Treatment of hepatocellular carcinoma

Opinion statement The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.     

Pretreatment assessment of hepatocellular carcinoma: expert consensus statement

Staging of hepatocellular carcinoma (HCC) is complex and relies on multiple factors including tumor extent and hepatic function. No single staging system is applicable to all patients with HCC. The staging of the American Joint Committee on Cancer / International Union for Cancer Control should be used to predict outcome following resection or liver transplantation. The Barcelona Clinic Liver Cancer scheme is appropriate in patients with advanced HCC not candidate for surgery. Dual phase computed tomography or magnetic resonance imaging can be used for pretreatment assessment of tumor extent but the accuracy of these methods remains poor to characterize <1 cm lesions. Assessment of tumor response should not rely only on tumor size and new imaging methods are available to evaluate response to therapy in HCC patients. Liver volumetry is part of the preoperative assessment of patients with HCC candidate for resection as it reflects liver function. Preoperative portal vein embolization is indicated in patients with small future liver remnant (≤ 20% in normal liver; ≤ 40% in fibrotic or cirrhotic liver). Tumor size is not a contraindication to liver resection. Liver resection can be proposed in selected patients with multifocal HCC. Besides tumor extent, surgical resection of HCC may be performed in selected patients with chronic liver disease.     

Laparoscopic vs open approach to resection of hepatocellular carcinoma in patients with known cirrhosis: Systematic review and meta-analysis

AIM: To review the currently available literature comparing laparoscopic to open resection of hepatocellular carcinoma (HCC) in patients with known liver cirrhosis.METHODS: A literature search of MEDLINE, EMBASE, and Cochrane databases was conducted. The search terms used included (laparoscopic OR laparoscopy) AND (hepatic or liver) AND (surgery or resection) AND “hepatocellular carcinoma” AND (cirrhosis or cirrhotic). Furthermore, to widen the search, we also used the “related articles” section. Studies reporting a comparison of outcomes and methods of open vs laparoscopic hepatic resection for HCC in patients with liver cirrhosis were included. Meta-analysis of results was performed using a random effects model to compute relative risk (RR) and for dichotomous variables and standard mean differences (SMD) for continuous variables.RESULTS: A total of 420 patients from 4 cohort studies were included in final analysis. Patients undergoing laparoscopic procedures had statistically less blood loss compared to the open cohort, SMD of -1.01 (95%CI: -1.23-0.79), P < 0.001, with a reduced risk of transfusion, RR = 0.19 (95%CI: 0.09-0.38), P < 0.001. A wider clearance at tumour resection margins was achieved following a laparoscopic approach, SMD of 0.34 (95%CI: 0.08-0.60), P = 0.011. No significant difference was noted between laparoscopic and open resection operative times, SMD of -0.15 (95%CI: 0.35-0.05), P = 0.142. The overall RR of suffering from postoperative morbidity is 0.25 in favour of the open surgery cohort (95%CI: 0.17-0.37), P < 0.001. Patients under-going laparoscopic surgery had significantly shorter length of stays in hospital compared to the open cohort, SMD of -0.53 (95%CI: -0.73 to -0.32), P < 0.001.CONCLUSION: This review suggests that laparoscopic resection of hepatocellular carcinoma in patients with cirrhosis is safe and may provide improved patient outcomes when compared to the open technique.     

Diagnosis and treatment of hepatocellular carcinoma: An update

Hepatocellular carcinoma(HCC) is one of the most common malignancies leading to high mortality rates in the general population; in cirrhotic patients, it is the primary cause of death. The diagnosis is usually delayed in spite of at-risk population screening recommendations, i.e., patients infected with hepatitis B or C virus. Hepatocarcinogenesis hinges on a great number of genetic and molecular abnormalities that lead to tumor angiogenesis and foster their dissemination potential. The diagnosis is mainly based on imaging studies such as computed tomography and magnetic resonance, in which lesions present a characteristic classical pattern of early arterial enhancement followed by contrast medium "washout" in late venous phase. On occasion, when imaging studies are not conclusive, biopsy of the lesion must be performed to establish the diagnosis. The Barcelona Clinic Liver Cancer staging method is the most frequently used worldwide and recommended by the international guidelines of HCC management. Currently available treatments include tumor resection, liver transplant, sorafenib and locoregional therapies(alcoholization, radiofrequency ablation, chemoembolization). The prognosis of hepatocarcinoma is determined according to the lesion’s stage and in cirrhotic patients, on residual liver function. Curative treatments, such as liver transplant, are sought in patients diagnosed in early stages; patients in more advanced stages, were not greatly benefitted by chemotherapy in terms of survival until the advent of target molecules such as sorafenib.     

Liver resection for hepatocellular carcinoma: Indications, techniques, complications, and prognostic factors

Although the resectability of hepatocellular carcinoma (HCC) has increased due to recent advances in diagnostic methods, the long-term results are far from satisfactory. Major hepatic resection is indicated in patients with noncirrhotic or mildly cirrhotic liver. Otherwise, limited resection should be carried out. Total or lobar hepatic inflow occlusion appears to decrease blood loss during surgery, and therefore to reduce postoperative morbidity and mortality rates. Total vascular exclusion with or without hypothermia may be indicated in selected patients. Hepatic resection is not necessarily contraindicated for HCC with tumor thrombus in the major portal veins, hepatic veins, inferior vena cava, and bile ducts. There are various postoperative complications, especially in cirrhotic patients, but if hepatic failure occurs, it is usually fatal. To prevent this complication, two factors may be most important: avoiding too great a resection and preventing such trigerring factors as hemorrhagic shock, infection, and gastrointestinal bleeding. Favorable prognostic factors are young age, female sex, and low serum AFP clinically, and small tumor, presence of capsule, absence of vascular invasion and/or daughter nodule, diploid or low proliferative tumor, and negative surgical margin pathologically. Increased necroinflammatory activity of the liver irrespective of viral type and hepatitis C virus-associated liver disease are associated with tumor recurrence in the remnant liver. The significance of adjuvant chemotherapy or interferon therapy remains to be elucidated.     

WJH 6~(th) Anniversary Special Issues(1): Management of hepatocellular carcinoma Management of “very early” hepatocellular carcinoma on cirrhotic patients

Due to the advances in screening of cirrhotic patients, hepatocellular carcinoma(HCC) is being diagnosed in earlier stages. For this reason the number of patients diagnosed of very early HCC(single tumors ≤ 2 cm) is continuously increasing. Once a patient has been diagnosed with this condition, treatment strategies include liver resection, local therapies or liver transplantation. The decision on which therapy should the patient undergo depends on the general patients performance status and liver disease. Anyway, even in patients with similar conditions, the best treatment offer is debatable. In this review we analyze the state of the art on the management of very early HCC on cirrhotic patients to address the best treatment strategy for this patient population.     

Hepatocellular carcinoma: surgical indications and results

Hepatocellular carcinoma (HCC) is a tumour of increasing incidence that usually arises in cirrhotic liver. Untreated, the prognosis is grim and the only curative treatment is surgical resection. The practical application of segmental surgery to the liver together with the use of ultrasound and other imaging techniques, patient selection criteria and improvements in perioperative technique and postoperative care have contributed to better results in hepatic surgery. Today, less than 10% mortality for resection of cirrhotic livers, with up to 50% 5-year survival rates are to be expected. However, the limits of resection for cure: intrahepatic recurrence makes stringent follow-up necessary. In this way the available modalities of treatment can be applied so as to improve survival. Herein, a current 'state-of-the-art' of surgical indications and results for HCC is given.     

Liver surgery in cirrhosis and portal hypertension

The prevalence of hepatic cirrhosis in Europe and the United States, currently 250 patients per 100000 inhabitants, is steadily increasing. Thus, we observe a significant increase in patients with cirrhosis and portal hypertension needing liver resections for primary or metastatic lesions. However, extended liver resections in patients with underlying hepatic cirrhosis and portal hypertension still represent a medical challenge in regard to perioperative morbidity, surgical management and postoperative outcome. The Barcelona Clinic Liver Cancer classification recommends to restrict curative liver resections for hepatocellular carcinoma in cirrhotic patients to early tumor stages in patients with Child A cirrhosis not showing portal hypertension. However, during the last two decades, relevant improvements in preoperative diagnostic, perioperative hepatologic and intensive care management as well as in surgical techniques during hepatic resections have rendered even extended liver resections in higher-degree cirrhotic patients with portal hypertension possible. However, there are few standard indications for hepatic resections in cirrhotic patients and risk stratifications have to be performed in an interdisciplinary setting for each individual patient. We here review the indications, the preoperative risk-stratifications, the morbidity and the mortality of extended resections for primary and metastatic lesions in cirrhotic livers. Furthermore, we provide a review of literature on perioperative management in cirrhotic patients needing extrahepatic abdominal surgery and an overview of surgical options in the treatment of hepatic cirrhosis.     

Selection criteria for liver resection in patients with hepatocellular carcinoma and chronic liver disease

Hepatocellular carcinoma （HCC） is one of the most common malignancies worldwide with an annual occurrence of one million new cases. An etiologic association between HBV infection and the development of HCC has been established with a relative risk 200-fold greater than in non-infected individuals. Hepatitis C virus is also proving an important predisposing factor for this malignancy with an incidence rate of 7% at 5 years and 14% at 10 years. The prognosis depends on tumor stage and degree of liver function, which affect the tolerance to invasive treatments. Although surgical resection is generally accepted as the treatment of choice for HCC, new treatment strategies, such as local ablative therapies, transarterial embolization and liver transplantation, have been developed nowadays. With increasing detection of small HCCs from screening programs for cirrhotic patients, it is foreseen that locoregional therapy will play an important role in the near future.     

Measurement of portal venous pressure is useful for selecting the optimal type of resection in cirrhotic patients with hepatocellular carcinoma

BACKGROUND/AIMS: In the present study the importance of measurement of portal venous pressure was focused on to predict the postoperative liver function before liver surgery, particularly in cirrhotic patients. METHODOLOGY: Ninety-two patients who underwent a hepatic resection for hepatocellular carcinoma (HCC) were retrospectively evaluated to predict their postoperative liver function by measuring the portal venous pressure. RESULTS: The portal venous pressure was not significantly correlated with the preoperative value of the indocyanine green (ICG) retention test. In patients with an ICG of over 20%, the risk of occurrence of postoperative hyperbilirubinemia was high when a major hepatic resection was the procedure of choice. Even in patients with an ICG of below 20%, a few patients developed complications after surgery when major resection was carried out. For patients undergoing a small excision, the complications were nil when the ICG was below 20% and the pressure was below 200mm in saline. CONCLUSIONS: The portal venous pressure was found to reflect to what degree the liver parenchyma is damaged. Measuring the portal venous pressure is useful for determining the final indications for surgery also in cirrhotic patients with HCC.     

Reappraisal of surgical treatment of small hepatocellular carcinomas in cirrhosis: Clinicopathological study of resection or transplantation

Thirty-two patients with hepatocellular carcinoma (HCC) occurring in individuals with cirrhosis had a potentially curative surgical procedure. Twenty-two had segmental hepatic resections (HR), and 10 underwent orthotopic liver transplantation (OLTx). The diagnosis of hepatic malignancy was established in each case preoperatively, and each case was studied intraoperatively by means of sonography. Postoperatively each surgical specimen was examined pathologically with attention to the possibility of intrahepatic tumor spread. Twenty-three of the 32 patients had single small HCC lesion (<5 cm diameter) identified preoperatively. Sixteen of these underwent HR and seven underwent OLTx. Multiple additional neoplastic lesions were found in 19% of the 16 HR cases and in 14% of those undergoing OLTx when the resection specimens were examined pathologically. Vascular invasion was present in 43% of the OLTx patients and in 25% of the HR patients. Subtotal hepatic resection for small HCC occurring in cirrhosis has produced few long-term survivals. Both pre- and intraoperative sonography have been shown to underestimate the extent and distribution of these tumors. Based upon this experience that (1) vascular spread occurs often in HCC and (2) a high risk of postoperative hepatic failure can be expected after HR in cirrhotic individuals, OLTx is the most rational surgical procedure for such cases as it has the potential to cure.     

Comparative study and systematic review of laparoscopic liver resection for hepatocellular carcinoma

AIM: To compare the surgical outcomes between laparoscopic liver resection (LLR) and open liver resection (OLR) as a curative treatment in patients with hepatocellular carcinoma (HCC).METHODS: A PubMed database search was performed systematically to identify comparative studies of LLR vs OLR for HCC from 2000 to 2014. An extensive text word search was conducted, using combinations of search headings such as “laparoscopy”, “hepatectomy”, and “hepatocellular carcinoma”. A comparative study was also performed in our institution where we analysed surgical outcomes of 152 patients who underwent liver resection between January 2005 to December 2012, of which 42 underwent laparoscopic or hand-assisted laparoscopic resection and 110 underwent open resection.RESULTS: Analysis of our own series and a review of 17 high-quality studies showed that LLR was superior to OLR in terms of short-term outcomes, as patients in the laparoscopic arm were found to have less intraoperative blood loss, less blood transfusions, and a shorter length of hospital stay. In our own series, both LLR and OLR groups were found to have similar overall survival (OS) rates, but disease-free survival (DFS) rates were higher in the laparoscopic arm.CONCLUSION: LLR is associated with better short-term outcomes compared to OLR as a curative treatment for HCC. Long-term oncologic outcomes with regards to OS and DFS rates were found to be comparable in both groups. LLR is hence a safe and viable option for curative resection of HCC.     

Surgical Treatment for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is an epithelial tumor derived from hepatocytes; it accounts for 80% of all primary liver cancers and ranks globally as the fourth leading cause of cancer-related deaths. HCC treatment is a multidisciplinary and a multimodal task, with surgery in the form of liver resection and liver transplantation (LT) representing the only potentially curative modality. However, there are variable opinions and discussions about applying these surgical options and using other supporting treatments. This article is a narrative review that includes articles published from 1984 to 2013 located by searching scientific databases such as PubMed, SCOPUS, and Elsevier, with the main keyword of hepatocellular carcinoma in addition to other keywords such as liver transplantation, liver resection, transarterial chemoembolization, portal vein embolization, bridging therapy, and downstaging. In this review, we focus mainly on the surgical treatment options offered for HCC, in order to illustrate the current relevant data available in the literature to help in applying these surgical options and to use other supporting treatment modalities when appropriate.     

From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world

Hepatocellular carcinoma(HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.     

Anatomical resection of hepatocellular carcinoma: A critical review of the procedure and its benefits on survival

Hepatocellular carcinoma(HCC) is the sixth most common type of cancer and the third most frequent cause of cancer-related death. Advances in preoperative assessment of HCC(e.g., imaging studies and liver function tests), surgical techniques, and postoperative care have improved the surgical outcomes and survival of patients who undergo hepatic resection for HCC. However, in the last 20 years, the long-term survival after hepatectomy has remained unsatisfactory owing to the high rates of local recurrence and multicentric occurrence. Anatomical liver resection(AR) was introduced in the 1980 s. Although several studies have revealed tangible benefits of AR for HCC, these benefits are still debated. Because most HCCs occur in patients with liver cirrhosis and poor hepatic function, there are many factors that affect survival, including the surgical method. Nevertheless, many studies have documented the perioperative and long-term benefits of AR in various conditions. In this article, we review the results of several recently published, well-designed comparative studies of AR, to investigate whether AR provides real benefits on survival outcomes. We also discuss the potential pitfalls associated with this approach.     

Management of small hepatocellular carcinoma

In the last years the incidence of hepatocellular carcinoma (HCC) is rising in cirrhotic patients worldwide. Due the importance of early and definite diagnosis of HCC, any nodular lesion detected in patients with chronic liver disease should be considered as suspicious for HCC. The screening and surveillance programs in patients with liver diseases have increased the number of small HCC detected at an early stage, when the therapeutic options available are able to provide benefit. The introduction of new imaging techniques has improved the accuracy of characterizing these nodules. According to the EASL recommendations, contrast-enhanced computed tomography (CT), contrast enhanced ultrasound (US) and magnetic resonance (MR) with different MR-contrast agents are currently used to characterize liver lesions. Imaging guided biopsy is recommended for small nodules or in lesions without typical features (arterial hypervascularization) in at least two imaging techniques. Frequently the differential diagnosis of small nodules is complicated by discordant vascularity and recent studies have also demonstrated the presence of small hypovascular HCC at perfusional US and helical CT. At present, different treatment options can be offered to patients with diagnosis of small HCC at an early stage; percutaneous techniques, surgical resection and liver transplantation can provide benefit in properly selected patients. This review describes some critical points regarding the detection, diagnosis and therapeutic management of small nodules of HCC in cirrhotic patients.     

Intermediate hepatocellular carcinoma: How to choose the best treatment modality?

Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team.     

Hepatocellular cancer: Resection or transplantation

Surgery remains the treatment of choice for hepatocellular carcinoma (HCC). For HCC without underlying cirrhosis resection remains the mainstay treatment option. Prognosis depends on the stage of the tumor. Survival appears to be better for small (less than 5 cm) solitary tumors with negative resection margins and absence of vascular invasion. At present, liver transplantation does not have an established role in the treatment of HCC in a non-cirrhotic liver. Because of the high recurrence rate, it should not be considered for more advanced disease which is not amenable to resection. The surgical approach in cirrhotics depends not only on the stage of the tumor but also on the liver functional reserve. Tumor size, presence of multifocal disease, and vascular invasion determine the risk of HCC recurrence after resection, and the functional stability of the liver determines both resectability and outcome. In societies in which transplantation is not available, small tumors will be treated with liver resection. The outcome in patients with well preserved liver function is relatively good, at least in the medium term. However, recurrent tumor and progressive hepatic decompensation have significant adverse effects on long-term survival. Poor functional reserve may be associated with significant perioperative mortality and lower survival due to progressive liver failure. In our opinion, for small cirrhosis-related HCCs, liver transplantation offers better long-term prospects than resection. Therefore, if liver transplantation is available as an option it should be considered as the treatment of choice, particularly for younger patients with otherwise good life expectancy.     

肝细胞癌降期转化的治疗策略

手术是肝细胞癌(HCC)最重要的根治性手段,但初诊时能获得手术切除的HCC患者不足30%。如何将不能切除转化为可根治性切除成为提高HCC生存率的重要方面,也是近年来的研究热点。目前,综合运用经肝动脉插管治疗、放射治疗、靶向治疗等方法让HCC实现降期,或者通过门静脉栓塞、联合肝脏隔断和门静脉结扎使残余肝体积快速增大,均可实现转化成功从而获得根治性切除的机会。但是,如何优化多种治疗模式,规范复杂性肝癌患者的多学科诊疗路径,提高手术切除的效率和安全性,仍需要进一步深入探讨和研究。