemoembolization plus sorafenib

AIM To identify clinical biomarkers that could early predict improved survival in patients with advanced-stage hepatocellular carcinoma(HCC) treated with transarterial chemoembolization combined with sorafenib(TACE-S).METHODS We retrospectively evaluated the medical records of consecutive patients with advanced-stage HCC who underwent TACE-S from January 2012 to December 2015. At the first follow-up 4-6 wk after TACE-S(median, 38 d; range, 33-45 d), patients exhibiting the modified Response Evaluation Criteria in Solid Tumors(m RECIST)-evaluated complete response, partial response, and stable disease were categorized as early disease control. At this time point, multiple variables were analyzed to identify the related factors affecting survival.RESULTS Ninety-five patients were included in this study, and 60 of these patients achieved early disease control, with an overall disease control rate(DCR) of 63.2%. Patients who got sorafenib at the first TACE(no previous TACE) and patients without portal vein tumor thrombus(PVTT) had a higher DCR than those who underwent previous TACE before TACE-S(72.4% vs 48.6%, P = 0.019) and those with PVTT(75.5% vs 50.0%, P = 0.010). Early disease control after TACE-S, no previous TACE, and no PVTT were the independent prognostic factors for survival in the uni-and multivariate analyses.CONCLUSION The first follow-up 4-6 wk after TACE-S can be used as the earliest time point to assess the response to TACE-S, and patients with m RECIST-evaluated early disease control, no previous TACE, and no PVTT had better survival.     

Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma

AIM: To compare the overall survival (OS) and progression-free survival (PFS) with associated adverse events (AE) in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) + sorafenib vs TACE alone. METHODS: In this retrospective cohort study we collected data on all consecutive patients with a diagnosis of unresectable HCC between 2007 and 2011 who had been treated with TACE + sorafenib or TACE alone. We hypothesized that the combination therapy is superior to TACE alone in improving the survival in these patients. Data extracted included patient’s demographics, etiology of liver disease, histology of HCC, stage of liver disease with respect to model of end stage liverdisease score and Child-Turcotte-Pugh (CTP) classification and Barcelona Clinic Liver Cancer (BCLC) staging for HCC. Computed tomography scan findings, alpha fetoprotein levels, number of treatments and related AE were also recorded and analyzed. RESULTS: Of the 43 patients who met inclusion criteria, 13 were treated with TACE + sorafenib and 30 with TACE alone. There was no significant difference in median survival: 20.6 mo (95%CI: 13.4-38.4) for the TACE + sorafenib and 18.3 mo (95%CI: 11.8-32.9) for the TACE alone (P = 0.72). There were also no statistically significant differences between groups in OS (HR = 0.82, 95%CI: 0.38-1.77; P = 0.61), PFS (HR = 0.93, 95%CI: 0.45-1.89; P = 0.83), and treatment-related toxicities (P = 0.554). CTP classification and BCLC staging for HCC were statistically significant (P = 0.001, P = 0.04 respectively) in predicting the survival in patients with HCC. The common AE observed were abdominal pain, nausea, vomiting and mild elevation of liver enzymes. CONCLUSION: Combination therapy with TACE + sorafenib is safe and equally effective as TACE alone in patients with unresectable HCC. CTP classification and BCLC staging were the significant predictors of survival. Future trials with large number of patients are needed to further validate this observation.     

New advances in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the leading cause of deaths in cirrhotic patients and the third cause of cancer related deaths.Most HCC are associated withwell known underlying risk factors,in fact,HCC arise in cirrhotic patients in up to 90%of cases,mainly due to chronic viral hepatitis and alcohol abuse.The worldwide prevention strategies are conducted to avoid the infection of new subjects and to minimize the risk of liver disease progression in infected patients.HCC is a condition which lends itself to surveillance as at-risk individuals can readily be identified.The American and European guidelines recommended implementation of surveillance programs with ultrasound every six months in patient atrisk for developing HCC.The diagnosis of HCC can be based on non-invasive criteria(only in cirrhotic patient)or pathology.Accurately staging patients is essential to oncology practice.The ideal tumour staging system in HCC needs to account for both tumour characteristics and liver function.Treatment allocation is based on several factors:Liver function,size and number of tumours,macrovascular invasion or extrahepatic spread.The recommendations in terms of selection for different treatment strategies must be based on evidence-based data.Resection,liver transplant and interventional radiology treatment are mainstays of HCC therapy and achieve the best outcomes in well-selected candidates.Chemoembolization is the most widely used treatment for unresectable HCC or progression after curative treatment.Finally,in patients with advanced HCC with preserved liver function,sorafenib is the only approved systemic drug that has demonstrated a survival benefit and is the standard of care in this group of patients.     

Management of recurrent hepatocellular carcinoma after liver transplant

Hepatocellular carcinoma(HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation(LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgicalresection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, highintensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease.     

Review of preoperative transarterial chemoembolization for resectable hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the few cancers whose incidence has been continually increasing over recent years.Resection of HCC offers the only hope for cure.However,recurrences are common in patients who have undergone resection.In our opinion,the effectiveness with which transarterial chemoembolization(TACE) as a neoadjuvant therapy for resectable HCC prevents recurrence and prolongs survival has not been conclusively demonstrated.All published meta-analyses have consistently failed to demonstrate that preoperative TACE improves the prognosis of resectable HCC.We believe that these published articles have several limitations and have our own views about the results of meta-analyses.It is very important that the scientific community shed more light on the pathogenesis of HCC and relate this to choice of therapy.This review mainly concerns our understanding of preoperative TACE for resectable HCC and briefly addresses desirable directions for future studies.