Current opinion on the role of resection and liver transplantation for hepatocellular cancer

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.     

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.     

Leberresektion vs. Lebertransplantation bei HCC

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the ninth most common cancer in women in the world. For surgical treatment, two options are available: surgical resection and orthotopic liver transplantation. The treatment algorithms in Germany are currently determined by the S3 guideline and by the revised guideline for organ transplantation; however, the final decision should be discussed on an individual basis in an interdisciplinary tumor conference. Surgical resection is recommended for all patients with resectable HCC without underlying cirrhosis or compensated chronic liver disease and sufficient liver function. Resection should be minimally invasive and parenchyma-sparing. For HCC in cirrhosis within the Milan criteria, liver transplantation is indicated in principle. A match model for end-stage liver disease (matchMELD) can be applied in order to facilitate timely organ allocation. Due to the organ shortage, liver donations from living donors should be evaluated. Bridging therapies such as transarterial chemoembolization are recommended. For non-transplantable patients, surgical resection or radiofrequency ablation is recommended in regard to the functional resectability.     

The evolution of liver transplantation for hepatocellular carcinoma (past, present, and future)

Over the past quarter-century, liver transplantation (LT) has been established as a durable therapy for all forms of end-stage liver disease. LT appears ideally suited for hepatocellular carcinoma (HCC), as it involves complete oncologic resection and correction of the underlying liver dysfunction. Since LT based on the Milan criteria has been shown to provide good diseasefree survival, LT is considered the optimal treatment for small HCC, especially in patients with underlying chronic liver disease. However, because there is a severe shortage of organ donors, not all patients in need can be offered LT. Transplant listing criteria must simultaneously determine the greatest number of suitable candidates for LT while rejecting the smallest number of those who could benefit from LT. The amended model for end-stage liver disease allocation policy has had a positive effect on liver transplant candidates with HCC, and their number has been increasing significantly over the past several years. To minimize dropout from the waiting list, the treatment of HCC with procedures such as chemoembolization, radiofrequency ablation, or ethanol injection in patients awaiting LT have become widespread. It is currently accepted that liver resection is the best option for the treatment of small HCC when liver function is well preserved, and that LT is preferred when liver function is severely impaired (Child-Pugh class B or C). However, the question arises as to what is the best option for Child-Pugh class A patients with early HCC eligible for both resection and LT, especially in Western countries. HCC is a major indication for living donor liver transplantation (LDLT), because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of LDLT may offer more patients a potentially curative treatment without reducing the donor pool of organs for patients on the waiting list with nonmalignant liver disease. However, imprudent expansion of the selection criteria may result in more patients with HCC being cured at the expense of a higher incidence of recurrence.     

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.     

Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria

Background/Purpose

It has been reported that hepatic resection may be preferable to other modalities for the treatment of small hepatocellular carcinomas (HCCs), by contributing to improved overall and disease-free survival. Ablation techniques such as radiofrequency ablation (RFA) have also been used as therapy for small HCCs; however, few studies have compared the two treatments based on long-term outcomes. The effectiveness of hepatic resection and RFA for small nodular HCCs within the Milan criteria were compared.

Methods

A retrospective cohort study was performed with 278 consecutive patients who underwent curative hepatic resection (n = 123) or initial RFA percutaneously (n = 110) or surgically (thoracoscopic-, laparoscopic-, and open-approaches; n = 45) for HCC. The selection criteria for treatment were based on uniform criteria. Mortality related to therapy and 3- and 5-year overall and disease-free survivals were analyzed.

Results

The model for endstage liver disease (MELD) scores for all patients in the series were less than 13. There were no therapy-related mortalities in either the hepatic resection or RFA groups. The incidence of death within 1 year after therapy (1.6 and 1.9%, respectively) was similar in the hepatic resection and RFA groups. The group that underwent hepatic resection showed a trend towards better survival (P = 0.06) and showed significantly better disease-free survival (P = 0.02) compared with the RFA group, although differences in liver functional reserve existed. The advantage of hepatic resection was more evident for patients with single tumors and patients with grade A liver damage. In contrast, patients with multinodular tumors survived longer when treated with RFA, regardless of the grade of liver damage. Further analysis showed that surgical RFA could potentially have survival benefits similar to those of hepatic resection for single tumors, and that surgical RFA had the highest efficacy for treating multinodular tumors.

Conclusions

In patients with small HCCs within the Milan criteria, hepatic resection should still be employed for those patients with a single tumor and well-preserved liver function. RFA should be chosen for patients with an unresectable single tumor or those with multinodular tumors, regardless of the grade of liver damage. In order to increase long-term oncological control, surgical RFA seems preferable to percutaneous RFA, if the patient’s condition allows them to tolerate surgery.     

Radiofrequency ablation or percutaneous ethanol injection for the treatment of liver tumors

The liver is a common location of both primary and secondary malignancies. For unresectable liver cancer, many local ablative therapies have been developed. These include e.g., percutaneous ethanol injection (PEI), percutaneous acetic acid injection, radiofrequency ablation (RFA), cryoablation, microwave ablation, laserinduced thermotherapy, and high-intensity focused ultrasound. RFA has recently gained interest and is the most widely applied thermoablative technique. RFA allows more effective tumor control in fewer treatment sessions compared with PEI, but with a higher rate of complications. However, there are certain circumstances where PEI therapy represents a better strategy to control liver tumors than RFA, especially in situations where RFA is difficult, for example when large vessels surround the tumor. In the context of hepatocellular carcinoma (HCC), both RFA and PEI are feasible and of benefit in non-operable patients. RFA seems superior to PEI in HCC 2 cm, and the combination of interventions may be of benefit in selected patients. Liver resection is superior to RFA for patients with HCC meeting the Milan criteria, but RFA can be employed in tumors ≤ 3 cm and where there is an increased expected operative mortality. In addition, some lines of evidence indicate that RFA and PEI can be employed as a bridge to liver transplantation. The use of RFA in colorectal liver metastases is currently limited to unresectable disease and for patients unfit for surgery. The aim of this article is to summarize the current status of RFA in the management of liver tumors and compare it to the cheap and readily available technique of PEI.     

Thermal ablative therapy for malignant liver tumors: a critical appraisal

The management of primary and secondary malignant liver tumors poses a great challenge to clinicians. Although surgical resection is the gold-standard treatment, most patients have unresectable malignant liver tumors. Over the past decade, various modalities of loco-regional therapy have gained much interest. Among them, thermal ablative therapy, including cryotherapy, microwave coagulation, interstitial laser therapy, and radiofrequency ablation (RFA), have been proven to be safe and effective. Despite the effective tumor eradication achieved within cryotherapy, the underlying freeze/thaw mechanism has resulted in serious complications that include bleeding from liver cracking and the 'cryoshock' phenomenon. Thermal ablation using microwave and laser therapy for malignant liver tumors is curative and is associated with minimal complications. However, this treatment modality is effective only for tumors <3 cm diameter. Radiofrequency ablation seems to be the most promising form of thermal ablative therapy in terms of a lower complication rate and a larger volume of ablation. However, its use is restricted by the difficulty encountered when using imaging studies to monitor the areas of ablation during and after the procedure. Moreover, the techniques of RFA need to be refined in order to achieve the same oncological radicality of malignant liver tumors as achieved by surgical resection. As each of the loco-regional therapies has its own advantages and limitations, a multidisciplinary approach using a combination of therapies will be the future trend for the management of malignant liver tumors.     

Complications of radiofrequency ablation of hepatic tumors:Frequency and risk factors

Radiofrequency ablation(RFA)has become an important option in the therapy of primary and secondary hepatic tumors.Surgical resection is still the best treatment option,but only a few of these patients are candidates for surgery:multilobar disease,insufficient liver reserve that will lead to liver failure after resection,extra-hepatic disease,proximity to major bile ducts and vessels,and co-morbidities.RFA has a low mortality and morbidity rate and is considered to be safe.Thus,complications occur and vary widely in the literature.Complications are caused by thermal damage,direct needle injury,infection and the patient’s co-morbidities.Tumor type,type of approach,number of lesions,tumor localization,underlying hepatic disease,the physician’s experience,associated hepatic resection and lesion size have been described as factors significantly associated with complications.The physician in charge should promptly recognize high-risk patients more susceptible to complications,perform a close post procedure follow-up and manage them early and adequately if they occur.We aim to describe complications from RFA of hepatic tumors and their risk factors,as well as a few techniques to avoid them.This way,others can decrease their morbidity rates with better outcomes.     

Liver transplantation for solitary hepatocellular carcinoma less than 3 cm in diameter in Child A cirrhosis

Liver transplantation for hepatocellular carcinoma (HCC) is the treatment of choice for patients with unresectable tumors within the Milan criteria associated with Child B or C cirrhosis. Liver transplantation provides the best cure for both the HCC and the underlying cirrhosis. In recent years, some authors have advocated liver transplantation even for resectable early HCC associated with Child A cirrhosis, leading to a controversy of whether resection or transplantation should be the first-line therapy for patients with small HCC in Child A cirrhosis. Recent studies comparing liver resection and transplantation for early HCC demonstrated similar long-term survival of 60-70%, but liver transplantation is associated with a lower tumor recurrence rate. However, the current shortage of deceased donor liver grafts limits the applicability of liver transplantation for HCC. The use of live donor liver transplantation for patients with a small solitary HCC in Child A cirrhosis that is resectable may not be justified ethically because of the potential risk to the donors. Patients put on a transplantation waiting list run a significant risk of tumor progression and dropout, while liver resection is immediately applicable to all. Advocating primary liver transplantation for patients with early HCC associated with compensated cirrhosis will increase the waiting time for transplantation and further increases the chance of dropout. Resection first and salvage transplantation for recurrent tumors or liver failure is an alternative strategy that may reduce the use of liver grafts. However, the long-term survival result of such a strategy compared with primary liver transplantation remains unclear.     

Current status of liver transplantation for treatment of hepatocellular carcinoma

Hepatocellular carcinoma accounts for more than 5% of all malignancies with a continuous increase worldwide. The most important risk factor is liver cirrhosis, frequently associated with hepatitis B virus or hepatitis C virus infection. Liver resection is the only treatment that can potentially achieve cure. In carefully selected patients with a tumor smaller than 5 cm the 5-year survival is around 50%. The presence of liver cirrhosis and portal hypertension limits the feasibility of hepatic resection. Child-Pugh A patients without major associated risk factors may be considered as the ideal target group for resection. A significant local disease recurrence rate of more than 70% at 5 years is the main problem of hepatic resection. Orthotopic liver transplantation offers the possibility of removing a potentially multicentric tumor and the underlying end-stage liver disease. Due to pure selection of suitable candidates the initial reports on the efficacy of liver replacement in a cohort of patients with hepatocellular carcinoma were disappointing. Taking the shortness of donor organs and the high posttransplant tumor recurrence rate into account, several groups developed criteria qualifying transplantation. A tumor size of >6 cm and gross intrahepatic portal vein involvement seem to be of significant prognostic importance. Patients with smaller solitary tumors or less than 3 tumors with a total tumor diameter of <8 cm have the same survival after transplantation as those with benign liver disease. Living donor liver transplantation offers a new approach to overcome the organ shortage and to theoretically extend the indication for transplantation in hepatocellular carcinoma.     

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND: Hepatocellular carcinoma (HCC) is a com-plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con-founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal-ity globally with a rising trend of incidence in some of the de-veloped countries, which indicates the need for better surgical and nonsurgical management strategies.
DATA SOURCES: PubMed database was searched for relevant articles in English on the issue of HCC management.
RESULTS: Surgical resection represents a potentially cura-tive option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and micro-wave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The signiifcant survival beneift with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treat-ment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential beneift is sug-gested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immuno-therapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches.
CONCLUSION: Treatment decisions have become increasing-ly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a compre-hensive, multidisciplinary approach.     

原发性肝癌外科治疗的理性思考

全球肝细胞癌（hepatocellular carcinoma,HCC）的发病率一直呈上升趋势,肝切除仍然是HCC患者的首选治疗。有临床症状肝癌患者的可切除率为20％～30％。大型肝切除术不输血是肝切除术的一个进展。原位肝移植应遵照米兰标准执行,并应把肝移植数量控制在肝切除数量的10％以下。HCC的微创治疗,包括经皮射频消融、经皮微波凝固治疗、冷冻治疗、高强度聚焦超声热疔等,一直在临床应用。芮静安提出的“120”肝外科技术适用于城市和农村的医院。未来,HCC患者治疗后的无瘤生存率将会提高。     

介入治疗在中晚期肝癌降期中的作用

介入治疗已成为中晚期肝癌姑息治疗的主力军。与此同时,在肝癌降期领域,介入治疗也发挥着越来越重要的作用,通过局部介入治疗可使中晚期肝癌的瘤灶体积减小、数量减小使之符合肝癌移植或者切除术标准。介入降期技术包括经肝动脉化疗栓塞术、药物缓释微球、经动脉放射性栓塞治疗以及各种消融治疗技术(射频消融、微波消融、冷冻消融、酒精消融)等。最佳的介入降期策略仍未达成共识,但是通过开展高级别循证医学研究,对不同方法的最佳可获益人群进行筛选,评估不同介入降期策略对后续肝移植手术在手术难度、安全性、术后疗效等方面的影响,有望提升介入治疗在中晚期肝癌降期的效果。     

Liver transplantation for malignancy:current treatment strategies and future perspectives

In 1967,Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma.In the following,liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies.Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed.In1996,Mazzaferro et al introduced the Milan criteria,offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma.Since then,liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research.In this context,several aspects must be considered:(1)Given the shortage of deceased-donor organs,long-term overall and disease free survival should be comparable with results obtained in patients transplanted for nonmalignant disease;(2)In this regard,living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice;and(3)Ongoing research focusing on perioperative therapy and antiproliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival.The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.     

Management of Hepatocellular Carcinoma: Current Status and Future Directions

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. This cancer commonly arises against a background of chronic liver disease. As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely utilized staging system is the Barcelona Clinic Liver Cancer staging system, which recommends treatments based on tumor size and the underlying liver disease and functional status of the patient. Treatment options range from surgical resection or transplantation to locoregional therapies with modalities such as radiofrequency ablation and transarterial chemoembolization to systemic chemotherapies. Future care involves the development of combination therapies that afford the best tumor response, further clarification of the patients best suited for therapies and the development of new oral chemotherapeutic agents.     

Local injection therapy for hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks the third most common cause of cancer-related death. Surgical resection, liver transplantation and percutaneous ablation are generally considered the only curative treatment for early stage HCC. Besides the limitations of insufficient organ donors and a long waiting time for liver transplantation, however, resection is applied only to patients with good hepatic reserve and localized tumors, with a resectability of 30%. DATA SOURCES: Local ablation therapy, which is minimally invasive but contributes to the significant improvement of survival in patients with unresectable tumor, hasbeen widely used in treating small HCC. Among the techniques of local therapy, percutaneous ethanol injection (PEI) with a complete response in 80% of HCCs less than 3 cm has been accepted as an alternative to surgery in patients with small HCC. Moreover, percutaneous hepatic quantified ethanol injection (PHQEI) or PEI according to the standard criteria has been confirmed to benefit patients with HCC, especially when quantified ethanol is given at a short interval (QESI, the interval was 2-3 days). RESULT: Several limitations related to local percutaneous methods may result in incomplete therapeutic effect in case of larger HCC nodules (>3 cm). CONCLUSION: The combined use of different methods according to the clinical status of patients or tumors may be essential to the effective treatment of HCC.     

In situ thermal ablation of focal liver neoplasms,with a special emphasis on the intraoperative ultrasound-guided radio frequency ablation method

In the last two decades an important number of image-guided procedures have been developed in order to treat focal liver tumors through ablation in a similar way with the surgical procedure, which is still considered as the curative method for patients with resectable hepatic tumours. Unfortunately this criteria does not apply to all patients and in those cases (nonsurgical patients), the techniques are becoming frequently used as standard independent or adjuvant therapies. Tumour ablation using thermal procedures is now considered as one of the most promising among these alternative ablation therapies. It is the goal of these techniques together with the continuous improvement in technology and increasing clinical experience, to become the treatment of choice for limited liver tumours, challenging surgical resection     

肝癌及其治疗

对于早期肝癌来讲,肝切除或肝移植是最好治疗方法,消融术及导管栓塞化疗有一定疗效,全身化疗效果较差。由于约80％的患者在肝癌手术时伴有严重的肝功能不全、肝内播散或远处转移,手术切除率低或术后复发率高,所以肝癌的综合治疗已经是公认的治疗模式。     

Results of liver transplantation in patients with preoperative diagnosis of hepatocellular carcinoma

BACKGROUND: [corrected] Hepatocellular carcinoma is the most frequent malignant hepatic tumor in humans, and its association with cirrhosis makes the therapeutic approach still a challenge. Liver transplantation is the treatment of choice for cirrhotic patients with unresectable early hepatocellular carcinoma AIM: To evaluate the post-transplant outcome of a cohort of 15 cirrhotic patients with preoperative diagnosis of unresectable early hepatocellular carcinoma according the Milan criteria who underwent liver transplantation between September 1991 and December 2003 METHODS: We retrospectively reviewed the clinical data from 15 liver transplant recipients and the explanted livers were assessed for the efficacy of preoperative therapy. Patient survival and tumor recurrence were evaluated as primary outcome measures RESULTS: The mean age of the patients was 49.2 +/- 14.3 years and hepatitis C was the etiology of the underlying liver disease in 60%. Preoperative therapy, either chemoembolization or percutaneous ethanol injection, was performed in 12 (86%) patients. Complete necrosis of all tumoral lesions were observed in 5 of 12 patients (44,66%); all others had variable amounts of viable tumor in the explanted liver. Only 4 of the 15 (26.6%) explanted livers had microscopic vascular invasion. The median post-transplant follow-up was 33 months (range: 8-71 months) and no tumor recurrence was detected during this period. The only death was an early event not related to the tumor. The recurrence-free survival rates at 1 and 3 years were 93% CONCLUSION: Liver transplantation has emerged as a good alternative for cirrhotic patients with early hepatocellular carcinoma not amenable to curative resection, offering excellent recurrence-free survival rates.