Recent advances in the surgical treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection (LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation (LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed.     

Value of radiofrequency ablation in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a malignant disease that substantially affects public health worldwide. It is especially prevalent in east Asia and sub-Saharan Africa, where the main etiology is the endemic status of chronic hepatitis B. Effective treatments with curative intent for early HCC include liver transplantation, liver resection (LR), and radiofrequency ablation (RFA). RFA has become the most widely used local thermal ablation method in recent years because of its technical ease, safety, satisfactory local tumor control, and minimally invasive nature. This technique has also emerged as an important treatment strategy for HCC in recent years. RFA, liver transplantation, and hepatectomy can be complementary to one another in the treatment of HCC, and the outcome benefits have been demonstrated by numerous clinical studies. As a pretransplantation bridge therapy, RFA extends the average waiting time without increasing the risk of dropout or death. In contrast to LR, RFA causes almost no intra-abdominal adhesion, thus producing favorable conditions for subsequent liver transplantation. Many studies have demonstrated mutual interactions between RFA and hepatectomy, effectively expanding the operative indications for patients with HCC and enhancing the efficacy of these approaches. However, treated tumor tissue remains within the body after RFA, and residual tumors or satellite nodules can limit the effectiveness of this treatment. Therefore, future research should focus on this issue.     

Biology of hepatic cancer stem cells

Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver and is the third most frequent cause of cancer death worldwide. Although advances in HCC detection and treatment have increased the likelihood of a cure at early stages of the disease, HCC remains largely incurable because of late presentation and tumor recurrence. Only 25% of HCC patients are deemed suitable for curative treatment, with the overall survival at just a few months for inoperable patients. Additionally, this disease is particularly difficult to treat because of the high recurrence rate, its chemotherapy-resistant nature and the premalignant nature of surrounding cirrhotic liver disease. In the past few years, compelling evidence has emerged in support of the hierarchic cancer stem cell (CSC)/tumor-initiating cell (T-IC) model for solid tumors, including HCC. Understanding the characteristics and function of CSCs in the liver has also shed light on HCC management and treatment, including the implications for prognosis, prediction and treatment resistance. In this review, a detailed summary of the recent progress in liver CSC research with regard to identification, regulation and therapeutic implications will be discussed.     

Advances in understanding of colorectal liver metastasis and implications for the clinic

Colorectal cancer is one of the most common cancers in both the USA and Europe. Over the course of diagnosis, treatment and surveillance, up to 50% of these patients will develop metastases to their liver. In the past 20 years alone, there have been multiple advances in the management of these colorectal metastases to the liver. These advances have been made in characterization of these tumors, diagnosis and in treatment, both locally and systemically. Because of this progress, there are subsets of patients with this stage IV disease who are cured of their disease. While significant progress has been made, there still exist limitations in the management of metastatic colorectal cancer to the liver. This review outlines current strategies and highlights recent advances in the management of colorectal liver metastases.     

Primary liver cancer

Liver cancer, whether primary or secondary, is one of the most difficult to treat among malignant solid tumors, with a miserable prognosis. In view of the relative lack of exciting progress in the management of metastatic liver cancer in recent years this lecture necessarily concerns primary liver cancer, particularly hepatocellular carcinoma (HCC). Time permits coverage of only several important aspects of general interest and recent advances in the study of HCC.     

Evidence-based medicine in the treatment of hepatocellular carcinoma

The incidence of hepatocellular carcinoma is increasing worldwide. Diagnosis at early stage is crucial to allow the application of curative treatments, that are the sole hope to increase their life expectancy. Surgical resection and liver transplantation are considered the first line options for early tumors, although there is no agreement on which is the best treatment approach. Resection achieves excellent results in patients with single tumors, absence of portal hypertension and normal bilirubin, but is limited by the high recurrence rate. Liver transplantation also achieves excellent results in patients with single tumors smaller than 5 cm or even three nodules smaller than 3 cm. However, this procedure is hampered by the shortage of donors and the increasing waiting times that have reduced their intention-to-treat outcomes. Treatment while waiting for a donor is controversial, but radical antitumoral therapies seem cost-effective in long waiting times. Percutaneous therapies are reserved for patients with single non-surgical tumors. More than 60 randomized clinical trials have been published to assess treatments for patients with advanced tumors, but there is no definitive evidence of survival benefits. A recent randomized trial reported that chemoembolization may benefit HCC patients in terms of survival, but additional studies to confirm this data are recommended.     

Comprehensive review of post-liver resection surgical complications and a new universal classification and grading system

Liver resection is the gold standard treatment for certain liver tumors such as hepatocellular carcinoma and metastatic liver tumors. Some patients with such tumors already have reduced liver function due to chronic hepatitis, liver cirrhosis, or chemotherapy-associated steatohepatitis before surgery. Therefore, complications due to poor liver function are inevitable after liver resection. Although the mortality rate of liver resection has been reduced to a few percent in recent case series, its overall morbidity rate is reported to range from 4.1% to 47.7%. The large degree of variation in the post-liver resection morbidity rates reported in previous studies might be due to the lack of consen-sus regarding the definitions and classification of postliver resection complications. The Clavien-Dindo(CD) classification of post-operative complications is widely accepted internationally. However, it is hard to apply to some major post-liver resection complications because the consensus definitions and grading systems for posthepatectomy liver failure and bile leakage established by the International Study Group of Liver Surgery are incompatible with the CD classification. Therefore, a unified classification of post-liver resection complications has to be established to allow comparisons between academic reports.     

Liver transplantation for patients with human immunodeficiency virus and hepatitis C virus co‐infection: update in 2013

Because of the progress of anti‐retroviral therapy (ART) for human immunodeficiency virus (HIV), mortality due to opportunistic infection resulting in AIDS has been remarkably reduced. However, meanwhile, half of those patients have died of end‐stage liver cirrhosis due to hepatitis C virus (HCV) with liver cirrhosis and early occurrence of hepatocellular carcinoma. Recently, in 2013, non‐cirrhotic portal hypertension due to ART drugs or still unknown mechanisms have become problematic with early progression of the disease in this patient population. Liver transplantation (LT) could be one treatment of choice in such cases, but the indications for LT perioperative management, including both HIV and HCV treatments and immunosuppression, are still challenging. In this review, we update the literature on HIV/HCV co‐infection and LT as well as recent effort for modifying allocation system for those patients.     

General management

Hepatocellular carcinoma is one of the most common malignancies worldwide. The general management of hepatocellular carcinoma begins with an accurate diagnosis. With advances in imaging studies, noninvasive diagnosis has become an accepted standard of care for hepatocellular carcinoma, though pathologic examination is still required in selected cases. Following diagnosis, accurate staging is the next most important step in selecting the most appropriate treatment modality. Patients with localised tumor and compensated liver disease should be considered for partial hepatectomy, and patients with poor hepatic function but early tumor stage are candidates for liver transplantation. Patients who do not qualify for either of these curative treatments may be evaluated for palliative therapy, of which transarterial chemoembolisation is most widely used. This review will discuss the role of biopsy, the pros and cons of noninvasive and pathologic tissue diagnosis as well as the general approach to choose the most appropriate treatment for patients with hepatocellular carcinoma.     

Medical management of adrenocortical carcinoma: Current recommendations,new therapeutic options and future perspectives

Adrenocortical carcinoma is a rare malignant tumor of poor prognosis, frequently requiring additional treatments after initial surgery. Due to its adrenolytic action, mitotane has become the first-line medical treatment in patients with aggressive adrenocortical carcinoma. Over the last 2 years, apart from the classical chemotherapy based on etoposide and platinum salts, several studies reported the use of drugs such as temozolomide, tyrosine kinase inhibitors or immunotherapy, with more or less convincing results. The aim of this review is to give further insights in the use of these drugs, and to describe potential therapeutic perspectives based on recent pangenomic studies, for the future management of these still difficult to treat tumors.     

Multidisciplinary management of hepatocellular carcinoma

Hepatocellular carcinoma is a leading cause of death in patients with cirrhosis. Management algorithms continually are increasing in sophistication and involve application of single and multimodality treatments, including liver transplantation, hepatic resection, ablation, transarterial chemoembolization, radioembolization, and systemic chemotherapy. These treatments have been shown to increase survival times. As many as 75% of patients with limited-stage disease who are given curative therapies survive 5 years, whereas less than 20% of untreated patients survive 1 year. Treatment can be optimized based on the patient's tumor stage, hepatic reserve, and functional status. However, because of the heterogeneity in presentation among patients, a multidisciplinary approach is required to treat hepatocellular carcinoma, involving hepatologists, surgeons, interventional radiologists, and oncologists. We present each specialist's viewpoint on controversies and advances in the management of hepatocellular carcinoma.     

Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor(IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed suchas monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor Ⅱ rather than insulin growth factor Ⅰ. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-Ⅰ signaling pathway for hepatocellular carcinoma treatment.     

Combined intraarterial 5-fluorouracil and intramuscular interferon-alpha therapy for advanced hepatocellular carcinoma

We report the case of a 66-year-old man with hepatic cirrhosis and multiple hypervascular tumors in both lobes of the liver as well as tumor thrombi in the portal vein. After unresectable hepatocellular carcinoma was diagnosed, transcatheter arterial embolization was considered to be difficult, because he had major portal vein thrombosis. Conventional ultrasonically-guided local treatments, such as percutaneous ethanol injection therapy and radiofrequency ablation, were also of no value because the tumors were huge and multiple. Ultimately, he was treated with a combination of intraarterial 5-fluorouracil and intramuscular interferon-alpha. After treatment, the multiple tumors became non-enhancing on contrast computed tomography scans and showed a marked decrease in size. There were no serious adverse effects (such as myelosuppression or hepatotoxicity) during treatment or follow-up and the patient is doing well at present. In conclusion, a combination of intraarterial 5-fluorouracil with intramuscular interferon-alpha appears to be useful for the management of advanced hepatocellular carcinoma, especially in patients for whom more aggressive treatment is not acceptable.     

Staging systems: is there a surgical staging and a medical one?

Clinical staging systems for cancer provide guidelines for patient assessments and therapeutic decisions. Furthermore, appropriate staging is essential for objective comparison between the outcomes of different treatments, including clinical trials. While the prognosis of most solid tumors is generally dependent on tumor stage at presentation, prediction of prognosis in hepatocellular carcinoma (HCC) patients is more complicated because underlying liver function also affects patient survival. The Okuda classification and the pathologic tumor–node–metastasis classification are most commonly used internationally, but each has its own limitation. Several new staging systems for HCC have recently been reported from Italy, Japan, and Spain. Most prognostic models consist of parameters reflecting tumor stage and liver function reservoir, which were selected based on analyses of large series of HCC patients. Ideally, staging systems should be applicable to any HCC patient. However, each existing staging system may have been characterized by the patient population based on which it was constructed. For practical purposes, staging systems should be simple and based on data that are easily obtainable. Consensus is yet to be achieved on the optimal staging system for HCC that assures progress in the development of novel therapies.     

Targets of immunotherapy for hepatocellular carcinoma: An update

Hepatocellular carcinoma, the most common primary liver cancer, in an immunogenic tumor with a poor prognosis because these tumors are diagnosed at late stages. Although, surgical resection, ablation, liver transplant, and locoregional therapies are available for early stages; however, there are yet no effective treatment for advanced and recurrent tumors. Immune checkpoint inhibitor therapy and adoptive cell transfer therapy has gained the popularity with some positive results because these therapies overcome anergy and systemic immune suppression. However, still there is a lack of an effective treatment and thus there is an unmet need of a novel treatment. At present, the focus of the research is on oncolytic viral therapy and combination therapy where therapies including radiotherapy, immune checkpoint therapy, adoptive cell transfer therapy, and vaccines are combined to get an additive or synergistic effect enhancing the immune response of the liver with a cytotoxic effect on tumor cells. This review discusses the recent key development, the basis of drug resistance, immune evasion, immune tolerance, the available therapies based on stage of the tumor, and the ongoing clinical trials on immune checkpoint inhibitor therapy, adoptive cell transfer therapy, oncolytic viral vaccine therapy, and combination therapy.     

Management of liver metastases from colorectal cancer

About 50% of colorectal cancer patients develop liver metastasis, and liver resection is considered the only curative therapy. However, the rate of recurrence is high, which contributes to poor prognosis. Since surgical resection coverage has increased because of improved hepatectomy including portal vein embolization, tumors shrink because of the effectiveness of recent chemotherapy, such as FOLFOX and FOLFIRI, and it has become possible for many patients whose cancer was judged unresectable before to undergo resection. Improvement of new anticancer drugs such as molecularly targeted biologics is greatly changing therapeutic systems of metastatic colorectal cancer, and it is time for us to innovate stage IV therapy. In this report, we will review new treatment strategies for metastatic liver cancer from colorectal cancer, clinical trials of new anticancer drugs for liver metastasis, surgery and ablation as local therapy, and further clarify complex therapeutic systems for metastatic liver tumors from colorectal cancer.     

Double primary mucoepidermoid carcinoma and hepatocellular carcinoma of the liver--a case report

Double primary mucoepidermoid-hepatocellular carcinoma of the liver is extremely rare, and only one case has previously been reported in the literature, although there have been about 14 cases of primary mucoepidermoid carcinoma of the liver. Most of the reported hepatic mucoepidermoid carcinoma showed a poor prognosis. We presently report the second case of a double primary mucoepidermoid carcinoma and hepatocellular carcinoma with a brief review of the published literature. A 52-year-old man was admitted because of epigastric pain that lasted for 2 months. A computed tomography of the abdomen revealed a 7-cm, ill-defined mass with irregular marginal enhancement in the left lobe of liver. Another 2-cm nodular tumor was found in segment 8 of the right lobe. The two separate nodules in the patient's liver demonstrated clearly different histologic and immunohistochemical features. The pathological diagnoses were mucoepidermoid carcinoma and hepatocellular carcinoma for the larger and the smaller tumors, respectively. The patient died of liver failure 6 months after a left lobectomy of the liver.     

An evidence-based multidisciplinary approach to the management of hepatocellular carcinoma (HCC): the Alberta HCC algorithm

Hepatocellular carcinoma (HCC) is one of only a few malignancies with an increasing incidence in North America. Because the vast majority of HCCs occur in the setting of a cirrhotic liver, management of this malignancy is best performed in a multidisciplinary group that recognizes the importance of liver function, as well as patient and tumour characteristics. The Barcelona Clinic Liver Cancer (BCLC) staging system is preferred for HCC because it incorporates the tumour characteristics (ie, tumour-node-metastasis stage), the patient's performance status and liver function according to the Child-Turcotte-Pugh classification, and then links the BCLC stage to recommended therapeutic interventions. However, the BCLC algorithm does not recognize the potential role of radiofrequency ablation for very early stage HCC, the expanding role of liver transplantation in the management of HCC, the role of transarterial chemoembolization in single large tumours, the potential role of transarterial radioembolization with 90Yttrium and the limited evidence for using sorafenib in Child- Turcotte-Pugh class B cirrhotic patients. The current review article presents an evidence-based approach to the multidisciplinary management of HCC along with a new algorithm for the management of HCC that incorporates the BCLC staging system and the authors' local selection criteria for resection, ablative techniques, liver transplantation, transarterial chemoembolization, transarterial radioembolization and sorafenib in Alberta.     

Hepatocellular carcinoma. Part 2. Treatment

Recent improvements on the therapeutical management of hepatocellular carcinoma are revised with special attention to evaluate the role of surgery for the disease. Considering that definitive surgical intervention is not feasible in most cases because of extreme tumor extension, multiplicity of tumor foci, and associated advanced liver cirrhosis at the time of diagnosis, others forms of treatment are listed, such as transcatheterarterial chemoembolization, percutaneous ethanol and acetic acid injections, and chemotherapy only to a small portion of patients with no indication for standard treatments. The emerging role of retinoic acid metabolism blocking agents, was examined and may offer a significant new potential treatment for cancer, inclusive the possibility of combining other anticancer drugs with exogenous retinoids or modulation of endogenous retinoids as a real opportunity to advance our ability to treat or prevent human cancer effectively Octreotide, nitrosamine and other drugs are analyzed and is concluded that improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma. The potential role of intersticial laser coagulation for patients with irresectable hepatic tumors was investigated, and in terms of experience, it has now been developed sufficiently to study its effect on these patients survival. The homeostatic control of angiogenesis and its influences on the tumor growth and for migration of metastatic cells, was focused in this concise review, given that hepatocytes are the source of much of the precursor pool, regulation of angiogenesis may be regarded as a new liver function with important consequences for tissue repair and cancer. Early hepatocellular carcinoma and its recognition in routine clinical practice contributes to improved patients survival. Recombinant-Interferon-alpha therapy surely prevents, the development of cirrhosis or hepatocellular carcinoma in about one-third of patients, with chronic hepatitis C, with sustained response. Finally, in individuals with life-threatening liver disease, such as those with cirrhosis and hepatocellular carcinoma, the liver transplantation, must be considered, besides controversial, however, with increasing experience the results of the procedure in these patients have improved, and may offer a better long-term survival than liver resection.