Liver transplantation in malignant disease

Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.     

Combined pancreatoduodenectomy and orthotopic liver transplantation for hepatocellular carcinoma with portal vein tumor thrombus： A case report

Hepatocellular cancer (HCC) is the most common primary malignant hepatic tumor that accounts for over 80% of primary liver tumors. The outlook for HCC is dismal if it is left untreated and the treatment for patients with HCC evolved into a complex task. The treatments for HCC are mainly surgical therapies including hepatic resection (HR) and liver transplantation. Although HR is a well accepted therapy for HCC, it is not suitable for patients with advanced cirrhosis. Orthotopic liver transplantation (OLT) is considered more appropriate in cases with HCC related to cirrhosis, because it may eliminate both the tumor and the underlying liver disease. In this study, we reported a patient with HCC and portal vein tumor thrombus underwent combined pancreatoduodenectomy with OLT and survived 23 months in our center.     

Liver transplantation for hepatocellular carcinoma in Asia

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, particularly in Asia where the major etiology, chronic hepatitis B virus infection, is endemic. The tumor frequently develops in a background of cirrhosis, and liver transplantation offers a chance to cure both the tumor and the underlying cirrhosis. The Milan criteria based on tumor size and number as an estimate of tumor burden are conventionally the gold standard in determining eligibility for transplantation, and the outcome is excellent. The shortage of organs from deceased donors has curtailed the adoption of extended criteria and led to the problems of long waiting times and dropouts. Several measures have been taken to tackle these issues, including prioritization of patients with HCC, use of pretransplant adjuvant treatment to prevent tumor progression, and living donor liver transplantation (LDLT). With a high incidence of HCC and a low organ donation rate, Asia has developed a distinctive pattern of indication and strategy in the application of liver transplantation. Over the last decade, the number of liver transplants in Asia has increased rapidly, by 10-fold, largely as a result of the development of LDLT. The proportion of patients who undergo liver transplantation for HCC is increasing and HCC comprises one third of the indication for liver transplantation in Asia. LDLT is the dominant strategy, accounting for 96% of the liver transplants for HCC. Many transplant programs accept patients beyond the Milan criteria, and the reported 3-year survival rate is about 60%. With the promotion of organ donation, better quantification of the benefit of LDLT for extended indications, and identification of predictors for survival, the practice of liver transplantation for HCC in Asia will continue to evolve.     

Liver resection for HCC with cirrhosis: Surgical perspectives out of EASL/AASLD guidelines

EASL/AASLD guidelines clearly define indications for liver surgery for HCC: patients with single HCC and completely preserved liver function without portal hypertension. These guidelines exclude from operation many patients that could benefit from radical resection and that are daily scheduled for hepatectomy in surgical centers. Patients with large tumors or with portal vein thrombosis cannot be transplanted or treated by interstitial treatments. In selected cases liver resection may obtain good long-term outcomes, significantly better than non-curative therapies. In cases of multinodular HCC, liver transplantation is the treatment of choice within Milan criteria; patients beyond these limits can benefit from liver resection, especially if only two nodules are diagnosed: even if they have a worse prognosis, survival results after liver surgery are better than those reported after TACE or conservative treatments. EASL/AASLD guidelines excluded from operating patients with portal hypertension but data about this topic are not conclusive and further studies are necessary. Selected patients with mild portal hypertension could probably be scheduled for liver resection and, considering the shortage of donors, listing for transplantation could be avoided.     

Strategies for the management of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) generally develops as a consequence of underlying liver disease, most commonly viral hepatitis. The development of HCC follows an orderly progression from cirrhosis to dysplastic nodules to early cancer development, which can be reliably cured if discovered before the development of vascular invasion (typically occurring at a tumor diameter of approximately 2 cm). The identifiable population at risk makes screening a realistic possibility, and liver imaging is recommended every 6 months for patients with cirrhosis. For patients with preserved liver function and no portal hypertension who develop HCC that is confined to one region of the liver, resection is the preferred treatment. If resection is not possible because of poor liver function, and the HCC is within the Milan criteria (1 nodule > or =5 cm, 2-3 nodules > or =3 cm), liver transplantation is the treatment of choice. To prevent tumor progression while waiting, nonsurgical treatments including percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are employed, but drop-out from the waiting list remains a problem. Living donor transplantation is an alternative that can eliminate drop-out and enable liver transplantation for patients with HCC whose disease does not fall within the Milan criteria. There is a need for more effective adjuvant therapies after resection and liver transplantation; newer antiangiogenic agents offer hope for improved outcomes in the future.     

Surgical resection of hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, primarily due to hepatitis C-related liver disease. Nearly 85%-90% of patients with HCC have underlying chronic liver disease or cirrhosis. Advanced tumor burden or prohibitive hepatic dysfunction precludes operative resection in most patients with HCC. Surgical resection is a treatment option with curative intent in patients with HCC not associated with cirrhosis or in patients with well-compensated liver disease. Tumor extent and hepatic function must be assessed preoperatively to avoid postresection hepatic failure, an often fatal condition that may require urgent liver transplantation. Appropriately selected candidates for liver resection have 5-year postoperative survival rates of 40%-70%, but recurrence rates approach 70%, especially in patients with cirrhosis. For this reason, the best resection for patients with HCC and cirrhosis is orthotopic liver transplantation, which has 5-year posttransplant survival rates of 65%-80% in well-selected candidates.     

Chirurgische Therapie neuroendokriner Tumoren der Leber und der Gallengänge

The indication for surgery for liver metastases from neuroendocrine tumors (NET) should be embedded in a multidisciplinary approach. There is a clear indication in patients in whom radical resection with curative intent is technically feasible. Despite high recurrence rates in the long run, the indication for liver resection is legitimated by the palliation of symptoms and the chance for cure. Improved long-term survival and concomitantly low perioperative mortality have been demonstrated in specialized centers. Based on the degree of evidence derived from published data, the indication for palliative resection, i.e., tumor mass reduction and palliation of symptoms, has not been finally confirmed. Accordingly, data do not conclusively prove a benefit for surgery in patients with liver metastases from asymptomatic NET. However, there is consensus about tumor mass reduction of more than 90% in patients without satisfactory palliation of symptoms by conservative therapy. Liver transplantation is indicated in very individual cases only and should be applied restrictively.     

Controversy as to the surgical treatment of hepatocellular carcinoma

Surgery has been the standard treatment modality for patients with hepatocellular carcinoma, however, controversy exists as to 1. which treatment is better for small HCC (surgery versus local ablation), 2. surgical indication for advanced HCC with multiple tumors, tumor thrombus, or extrahepatic metastasis, and 3. indication of liver transplantation. These points were discussed reviewing our results and current papers.     

Liver transplantation for hepatocellular carcinoma

Liver transplantation has emerged as an optimal treatment for stage I and II hepatocellular carcinoma for patients with underlying cirrhosis as it provides a treatment for the underlying liver disease as well as a reduced incidence of recurrent cancer. The current system of organ allocation in the United States allows an opportunity for liver transplantation for patients with tumor burden within the Milan criteria (a single tumor 2-5 cm or up to 3 lesions with none >3 cm). Outcomes of patients receiving transplants within these criteria approach outcomes for patients receiving transplants for all indications (85.9%, 74.8%, and 64.1% actuarial survival at 1, 3, and 5 years, respectively, for those with HCC receiving transplants compared with 82%, 73%, and 67% for the entire cohort). Transarterial chemoembolization, radiofrequency ablation, and other pretransplant treatment modalities aimed to slowing tumor growth for patients on a transplant waiting list are commonly used, although the impact on pretransplant disease progression or posttransplant survival remains uncertain. There is continued controversy over expanding patient selection criteria, in particular for those who have undergone downstaging of tumors. In addition, the role of certain immunosuppressive agents such as sirolimus in the reducing HCC recurrence posttransplant remains unclear.     

Liver Transplantation for Malignancies

Liver transplantation (LT) has become an acceptable and effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recently, LT has been tried in different primary and secondary malignancies of the liver. The outcomes of LT for very selected group of patients with hilar cholangiocarcinoma (CCA) have been promising. Excellent results have been reported in LT for patients with unresectable hepatic epithelioid hemangioendothelioma (HEHE). In contrast to excellent results after LT for HEHE, results of LT for angiosarcoma have been disappointing with no long-term survivors. Hepatoblastoma (HB) is the most common primary liver cancer in pediatric age group. Long-term outcomes after LT in patients with unresectable tumor and good response to chemotherapy have been promising. Indication for LT for hepatic metastasis from neuroendocrine tumors (NETs) is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. More recent limited outcomes data on LT for unresectable hepatic metastases from colorectal cancer have claimed some survival benefit compared to the previous reports. However, due to the high rate of tumor recurrence in a very short time after LT, especially in the era of organ shortage, this indication has not been favored by the transplant community.     

Exploring the role of resection of extrahepatic metastases from hepatocellular carcinoma

The role of hepatic resection, taking into consideration the functional status of the liver, for localized hepatocellular carcinoma (HCC) is an established curative treatment. In advance disease, a variety of interventional-based liver-directed therapies and more recently systemic therapy with sorafenib are available to treat unresectable tumors. Extrahepatic Metastasis (EHM) of HCC may occur at initial diagnosis or during recurrence following treatment. This may occur with or without concurrent intrahepatic disease. We reviewed the published works on surgical metastasectomy for common sites of EHM of HCC metastases. It appears from the studies reported in the literature that from selected cases reported, long-term survival may be achieved from resecting metastasis at sites of the abdominal lymph node, adrenal gland, lung, and peritoneum. The encouraging results presented demonstrate that highly selected fit patients may be suitable candidates for these radical curative pursuits. It is likely that indications for resection of EHM HCC may benefit patients with limited isolated metastasis, who have a preserved liver function, and whose primary tumor has been adequately controlled. A registry study to pull the results of case reports and institutional experiences may be useful in cumulating evidence of this practice.     

Primary hepatic malignancies: resection or liver transplantation?

Liver transplantation in malignancies must be confined to patients with potentially curable disease. The indication is widely accepted, however, in non-resectable tumors or in patients with cirrhosis that excludes major resection. Without treatment prognosis is extremely poor in these patients. In our own experience 12 out of 13 non-cirrhotic patients with hepatocellular carcinoma (HCC) died within 9 months, and 17 out of 19 cirrhotic patients died within the first year of non-curative or explorative surgery. None of our patients with HCC in non-cirrhotic livers has lived longer than 38 months, and those with cirrhotic livers more than 61 months even after curative resection. After liver transplantation 1-year survival rate was 54% in 14 patients with primary hepatic carcinomas (12 HCC, 2 CCC). In cirrhotic patients with large or infiltrating HCC the results of resection are worse than after grafting, at least in the Western World, so liver transplantation must be taken into consideration. The lack of grafts limits treatment by transplantation in these patients. Transplantation is only exceptionally indicated for patients with metastatic liver disease.     

Hepatocellular carcinoma in patients with chronic renal disease: Challenges of interventional treatment

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, recognized as the fourth most common cause of cancer related death. Many risk factors, leading to liver cirrhosis and associated HCC, have been recognized, among them viral hepatitis infections play an important role worldwide. Patients suffering from chronic kidney disease (CKD), especially those on maintenance dialysis, show a higher prevalence of viral hepatitis than the general population what increases the risk of HCC onset. In addition, renal dysfunction may have a negative prognostic impact on both immediate and long-term outcomes after malignancy treatment. Several interventional procedures for the treatment of HCC are currently available: thermal ablation, transcatheter arterial chemoembolization, liver surgery or even liver transplantation. The Barcelona Clinic Liver Cancer system provides an evidence-based treatment algorithm to address different categories of patients to the most-effective treatment in consideration of the extension of disease, liver function and performance status. Liver resection and transplantation are usually reserved to patients with early stage HCC and acceptable performance status, while the other treatments are more indicated in case of impaired liver function or locally advanced or unresectable tumors. However, there is no validated treatment algorithm for HCC in CKD patients, mainly due to the rarity of reports in this cohort of patients. Hereby we discuss the available evidences on interventional HCC treatments in CKD patients, and briefly report up-to-date pharmacological therapy for HCC patients affected by viral hepatitis.     

Decreasing disparity in liver transplantation among white and Asian patients with hepatocellular carcinoma : California, 1998-2005

BACKGROUND.

A preliminary study using national cancer surveillance data from 1998 through 2002 suggested that there were significant differences between non‐Hispanic whites (‘whites’) and Asian/Pacific Islanders (APIs) in the use of liver transplantation as a treatment for hepatocellular carcinoma (HCC).

METHODS.

The objective of the current study was to examine whether differences in liver transplantation between whites and APIs with HCC were changing over time. By using a population‐based, statewide cancer registry, data were obtained on all HCC cases diagnosed in California between 1998 and 2005, and the study was limited to white and API patients with nonmetastatic HCC who had tumors that measured ≤5 cm in greatest dimension (n = 1728 patients).

RESULTS.

From 1998 through 2003 (n = 1051 patients), the odds of undergoing liver transplantation were 2.56 times greater for white patients than for API patients (95% confidence interval [CI], 1.72–3.80 times higher), even after adjusting for age, sex, marital status, year of diagnosis, TNM stage, and tumor grade. In contrast, during 2004 and 2005 (n = 677 patients), there were no significant differences in the odds of undergoing liver transplantation. Between 2002 and 2004, changes in liver transplantation policy assigned priority points to patients with HCC (initially to stage I and II, then to stage II only). After the policy changes, API patients with HCC experienced a significant increase in stage II diagnoses, whereas white patients did not.

CONCLUSIONS.

In California, there was a large and significant disparity in the rate of liver transplantation among white and API patients with HCC from 1998 through 2003 but not during 2004 and 2005. Changes in liver transplantation policy from 2002 through 2004 may have played a role in decreasing this difference. Cancer 2008. © 2008 American Cancer Society.     

Liver transplantation as a therapeutic option for hepatocellular carcinoma

Better outcomes of the patients receiving liver transplantation for viral hepatitis and hepatocellular carcinoma (HCC) are achieved by improved patient selection and perioperative treatment with antiviral agents including lamivudine, ribavirin and interferon. Patient selection is accomplished by high-quality imaging as well as exclusion of patients with large tumors, obvious extrahepatic disease or macroscopic vascular invasion. Using such criteria, a 5-year survival of 92% has been reached in the Queensland Liver Transplant Service on a small number of highly selected patients with HCC. The treatment algorithm of Makuuchi has guided us in recommending resection, estimating to what extent the liver resection can be performed safely, and timing liver transplantation when it is the only option. Adult-to-adult living-donor liver transplantation is being performed safely in many centers worldwide. The transplantation of liver from living donors to HCC patients, when standard criteria for the likelihood of good outcomes are fulfilled, will increase in Japan in the near future.     

Hepatitis C and hepatocellular carcinoma

Chronic hepatitis C infection (HCV) accounts for approximately 50% of the cases of hepatocellular carcinoma (HCC) in the United States. Cirrhosis or an advanced stage of fibrosis is the major risk factor of HCC; patients with cirrhosis are recommended to undergo surveillance with alpha-fetoprotein and ultrasound. Alpha interferon (IFN-alpha) is associated with a reduced risk of HCC in patients with chronic infection but insufficient data exist to recommend treatment of patients with cirrhosis and HCV for this reason alone. Resection and liver transplantation are the only "curative" therapies available. Advanced fibrosis or cirrhosis in patients with HCC limits the number of patients for whom resection is applicable. Moreover, the remaining liver is at high risk of developing a second primary tumor. Partial hepatic resection for hepatocellular carcinoma should be restricted to patients with well-compensated cirrhosis (Child's A class). Acceptable parameters include a single lesion not exceeding 5 cm, normal levels of bilirubin, and absence of portal hypertension. Liver transplantation is the best definitive treatment for HCV-infected patients who have small, localized HCC (solitary lesion not greater than 5 cm, or no more than 3 lesions, none of which are greater than 3 cm). Limitations of liver transplantation as a therapy for HCC are the scarcity of donor organs and the prolonged waiting time during which continued tumor growth occurs. Living donors can reduce waiting time and increase the number of patients treatable by transplantation. Chemoembolization and local ablation therapies have not been shown to confer survival benefits as primary treatments for HCC. The potential benefit of these procedures in controlling tumor growth to "bridge" patients to liver transplantation must be further investigated. Similarly, systemic chemotherapy and hormonal therapy do not generally produce a survival advantage. However, recent studies that used octreotide and combination doxorubicin/cisplatin/5-FU/interferon appear to be promising.     

Lebertransplantation bei Patienten mit hepatozellulärem Karzinom

Hepatocellular cancer (HCC) is the most common primary malignant tumor of the liver. The main method of treatment for therapeutic curative approaches is nowadays radical surgical removal of the tumor. For non-cirrhotic livers a partial resection is definitely preferable. The diagnosis of HCC is mostly achieved by imaging and an elevated AFP value (more than 60% of patients with HCC have elevated AFP). A biopsy for confirmation is only considered necessary for questionable small lumps, not for large ones. Important factors for the long-term prognosis for patients with HCC and liver cirrhosis are i) the tumor stage, aggressiveness of growth and growth rate, ii) the general condition and comorbidity, iii) liver function and iv) therapy. If the therapy option of liver transplantation for patients with HCC limited to a cirrhotic liver is formally considered, the treatment method of radical removal of the tumor also achieves a parallel treatment of the underlying cirrhosis (as precancerous). In the Eurotransplant region (since 15.12.2006), as well as in the USA, patients are nowadays listed according to functional criteria of urgency according to MELD. The Milan criteria, which allow a patient to attain additional urgency points in the waiting list in many transplantation regions, are under discussion. Post-mortem organ donation can occur for patients with HCC technically in exactly the same way as for patients with a benign underlying disease.     

Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma

Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the re-establishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.     

Role of Organ Transplantation in the Treatment of Malignancies – Hepatocellular Carcinoma as the Most Common Tumour Treated with Transplantation

There are only few malignant tumours where organ transplantation is the treatment of choice. Transplantation can be considered individually in certain lung carcinomas, unresectable heart tumours, cholangiocellular carcinoma and Klatskin tumour. It is acceptable in unresectable chemosensitive hepatoblastoma, epitheloid haemangioendothelioma, liver metastasis of neuroendocrine tumours and as the most common indication, the early hepatocellular carcinoma (HCC) in cirrhotic liver. Results of liver transplantation (LT) for HCC according to Milan criteria as a “gold standard” are excellent. Time of LT has a great influence on the results. While patients are on waiting list, locoregional therapies may help prevent tumour progress. Living donor LT is an acceptable treatment of HCC. The greatest experience with this procedure is in Asia. Despite the favourable results, LT as the treatment of HCC is debated and raises several questions: regarding indication and expectable outcome. Milan criteria seem to answer this questions although they are too strict. The number and size of HCC foci per se is not sufficient predictor of eligibility to transplantation and for prognosis. Majority of the prognostic factors can be evaluated only after transplantation with pathological examination of HCC. Aim of the present research is to find prognostic factors that are characteristic of biological behaviour of HCC, which can be detected before LT in order to select patients who have the greatest benefit from LT. Re-definition of eligibility criteria is an actual question; an international consensus based on additional prospective studies is required for the “new” recommendation.     

Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Hepatocellular carcinoma (HCC), the third leading cause of cancer death in the world, is the most general type of primary liver cancer. Although current treatment modalities, such as liver transplantation, resection, percutaneous ablation, transarterial embolization, chemotherapy and radiotherapy are potentially curative, these methods are not universally applicable to all of HCC patients, especially for those with poor prognosis in which no effective remedy is available. Therefore, development of novel therapeutic approach for the treatment of HCC is urgently needed. In the current study, we developed a promising HCC-targeted gene therapy vector driven by liver cancer-specific α-fetoprotein promoter/enhancer coupled to an established platform technology. The activity of this expression vector is comparable with or even higher than that of strong cytomegalovirus (CMV) promoter and exhibits strong promoter activity in liver cancer cells/tumors, but has nearly no or very low activity in normal cells/organs in vitro and in orthotopic animal models in vivo. Its cancer specificity exceeds that of the CMV promoter, which expresses non-specifically in both normal and tumor cells. In addition, targeted expression of a therapeutic BikDD, a mutant of proapoptotic gene Bik effectively and preferentially killed liver cancer cells, but not normal cells and significantly repressed growth of HCC tumors, and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of HCC through intravenous systemic gene delivery. Importantly, systemic administration of BikDD by our expression vector exerted no systemically acute toxicity compared with CMV-BikDD in mice. Taken together, this study elucidates a relatively safe and highly effective and specific systemic gene therapy strategy for liver cancer, and is worthy of further development for future clinical trials.