Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review

Liver transplantation(LT) has been accepted as an effective therapy for hepatocellular carcinoma(HCC). The Milan criteria(MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alphafetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.     

Hangzhou criteria as downstaging criteria in hepatocellular carcinoma before liver transplantation: A multicenter study from China

BackgroundThe downstaging of hepatocellular carcinoma (HCC) has been confirmed to benefit liver transplantation (LT) patients whose tumors are beyond the transplantation criteria. Milan criteria (MC), a tumor size and number-based assessment, is currently used as the endpoint in these patients. However, many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy. Hence, this study aimed to explore the feasibility of Hangzhou criteria (HC), which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number, as an endpoint of downstaging.MethodsWe performed a multicenter and retrospective study of 206 patients accepted locoregional therapy (LRT) as downstaging/bridge treatment prior to LT in three centers of China.ResultsRecipients were divided into four groups: failed downstaging to the HC (group A, n = 46), successful downstaging to the HC (group B, n = 30), remained within the HC all the time (group C, n = 113), and tumor progressed (group D, n = 17). The 3-year HCC recurrence probabilities of groups B and C were not significantly different (10.3% vs. 11.6%, P = 0.87). The HCC recurrent rate was significantly higher in group A (52.3%) compared with that in group B/C (P < 0.05). Seven patients (7/76, 9.2%) whose tumor exceeded the the HC were successfully downstaged to the MC, and 39.5% (30/76) to the the HC. In group B, 23 patients remained beyond the MC and their survivals were as well as those of patients within the MC.ConclusionsCompared to the MC, HC downstaging criteria can give more HCC patients access to LT and furthermore, the outcome of these patients is the same as those matching MC downstaging criteria. Hangzhou downstaging criteria therefore is applicable in clinical practice.     

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.     

Hepatocellular carcinoma beyond Milan criteria: Management and transplant selection criteria

Liver transplantation(LT) for hepatocellular carcinoma(HCC) has been established as a standard treatment in selected patients for the last two and a half decades. After initially dismal outcomes, the Milan criteria(MC)(single HCC ≤ 5 cm or up to 3 HCCs ≤ 3 cm) have been adopted worldwide to select HCC patients for LT, however cumulative experience has shown that MC can be too strict. This has led to the development of numerous expanded criteria worldwide. Morphometric expansions on MC as well as various criteria which incorporate biomarkers as surrogates of tumor biology have been described. HCC that presents beyond MC initially can be downstaged with locoregional therapy(LRT). Post-LRT monitoring aims to identify candidates with favorable tumor behavior. Similarly, tumor marker levels as response to LRT has been utilized as surrogate of tumor biology. Molecular signatures of HCC have also been correlated to outcomes; these have yet to be incorporated into HCC-LT selection criteria formally. The ongoing discrepancy between organ demand and supply makes patient selection the most challenging element of organ allocation. Further validation of extended HCCLT criteria models and pre-LT treatment strategies are required.     

Liver transplantation for hepatocellular carcinoma

The role of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) has evolved over the past two decades, and transplantation has become one of the few curative treatment modalities for patients with HCC. Early results were poor, but the current restrictive selection criteria can yield excellent results. This review will discuss recent issues in the field, including (1) factors affecting the recurrence of HCC after LT; (2) the effect of downstaging HCC before LT, including transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA); and (3) living-donor versus deceased-donor liver transplantation for HCC patients. The most important factors that have been described to affect LT survival include the tumor size, vascular invasion, and the degree of tumor differentiation. Recently, tumor markers, including alpha-fetoprotein and des-gamma carboxy prothrombin, were reported as predictors of HCC recurrence after LT. Furthermore, the experience accumulated with locoregional therapies such as TACE and RFA as bridging procedures to LT, along with the reduced waiting time under the HCC-adjusted MELD (model for endstage liver disease) system for organ allocation has led to improved outcomes. With the recent advances in adult living-donor liver transplantation (LDLT), there may be a marked change in the role of liver transplantation for hepatic malignancies, in particular for HCC.     

Hepatocellular Carcinoma: Downstaging to Liver Transplantation as Curative Therapy

Hepatocellular carcinoma (HCC) ranks among the leading cancer-related causes of morbidity and mortality worldwide. Downstaging of HCC has prevailed as a key method to curative therapy for patients who present with unresectable HCC outside of the listing criteria for liver transplantation (LT). Even though LT paves the way to lifesaving curative therapy for HCC, perpetually severe organ shortage limits its broader application. Debate over the optimal protocol and assessment of response to downstaging treatment has fueled immense research activity and is pushing the boundaries of LT candidate selection criteria. The implicit obligation of refining downstaging protocol is to ensure the maximization of the transplant survival benefit by taking into account the waitlist life expectancy. In the following review, we critically discuss strategies to best optimize downstaging HCC to LT on the basis of existing literature.     

Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation

The Milan criteria (MC) have been widely accepted as an effective way of selecting patients with early‐stage hepatocellular carcinoma (HCC) for curative liver transplantation (LT). However, since a substantial subset of HCC patients exists that is beyond the MC but with the potential for good outcomes after LT, several institutions have recently proposed new extended criteria. To explore optimal criteria that can reasonably predict the risk of recurrence, it is considered that new markers of biological behavior are needed in addition to morphological tumor size and number. Several promising candidates for such biological markers have been reported, including serum tumor markers such as alpha‐fetoprotein and des‐gamma‐carboxy prothrombin, inflammatory markers such as C‐reactive protein and neutrophil‐to‐lymphocyte ratio, response to pre‐transplant treatments for bridging therapy or down‐staging, and fluorine‐18‐fluorodeoxyglucose positron emission tomography. However, the role of these biological markers in patient selection criteria for LT has yet to be clarified. This review article aims to summarize the results of recent reported studies and to display perspectives for the establishment of optimal criteria that incorporate such biological markers.     

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     

Alpha-fetoprotein and ~(18 )F-FDG standard uptake value predict tumor recurrence after liver transplantation for hepatocellular carcinoma with portal vein tumor thrombosis: Preliminary experience

Background: Portal vein tumor thrombosis(PVTT) is regarded as a contraindication for liver transplantation(LT) in hepatocellular carcinoma(HCC). However, some of these patients may have a favorable prognosis after LT. In this study, we evaluated the biological behavior of HCC with PVTT using tumor biomarker(alpha-fetoprotein, AFP) and 18 F-FDG positron emission tomography(tumor standard uptake value) to identify a subset of patients who may be suitable for LT. Methods: Seventy-five HCC-PVTT liver recipients transplanted during February 2016 and June 2018 were analyzed. Different pre-transplant prognostic factors were identified by univariate and multivariate analyses. PVTT status was identified following Vp classification(Vp1-Vp4). Results: Three-year recurrence-free survival and overall survival rates were 40% and 65.4% in Vp2-Vp3 PVTT patients, 21.4% and 30.6% in Vp4 PVTT patients( P 0.05). Total tumor diameter 8 cm, pretransplant AFP level 10 0 0 ng/m L and intrahepatic tumor maximal standard uptake value(SUVmaxtumor 5) were independent risk factors for HCC recurrence and overall survival after LT in Vp2-3 PVTT patients. Low risk patients were defined as total tumor diameter ≤8 cm; or if total tumor diameter more than 8 cm, with both pre-transplant AFP level less than 10 0 0 ng/m L and intrahepatic tumor SUVmax less than 5, simultaneously. Twenty-two Vp2-3 PVTT HCC patients(46.8%) were identified as low risk patients, and their 3-year recurrence-free and overall survival rates were 67.6% and 95.2%, respectively. Conclusions: Patients with segmental or lobar PVTT and biologically favorable tumors defined by AFP and 18 F-FDG SUVmax might be suitable for LT.     

Clinicopathological Distinction of Low-AFP-Secreting vs. High-AFP-Secreting Hepatocellular Carcinomas

Ilntroduction and aims. We aimed to investigate the clinical and pathological differences between low-AFP-secreting (AFP < 20 ng/mL) and high-AFP-secreting (AFP ≥ 20 ng/mL) hepatocellular carcinomas in patients who undergo liver transplant (LT).Material and methods. We evaluated 145 patients who underwent deceased donor LT for HCC from January 1, 2005 until August 1, 2015 at the Johns Hopkins Hospital.Results. Median pre-LT AFP in the entire cohort was 13 ng/mL (IQR 6-59). Using serum AFP cutoff of 20 ng/mL, 61 (42%) patients had high-AFP-secreting tumors and 84 (58%) had low-AFP-secreting tumors. Patients with high-AFP-secreting tumors had larger lesions (3 cm vs. 2.4 cm, p = 0.024), and were more likely to have microvascular-invasion (36.1% vs. 20.2%, p = 0.02) and poor-differentiation (18% vs. 4.8%, p = 0.01), and tumor recurrence following LT (28% vs. 6%, p < 0.001). The 1-year, 3-year, and 5-year recurrence-free survival for patients in the low-AFP-secreting group compared to the high-AFP-secreting group were 100%, 92%, 92% vs. 81.3%, 71.3%, 68.5% respectively (p = 0.0003).Conclusion. AFP is a suboptimal predictor of tumor recurrence following liver transplant in HCC patients. However, it can have some value in distinguishing more aggressive forms of HCC (high-AFP-secreting) that are associated with higher tumor recurrence. Novel tumor biomarkers are needed that can enhance predicting tumor recurrence following LT based on tumor biology.     

The Value of Serum α-Fetoprotein in Predicting Tumor Recurrence After Liver Transplantation for Hepatocellular Carcinoma

Background Many patients with hepatocellular carcinoma (HCC) who undergo liver transplantation (LT) subsequently develop tumor recurrence; this is the main factor affecting long-term survival after LT. Factors associated with tumor recurrence should be determined to improve the outcome of LT. The purpose of the study was to evaluate the value of α-fetoprotein (AFP) in forecasting tumor recurrence after LT for patients with HCC. Methods AFP data before and after LT for 97 patients with HCC who underwent LT in our center were analyzed retrospectively. Results The mean follow-up time was 17.1 ± 2.1 months for all 97 patients, overall tumor recurrence rate was 32.9% (32/97), and mean recurrence time was 7.2 ± 3.2 months. The most common tumor recurrence sites were liver, lung, skeleton, and other sites. Pre-transplant AFP levels >400 ng/ml were associated with higher tumor recurrence. Post-transplant AFP levels not decreasing to ≤20 ng/ml within 2 months were also indicative of higher risk of recurrence. Conclusions Pre-transplant AFP and the dynamic change of AFP after LT were valuable in predicting tumor recurrence after LT for patients with HCC.     

Living donor liver transplantation for hepatocellular carcinoma: the impact of neo-adjuvant treatments on the long term results

Background/Aims: LDLT may represent a valid therapeutic option allowing several advantages for patients affected by HCC and waiting for liver transplantation (LT). However, some reports show a worse long term survival and disease free survival among patients treated by LDLT for HCC than deceased donor liver transplantation (DDLT) recipients. Methodology: Among 1145 LT patients, 63 received LDLT. From January 2000 to December 2008, 179 patients underwent LT due to HCC, 30 (16.7%) received LDLT and 154 (86.0%) received DDLT. Patients were selected based on the Milan criteria. TACE, radiofrequency ablation, percutaneous alcoholization, or liver resection were applied as downstaging procedures, while on the waiting list. Results: Overall 3- and 5-year survival rate was 77.3% and 68.7% vs. 82.8% and 76.7%, respectively for LDLT and DDLT recipient with not significant differences. Moreover, 3- and 5- years of recurrence free survival rate was 95.5% (LDLT) vs. 90.5% and 89.4% (DDLT) and resulted not significantly different. Conclusions: LDLT guarantees same long term results than DDLT if the selection criteria of candidates are analogues. Milan criteria remains a valid candidate selection tool to obtain optimal long term results in LDLT. An aggressive downstaging policy seems to improve the long-term results in LDLT, thus LRT may be considered useful to prevent tumor progression waiting for transplantation as well as a neoadjuvant therapy for HCC. A literature detailed meta-analysis could definitely clarify if LDLT is an independent risk factor for HCC recurrence.     

Diferencias de la presentación y tratamiento en las neoplasias primarias de hígado en un centro de hepatología y un centro oncológico

Introduction and aimsPrimary liver cancer is a public health problem in Mexico and the world. Liver transplantation (LT) is the ideal treatment for early hepatocellular carcinoma (HCC). Our aim was to evaluate the characteristics of patients with HCC and cholangiocarcinoma (CC) at two centers and identify transplantation candidates.Materials and methodsA retrospective observational study was conducted at the Hepatology Center (HC) and the University Center Against Cancer (UCAC), within the time frame of 2012-2018. HCC or intrahepatic CC was confirmed in 109 patients. Staging classifications, transplant selection models, and a predictive model for post-LT recurrence were applied to the HCC patients.ResultsOf the total population, 93% (n = 102) presented with cirrhosis, 86% (n = 94) had HCC (HC: 58%, UCAC: 42%), and 14% (n = 15) had intrahepatic CC (HC: 40%, UCAC: 60%). Of the HC patients with HCC, Okuda I-II, BCLC A-B, and AFP levels < 100 ng/m predominated, whereas Okuda II-III, BCLC C-D, and AFP levels > 1,000 ng/mL predominated in the UCAC patients. Half of the HC population with HCC met the criteria for LT, in contrast to 23% of the UCAC patients. Fifteen patients were evaluated for LT, and at present, six have undergone transplantation.ConclusionsThe most frequent primary liver tumor was HCC. Patients from the HC presented with earlier-stage disease and a high number of them met the criteria for LT. Only patients from the HC underwent transplantation.     

Liver transplantation for hepatic tumors:a systematic review

Improvements in the medical and pharmacological management of liver transplantation(LT)recipients have led to a better long-term outcome and extension of the indications for this procedure.Liver tumors are relevant to LT;however,the use of LT to treat malignancies remains a debated issue because the high risk of recurrence.In this review we considered LT for hepatocellular carcinoma(HCC),cholangiocarcinoma(CCA),liver metastases(LM)and other rare tumors.We reviewed the literature,focusing on the past 10 years.The highly selected Milan criteria of LT for HCC(single nodule<5 cm or up to 3 nodules<3cm)have been recently extended by a group from the University of S.Francisco(1 lesion<6.5 cm or up to3 lesions<4.5 cm)with satisfying results in terms of recurrence-free survival and the"up-to-seven criteria".Moreover,using these criteria,other transplant groups have recently developed downstaging protocols,including surgical or loco-regional treatments of HCC,which have increased the post-operative survival of recipients.CCA may be treated by LT in patients who cannot undergo liver resection because of underlying liver disease or for anatomical technical challenges.A well-defined protocol of chemoirradiation and staging laparotomy before LT has been developed by the Mayo Clinic,which has resulted in long term diseasefree survival comparable to other indications.LT for LM has also been investigated by multicenter studies.It offers a real benefit for metastases from neuroendocrine tumors that are well differentiated and when a major extrahepatic resection is not required.If LT is an option in these selected cases,liver metastases from colorectal cancer is still a borderline indication because data concerning the disease-free survival are still lacking.Hepatoblastoma and hemangioendothelioma represent rare primary tumors for which LT is often the only possible and effective cure because of the frequent multifocal,intrahepatic nature of the disease.LT is a very promising procedure for both primary and secondary liver malignancies;however,it needs an accurate evaluation of the costs and benefits for each indication to balance the chances of cure with actual organ availability.     

Hepatocellular Carcinoma and Liver Transplantation: State of the Art

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in chronic liver disease and cirrhosis. The incidence of HCC is growing worldwide.With respect to any other available treatment for liver cancer, liver transplantation (LT) has the highest potential to cure. LT allows for removal at once of both the tumor (“seed”) and the damaged-hepatic tissue (“soil”) where cancerogenesis and chronic liver disorders have progressed together. The Milan criteria (MC) have been applied worldwide to select patients with HCC for LT, yielding a 4-year survival rate of 75%. These criteria represent the benchmark for patient selection and are the basis for comparison with any other suggested criteria.However, MC are often considered to be too restrictive, and recent data show that between 25% and 50% of patients with HCC are currently transplanted beyond conventional indications. Consequently, any unrestricted expansion of selection criteria will increase the need for donor organs, lengthen waiting periods, increase drop-out rates, and impair outcomes on intention-to-treat analysis. Management of HCC recurrence after LT is challenging. There are a few reports available regarding the safety and efficacy of sorafenib for HCC recurrence after LT, but the data are heterogeneous. A multi-center prospective randomized controlled trial comparing placebo with sorafenib is advised. Alternatively, a meta-analysis of patient survival with sorafenib for HCC recurrence after LT could be helpful to characterize the therapeutic benefit and safety of sorafenib.Here, we review the use of LT for HCC, with particular emphasis on the selection criteria for transplantation in patients with HCC and management of HCC recurrence after LT.     

Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria(MC), liver transplant(LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection(LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible(within MC) patients with recurrent HCC post LR, salvage liver transplant(SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of "de principe liver transplant"(i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as time goes by. Regarding tumor-related factors, histopathological features of the resected specimen are used mostly for determining the prognosis of early HCC recurrences. Suchprognostic factors include the presence of microvascular invasion, poor tumor differentiation, the presence of microsatellites, the presence of multiple tumors, and the presence of the gene-expressing signature associated with aggressive HCC. These prognostic factors might be used as a selection tool for SLT or prophylactic LT, while remaining mindful of the fact that most of them are also prognostic factors for post-transplant HCC recurrence. Regarding underlying liver disease-related factors, progression of chronic viral hepatitis and high viral load may contribute to the development of late(de novo) HCC recurrence as a consequence of sustained inflammatory reaction. However, correlation between the severity of liver fibrosis and tumor recurrence is still controversial. Some prognostic scoring systems that integrate these three factors have been proposed to predict recurrence patterns after LR for HCC. Theoretically, after excluding patients with high risk of post-transplant HCC recurrence, either by observation of a cancer-free period or by measurement of biological factors(such as alpha fetoprotein), prophylactic LT following curative resection of HCC could be considered for selected patients with high risk of recurrence to provide longer survival.     

Efficacy of selective transarterial chemoembolization in inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas

Transarterial chemoembolization (TACE) is commonly used as a bridge therapy for patients awaiting liver transplantation (LT) and for downstaging patients initially not meeting the Milan criteria. The primary aim of this study was to analyze whether a difference exists between selective/superselective and lobar TACE in determining tumor necrosis by a pathological analysis of the whole lesion at the time of LT. The secondary aim was to investigate the relationship between the tumor size and the capacity of TACE to induce necrosis. Data were extracted from a prospective database of 67 consecutive patients who underwent LT for hepatocellular carcinoma and cirrhosis from 2003 to 2009 and were treated exclusively with TACE as a bridging (n = 53) or downstaging therapy (n = 14). We identified 122 nodules; 53.3% were treated with selective/superselective TACE. The mean histological necrosis level was 64.7%; complete tumor necrosis was obtained in 42.6% of the nodules. In comparison with lobar TACE, selective/superselective TACE led to significantly higher mean levels of necrosis (75.1% versus 52.8%, P = 0.002) and a higher rate of complete necrosis (53.8% versus 29.8%, P = 0.013). A significant direct relationship was observed between the tumor diameter and the mean tumor necrosis level (59.6% for lesions < 2 cm, 68.4% for lesions of 2.1-3 cm, and 76.2% for lesions > 3 cm). Histological necrosis was maximal for tumors > 3 cm: 91.8% after selective/superselective TACE and 66.5% after lobar procedures. Independent predictors of complete tumor necrosis were selective/superselective TACE (P = 0.049) and the treatment of single nodules (P = 0.008). Repeat sessions were more frequently needed for nodules treated with lobar TACE (31.6% versus 59.3%, P = 0.049). CONCLUSION: Selective/superselective TACE was more successful than lobar procedures in achieving complete histological necrosis, and TACE was more effective in 3- to 5-cm tumors than in smaller ones.     

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.