Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation

Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma(HCC)awaiting liver transplantation(LT).The most used treatments include transarterial chemoembolization and radiofrequency ablation.Surgical resection has also been successfully used as a bridging procedure,and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function.The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation,reducing HCC recurrence after transplantation,and improving post-transplant overall survival.To date,no data from prospective randomized studies are available;however,for HCC patients listed for LT within the Milan criteria,prolonging the waiting time over 6-12 mo is a risk factor for tumor spread.Bridging treatments are useful in containing tumor progression and decreasing dropout.Furthermore,the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT.Lastly,although a definitive conclusion can not be reached,the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival.Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT.Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.     

Transplant benefit for patients with hepatocellular carcinoma

Although liver transplantation is theoretically the best treatment for hepatocellular carcinoma(HCC),it is limited by the realities of perioperative complications,and the shortage of donor organs.Furthermore,in many cases there are available alternative treatments such as resection or locoregional therapy.Deciding upon the best option for a patient with HCC is complicated,involving numerous ethical principles including:urgency,utility,intention-to-treat survival,transplant benefit,harm to candidates on waiting list,and harm to living donors.The potential contrast between different principles is particularly relevant for patients with HCC for several reasons:(1)HCC candidates to liver transplantation are increasing;(2)the great prognostic heterogeneity within the HCC population;(3)in HCC patients tumor progression before liver transplantation may significantly impair post transplant outcome;and(4)effective alternative therapies are often available for HCC candidates to liver transplantation.In this paper we suggest that allocating organs by transplant benefit could help balance these competing principles,and also introduce equity between patients with HCC and nonmalignant liver disease.We also propose a triangular equipoise model to help decide between deceased donor liver transplantation,living donor liver transplantation,or alternative therapies.     

The role of liver transplantation for hilar cholangiocarcinoma

BACKGROUND: Hilar cholangiocarcinoma is a devastating disease. Surgery is the only potentially curative modality. However, the results of surgical resection for hilar cholangiocarcinomas are disappointing. The introduction of liver transplantation for this condition has brought new hope for the management of this disease. The aim of this review is to discuss the role of liver transplantation in this disease. DATA SOURCES: A MEDLINE search was conducted for the articles on liver transplantation for hilar cholangiocarcinoma. Their results have been compiled and compared with the existing literature on resection for this disease. RESULTS: The earlier series on liver transplantation for hilar cholangiocarcinoma were not encouraging because of poor patient selection. The Mayo Clinic protocol of neoadjuvant chemoradiation followed by liver transplantation has shown remarkable success (survival at 1-, 3-, and 5-year post-transplantation being 92%, 82%, and 82%, respectively). With better patient selection and integration of neoadjuvant chemoradiation, the long-term survival is superior to that of the patients who undergo resection, as shown by the published literature on resection. The limitations of organ availability can be overcome by the living donor liver transplantation programme. This review article discusses the rationale, pros and cons of liver transplantation vis-à-vis resection for hilar cholangiocarcinoma.CONCLUSIONS: Liver transplantation, especially living donor liver transplantation, is a new and exciting alternative to resection for hilar cholangiocarcinoma. Integration of neoadjuvant chemoradiation has the potential to further improve the curative potential of liver transplantation. The strategy of combining neoadjuvant chemoradiation and liver transplantation brings new hope for the treatment of this difficult disease.     

Transplantation vs resection for hepatocellular carcinoma with compensated liver function after downstaging therapy

AIM:Our study aimed to compare the results of liver transplantation (LT) and liver resection (LR) in patients with hepatocellular carcinoma (HCC) that met the Milan criteria after successful downstaging therapy. METHODS:From February 2004 to August 2010, a consecutive series of 102 patients were diagnosed with advanced-stage HCC that met the modified UCSF down-staging protocol inclusion criteria. All of the patients accepted various down-staging therapies. The types and numbers of treatments were tailored to each patient according to the tumor characteristics, location, liver function and response. After various downstaging therapies, 66 patients had tumor characteristics that met the Milan criteria; 31 patients accepted LT in our center, and 35 patients accepted LR. The baseline characteristics, down-staging protocols, postoperative complications, overall survival and tumor free survival rate, and tumor recurrence rate were compared between the two groups. Kaplan-Meier analyses were used to estimate the long-term overall survival and tumor-free survival rate. Meanwhile, a Cox proportional hazards model was used for the multivariate analyses of overall survival and disease-free survival rate. RESULTS:No significant difference was observed between the LT and LR groups with respect to the downstaging protocol, target tumor characteristics, and baseline patient characteristics. Fifteen patients suffered various complications after LT, and 8 patients had complications after LR. The overall complication rate for the LT group was 48.4%, which was significantly higher than the LR group (22.9%) (P = 0.031). The overall in-hospital mortality in hospital for the LT group was 12.9% vs 2.9% for the LR group (P = 0.172). The overall patient survival rates at 1-, 3and 5-years were 87.1%, 80.6% and 77.4%, respectively, after LT and 91.4%, 77.1% and 68.6%, respectively, after LR (P = 0.498). The overall 1-, 3and 5-year tumor recurrencefree rates were also comparable (P = 0.656). Poorer tumor differentiation (P = 0.041) and a hi     

Surgical management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumourrelated and hepatic function-related considerations. As such, HCC is currently managed largely through nonsurgical means as the criteria, in relation to the above considerations, for surgical management is still largelyrestrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.     

Patients without hepatocellular carcinoma progression after transarterial chemoembolization benefit from liver transplantation

AIM： To assess the outcome of patients, who underwent transarterial chemoembolization （TACE） for hepatocellular carcinoma （HCC） and subsequently liver transplantation （OLT） irrespective of tumor size when no tumor progression was observed. METHODS： Records, imaging studies and pathology of 84 patients with HCC were reviewed. Ten patients were not treated at all, 67 patients had TACE and 35 of them were listed for OLT. Tumor progression was monitored by ultrasound and AFP level every 6 wk. Fifteen patients showed signs of tumor progression without transplantation. The remaining 20 patients underwent OLT. Further records of 7 patients with HCC seen in histological examination after OLT were included. RESULTS： The patients after TACE without tumor progression underwent transplantation and had a median survival of 92.3 too. Patients, who did not qualify for liver transplantation or had signs of tumor progression had a median survival of 8.4 mo. The patients without treatment had a median survival of 3.8 mo. Independent of International Union Against Cancer （UICC） stages, the patients without tumor progression and subsequent OLT had longer median survival. No significant difference was seen in the OLT treated patients if they did not fulfill the Milan criteria. CONCLUSION： Selection of patients for OLT based on tumor progression results in good survival. The evaluation of HCC patients should not only be based on tumor size and number of foci but also on tumor progression and growth behavior under therapy.     

Liver transplantation for Wilson disease

The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options mayinclude hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD.     

Inflammatory markers as selection criteria of hepatocellular carcinoma in living-donor liver transplantation

AIM:To investigate that inflammatory markers can predict accurately the prognosis of hepatocelluar carcinoma(HCC)patients in living-donor liver transplantation(LDLT).METHODS:From October 2000 to November 2011,224 patients who underwent living donor liver transplantation for HCC at our institution were enrolled in this study.We analyzed disease-free survival(DFS)and overall survival(OS)after LT in patients with HCC and designed a new score model using pretransplant neutrophil-lymphocyte ratio(NLR)and C-reactive protein(CRP).RESULTS:The DFS and OS in patients with an NLR level≥6.0 or CRP level≥1.0 were significantly worse than those of patients with an NLR level<6.0 or CRP level<1.0(P=0.049,P=0.003 for NLR and P=0.010,P<0.001 for CRP,respectively).Using a new score model using the pretransplant NLR and CRP,we can differentiate HCC patients beyond the Milan criteria with agood prognosis from those with a poor prognosis.CONCLUSION:Combined with the Milan criteria,new score model using NLR and CRP represent new selection criteria for LDLT candidates with HCC,especially beyond the Milan criteria.     

Hepatic resection for hepatocellular carcinoma in end-stage renal disease patients： Two decades of experience at Chang Gung Memorial Hospital

AIM: Hepatocellular carcinoma (HCC) is a common disease in Taiwan. The prevalence of viral hepatitis infection and the subsequent development of HCC are well known to be higher in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) or peritoneal dialysis (PD) than among the general population. However, information on hepatic resection for ESRD-HCC patients is limited. METHODS: The clinical features of 26 ESRD-HCC patients who underwent hepatic resection from 1982 to 2001 were retrospectively reviewed. Meanwhile, the clinicopathological features and the outcome of 1 198 HCC patients without ESRD undergoing hepatic resection were used for comparison. RESULTS: Of 1 224 surgically resected HCC patients,26 (4.2%) were ESRD-HCC. Univariate analysis revealed more associated disease,more physical signs of anemia and postoperative complications,lower hemoglobin, platelet,α-fetoprotein, elevated blood urea nitrogen (BUN) and creatinine levels, smaller tumors, lower HBsAg positivity, higher HCV positivity, and longer hospital stays in the ESRD-HCC group compared with the HCC group. Furthermore, multivariate stepwise logistic regression analysis revealed that elevated BUN and creatinine levels were the only two independently significant factors in the patients in the ESRD-HCC group. Overall and disease-free survival rates were similar between the ESRD-HCC and HCC groups. CONCLUSION: Elevated BUN and creatinine were the only two main independent factors differentiating ESRD-HCC from HCC patients. ESRD should not be a contraindication of hepatic resection in HCC patients; however, careful operative techniques and perioperative care are crucial to achieving lower morbidity and mortality. Comparable overall survival and disease-free survival can be achieved in selected ESRD-HCC patients undergoing hepatic resection when compared with conventional HCC patients.     

Diagnosis and surgical treatments of hepatocellular carcinoma with tumor thrombosis in bile duct： Experience of 34 patients

AIM: Hepatocellular carcinoma (HCC) with bile duct tumor thrombosis (BDT) is a rare event. The prognosis of this type of patients is very dismal. The aim of this study was to share the experience in the diagnosis and treatment of HCC with BDT, to further improve the prognosis of these patients.METHODS: Thirty-four patients of HCC with BDT received surgical treatment in authors‘ institute from July 1987 to January 2003 were reviewed retrospectively. The experience in the diagnosis and treatment, and the outcome of this type of HCC patients were summarized.RESULTS: Thirty of the 34 patients (88.2%) were positive for alpha-fetoprotein (AFP) (&gt;20 μg/L), and 12 patients (35.3%) were found having obstructive jaundice before operation, 18 cases were suspected of “obstruction of bile duct“ preoperatively. The primary tumors were frequently located at the left medial (13 cases) or right anterior lobe(14 cases). Thirty-one patients received liver resections and removal of BDT, while the other 3 patients received removal of BDT combined with hepatic artery ligation and cannulation(HAL+HAI), or only removal of BDT because their liver function reservation and general condition could not tolerate the primary tumor resection. The 1-year survival rate was 71.4%(20/28). The longest disease-free survival was over 15 years. The intrahepatic tumor recurrence within 1 year after operation was found in 14 patients (14/28, 50.0%).CONCLUSION: Surgical removal of primary tumors and BDT is safe and beneficial to the HCC patients with BDT. Early detection, diagnosis, and surgical treatment are the key points to prolong the survival time of patients.     

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.     

Survival analysis of patients with stage I and II hepatocellular carcinoma after a liver transplantation or liver resection

IntroductionLiver transplantation (LT) is a treatment option in select patients with hepatocellular carcinoma (HCC). The aim of the present study was to compare survival in Stage I or II HCC patients undergoing either liver transplant (LT) or a liver resection (LR).MethodThe study is a retrospective analysis of the National Cancer Data Base (1998–2011). In total, 148 882 patients with liver cancer were identified, of which 5-year survival data (1998–2006) were available for 64 227 patients. Patients were stratified by the American Joint Committee on Cancer (AJCC) clinical stage I and II. Kaplan–Meier curves and log-rank tests were used for statistical analysis.Results3340 HCC patients met analysis criteria. Among stage I HCC, 860 had LT and 871 had LR. Among stage II HCC, 833 had LT and 776 LR. In stage I patients the median survival for LT and LR were 127.9 and 56.7 months, respectively, (P < 0.0001) and in stage II patients the median survival was 110.8 and 42.8 months (P < 0.0001). Unlike LT patients, LR patients with Stage I HCC had a longer median survival compared with Stage II patients (P = 0.0002).ConclusionLiver transplantation offers a survival advantage compared with a liver resection among patients with Stage I and II HCC. LT is the best surgical treatment for early stage (I/II) HCC in patients with advanced fibrosis or cirrhosis, whereas LR provides equivalent outcomes to LT in patients without advanced fibrosis and should be considered as the first surgical option.     

Intention-to-treat analysis of liver transplantation,resection and thermal ablation for hepatocellular carcinoma in a single centre

Background

potentially curative treatment options for hepatocellular carcinoma (HCC) include liver transplantation (LT), liver resection (LR) and thermal ablation (TA). Long term intent-to-treat (ITT) analysis from a single-centre using all three modalities contemporaneously has not been published.

Surgical treatment of hepatocellular carcinoma

Surgery for hepatocellular carcinoma (HCC) includes partial liver resection (LR) and liver transplantation (LT). Although LT represents the most efficient treatment in patients with small HCC, <30% of patients are eligible for LT because of restrictive criteria (one nodule <5 cm or two to three nodules <3 cm without macroscopic vascular invasion), graft unavailability and the high cost of the procedure. For large HCC, LR remains the only potential curative treatment. LR is now safer, with a low rate of mortality. Selective preoperative morphological assessment, preoperative use of portal vein embolization for increasing future remnant liver volume and the improvement of surgical techniques such as the use of intermittent clamping and anterior approach are factors that improve the safety and tolerance of LR. In patients with small HCCs and a preserved liver function (Child-Pugh grade A), good long-term survival can be achieved after anatomical resection that removes the tumor(s) and its portal vein territory. These good results of LR for small HCC and the increasing duration of the waiting list for candidates of LT have renewed the place of LR as a bridge treatment before LT.     

Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation

Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral Published online: January 27, 2019 recurrence after LT.Liver transplantation(LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma(HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to85%of 3-to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, desgamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-tolymphocyte ratio, can predict the risk for HCC recurrence after transplantation.These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.     

Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis

Liver resection (LR) for hepatocellular carcinoma (HCC) as the first-line treatment in transplantable patients followed by "salvage transplantation" (ST) in case of recurrence is an attractive concept. The aim was to identify patients who gain benefit from this approach in an intention-to-treat study. From 1998 to 2008, among 329 potential candidates for liver transplantation (LT) with HCC within the Milan criteria (MC), 138 with good liver function were resected (LR group) from a perspective of ST in case of recurrence, and 191 were listed for LT first (LT group). The two groups were compared on an intention-to-treat basis with special reference to management of recurrences and transplantability after LR. Univariate and multivariate analyses were performed to identify resected patients who developed recurrence beyond MC. Five-year overall and disease-free survival was similar in both groups: LT versus LR group, 60% versus 77% and 56% versus 40%, respectively. Among the 138 patients in the LR group, 20 underwent LT before recurrence, 39 (28%) had ST, and 51 (37%) with recurrence were not transplanted including 21 within MC who were excluded for advanced age, acquired comorbidities, or refusal and 30 (22%) with recurrence beyond MC. Predictive factors for nontransplantability due to recurrence beyond MC included microscopic vascular invasion (hazard ratio [HR] 2.38 [range, 1.10-7.29]), satellite nodules (HR 2.46 [range, 1.01-6.68]), tumor size > 3 cm (HR 1.34 [range, 1.03-3.12]), poorly differentiated tumor (HR 3.18 [range, 1.31-7.70]), and liver cirrhosis (HR 1.90 [range, 1.04-3.12]). CONCLUSION: The high risk of failure of ST after initial LR for HCC within MC suggests the use of tissue analysis as a selection criterion. The salvage LT strategy should be restricted to patients with favorable oncological factors.     

Resection or transplant-listing for solitary hepatitis C-associated hepatocellular carcinoma: an intention-to-treat analysis

Objectives

The relative roles of liver resection (LR) and liver transplantation (LT) in the treatment of a solitary hepatocellular carcinoma (HCC) remain unclear. This study was conducted to provide a retrospective intention-to-treat comparison of these two curative therapies.

Methods

Records maintained at the study centre for all patients treated with LR or listed for LT for hepatitis C-associated HCC between January 2002 and December 2007 were reviewed. Inclusion criteria required: (i) an initial diagnosis of a solitary HCC lesion measuring ≤ 5 cm, and (ii) Child–Pugh class A or B cirrhosis. The primary endpoint analysed was intention-to-treat survival.

Results

A total of 75 patients were listed for transplant (LT-listed group) and 56 were resected (LR group). Of the 75 LT-listed patients, 23 (30.7%) were never transplanted because they were either removed from the waiting list (n = 13) or died (n = 10). Intention-to-treat median survival was superior in the LR group compared with the LT-listed group (61.8 months vs. 30.6 months), but the difference did not reach significance. Five-year recurrence was higher in the LR group than in the 52 LT patients (71.5% vs. 30.5%; P < 0.001).

Conclusions

In the context of limited donor organ availability, partial hepatectomy represents an efficacious primary approach in properly selected patients with hepatitis C-associated HCC.     

Survival advantage of primary liver transplantation for hepatocellular carcinoma within the up-to-7 criteria with microvascular invasion

Purpose  

Microvascular invasion of hepatocellular carcinoma (HCC) is considered a poor prognostic factor of liver resection (LR) and liver transplantation (LT), but its significance for lesions within the up-to-7 criteria is unclear. This study investigated the survival benefit of primary LT against LR for HCC with microvascular invasion and within the up-to-7 criteria.