Multimodal and systemic therapy with cabozantinib for treatment of recurrent hepatocellular carcinoma after liver transplantation: A case report with long term follow-up outcomes

Rationale:Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major therapeutic challenge. In recent years, new molecular-targeted therapies, such as cabozantinib, have been approved for the treatment of advanced HCC. However, clinical experience with these new drugs in the treatment of HCC in the LT setting is very limited.Patient concerns:In 2003, a 36-year-old woman was referred to the hospital with right upper abdominal pain.Diagnosis:An initial ultrasound of the liver demonstrated a large unclear lesion of the left lobe of the liver. The magnet resonance imaging findings confirmed a multifocal inoperable HCC in a non-cirrhotic liver. Seven years after receiving a living donor LT, pulmonary and intra-hepatic recurrence of the HCC was radiologically diagnosed and histologically confirmed.Interventions:Following an interdisciplinary therapy concept consisting of surgical, interventional-radiological (with radiofrequency ablation [RFA]) as well as systemic treatment, the patient achieved a survival of more than 10 years after tumor recurrence. As systemic first line therapy with sorafenib was accompanied by grade 3 to 4 toxicities, such as mucositis, hand-foot skin reaction, diarrhea, liver dysfunction, and hyperthyroidism, it had to be discontinued. After switching to cabozantinib from June 2018 to April 2020, partial remission of all tumor manifestations was achieved. The treatment of the remaining liver metastasis could be completed by RFA. The therapy with cabozantinib was well tolerated, only mild arterial hypertension and grade 1 to 2 mucositis were observed. Liver transplant function was stable during the therapy, no drug interaction with immunosuppressive drugs was observed.Outcomes:More than 10 years survival after recurrence of HCC after living-donor LT due to intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy with cabozantinib in the second line therapy.Lessons:In conclusion, this report highlights the tolerability and effectiveness of cabozantinib for the treatment of HCC recurrence after LT. We show that our patient with a late recurrence of HCC after LT benefitted from intensive multimodal therapy concepts, including surgery, RFA, and systemic therapy.     

Liver transplantation for HCC: its role

Liver transplantation (LT) is the only treatment that offers a chance of cure for hepatocellular carcinoma (HCC) and the underlying liver cirrhosis simultaneously, but the availability of liver grafts and the aggressiveness of tumor recurrence are critical limiting factors of LT for patients with HCC. In most Asian countries, the serious shortage of deceased donors and the strong demand for LT has lead to the development of living-donor LT (LDLT) as a practical alternative replacing deceased-donor LT (DDLT). Grafts in Western countries are issued from DDLT and graft allocations are under the responsibilities of state agencies which apply strict rules based on the MELD (model for end-stage liver disease) score. Considering that HCC recurrence is the most common cause of post-transplant patient death, recipient candidates should be prudently selected through objectively established criteria. Points in addition to the MELD score can be allotted to patients with HCC providing that the HCC remains within the Milan criteria. The increasing number of LT candidates with HCC results in increasing waiting periods, which necessitate the consideration of pretransplant treatment of HCC, including partial liver resection. Both specific Western units and some Asian major LDLT centers have challenged the Milan criteria. The eligibility criteria of both DDLT and LDLT for HCC are likely to be expanded more than before, but this still requires further qualified risk–benefit analyses. The development of new effective treatment modalities before LT and for HCC recurrence might expand the selection criteria further without incurring an increased recurrence rate.     

Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system

Hepatocellular carcinoma(HCC),the fifth most common cancer that predominantly occurs in liver cirrhosis patients,requires staging systems to design treatments. The barcelona clinic liver cancer staging system(BCLC) is the most commonly used HCC management guideline. For BCLC stage B(intermediate HCC),transarterial chemoembolization(TACE) is the standard treatment. Many studies support the use of TACE in early and advanced HCC patients. For BCLC stage 0(very early HCC),TACE could be an alternative for patients unsuitable for radiofrequency ablation(RFA) or hepatic resection. In patients with BCLC stage A,TACE plus RFA provides better local tumor control than RFA alone. TACE can serve as bridge therapy for patients awaiting liver transplantation. For patients with BCLC B,TACE provides survival benefits compared with supportive care options. However,because of the substantial heterogeneity in the patient population with this stage,a better patient stratification system is needed to select the best candidates for TACE. Sorafenib represents the first line treatment in patients with BCLC C stage HCC. Sorafenib plus TACE has shown a demonstrable effect in delaying tumor progression. Additionally,TACE plus radiotherapy has yielded better survival in patients with HCC and portal venous thrombosis. Considering these observations together,TACE clearly has a critical role in the treatment of HCC as a stand-alone or combination therapy in each stage of HCC. Diverse treatment modalities should be used for patients with HCC and a better patient stratification system should be developed to select the best candidates for TACE.     

Milan criteria are useful predictors for favorable outcomes in hepatocellular carcinoma patients undergoing liver transplantation after transarterial chemoembolization

INTRODUCTION Hepatocellular carcinoma (HCC) is a major global health problem involving more than 500 000 new cases a year. Several treatment modalities, such as liver transplantation (LT), surgical resection, radiofrequency ablation (RFA), and percutaneou…     

Management of hepatocellular carcinoma recurrence after liver transplantation

Despite careful selection for liver transplantation (LT) of patients with hepatocellular carcinoma (HCC), HCC may still recur after LT and is frequently associated with dismal outcome. Tumor factors, including serum alpha-fetoprotein (AFP), the presence of microvascular invasion, tumor grade/differentiation, and largest tumor size are amongst the most important predictors of recurrence after transplantation. The nature of recurrence can be highly variable, but often presents with extra-hepatic involvement. As such, management of patients with HCC can be challenging, and consensus guidelines are lacking. Curative options, with surgery or ablation, which may be applicable in patients with isolated intra-or extrahepatic metastases, offer the best chance for improved long-term outcome in patients with HCC recurrence after transplantation. Most patients with recurrence have unresectable disease, and may benefit from palliative treatments, including intra-arterial therapies and/or systemic therapy.     

Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients

Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., “non-oncological factors”), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival.     

Role of Radiofrequency Ablation in Patients with Hepatocellular Carcinoma Who Undergo Prior Transarterial Chemoembolization: Long-Term Outcomes and Predictive Factors

Background/Aims

The role of radiofrequency ablation (RFA) remains uncertain in patients with viable hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE).

Methods

A total of 101 patients (April 2007 to August 2010) underwent RFA for residual or recurrent HCC after TACE. We analyzed their long-term outcomes and predictive factors.

Results

The overall survival rates after RFA were 93.1%, 65.4%, and 61.0% at 1, 3, and 5 years, respectively. Predictive factors for favorable overall survival were Child-Pugh class A (hazard ratio [HR], 3.45; p=0.001), serum α-fetoprotein (AFP) level <20 ng/mL (HR, 2.90; p=0.02), and recurrent tumors after the last TACE (HR, 3.14; p=0.007). The cumulative recurrence-free survival rate after RFA at 6 months was 50.1%. Predictive factors for early recurrence (within 6 months) were serum AFP level 20 ng/mL (HR, 3.02; p<0.001), tumor size 30 mm at RFA (HR, 2.90; p=0.005), and nonresponse to the last TACE (HR, 2.13; p=0.013).

Conclusions

Patients with recurrent or residual HCC who undergo prior TACE show a favorable overall survival, although their tumors seem to recur early and frequently. While good liver function, a low serum AFP level, and recurrent tumors were independent predictive factors for a favorable overall survival, poor response to TACE, a high serum AFP level, and large tumors are associated with early recurrence.     

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.     

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.     

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.     

Living-donor vs deceased-donor liver transplantation for patients with hepatocellular carcinoma

With the increasing prevalence of living-donor liver transplantation(LDLT) for patients with hepatocellular carcinoma(HCC),some authors have reported a potential increase in the HCC recurrence rates among LDLT recipients compared to deceased-donor liver transplantation(DDLT) recipients.The aim of this review is to encompass current opinions and clinical reports regarding differences in the outcome,especially the recurrence of HCC,between LDLT and DDLT.While some studies report impaired recurrence- free survival and increased recurrence rates among LDLT recipients,others,including large database studies,report comparable recurrence- free survival and recurrence rates between LDLT and DDLT.Studies supporting the increased recurrence in LDLT have linked graft regeneration to tumor progression,but we found no association between graft regeneration/initial graft volume and tumor recurrence among our 125 consecutive LDLTs for HCC cases.In the absence of a prospective study regarding the use of LDLT vs DDLT for HCC patients,there is no evidence to support the higher HCC recurrence after LDLT than DDLT,and LDLT remains a reasonable treatment option for HCC patients with cirrhosis.     

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.     

High rate of complete histopathological response in hepatocellular carcinoma patients after combined transarterial chemoembolization and stereotactic body radiation therapy

BACKGROUNDLiver transplantation (LT) presents a curative treatment option in patients with early stage hepatocellular carcinoma (HCC) who are not eligible for resection or ablation therapy. Due to a risk of up 30% for waitlist drop-out upon tumor progression, bridging therapies are used to halt tumor growth. Transarterial chemoembolization (TACE) and less commonly stereotactic body radiation therapy (SBRT) or a combination of TACE and SBRT, are used as bridging therapies in LT. However, it remains unclear if one of those treatment options is superior. The analysis of explant livers after transplantation provides the unique opportunity to investigate treatment response by histopathology.AIMTo analyze histopathological response to a combination of TACE and SBRT in HCC in comparison to TACE or SBRT alone. METHODSIn this multicenter retrospective study, 27 patients who received liver transplantation for HCC were analyzed. Patients received either TACE or SBRT alone, or a combination of TACE and SBRT as bridging therapy to liver transplantation. Liver explants of all patients who received at least one TACE and/or SBRT were analyzed for the presence of residual vital tumor tissue by histopathology to assess differences in treatment response to bridging therapies. Statistical analysis was performed using Fisher-Freeman-Halton exact test, Kruskal-Wallis and Mann-Whitney-U tests.RESULTSFourteen patients received TACE only, four patients SBRT only, and nine patients a combination therapy of TACE and SBRT. There were no significant differences between groups regarding age, sex, etiology of underlying liver disease or number and size of tumor lesions. Strikingly, analysis of liver explants revealed that almost all patients in the TACE and SBRT combination group (8/9, 89%) showed no residual vital tumor tissue by histopathology, whereas TACE or SBRT alone resulted in significantly lower rates of complete histopathological response (0/14, 0% and 1/4, 25%, respectively, P value < 0.001). CONCLUSIONOur data suggests that a combination of TACE and SBRT increases the rate of complete histopathological response compared to TACE or SBRT alone in bridging to liver transplantation.     

Actual therapeutic efficacy of pre-transplant treatment on hepatocellular carcinoma and its impact on survival after salvage living donor liver transplantation

Background  The exact efficacy of pre-liver transplant (LT) therapy for hepatocellular carcinoma (HCC) and the impact on survival after LT remain controversial in regard to salvage LT. Materials and methods  Of 79 patients transplanted in Nagasaki University Hospital between August 1997 and December 2007, 29 patients (36.7%) were indicated for HCC based on the Milan criteria using computed tomography and magnetic resonance imaging. Pre-LT therapy other than liver resection had been performed in 18 cases (62.1%) for 24 lesions. Treated lesions were analyzed histologically using thin slices of the whole explanted liver. Results  Pre-LT therapy included transarterial chemoembolization (TACE) for 10 lesions, percutaneous ethanol injection (PEI) + TACE for 1 lesion, PEI in 6 lesions and ablation therapy in 7 lesions. Under preoperative imaging study, 19 lesions (79.1%) were “thought-to-be” necrotic by pre-LT therapy. However, histologically, viable HCCs were still observed in 9 lesions (9/19 47%). A median interval between the first pre-therapy and LT was 22 months, while last pre-LT therapy and LT was 11 months. No sarcomatous HCC or forced portal venous tumor thrombus was found in all cases with residual lesions. One peritoneal recurrence has occurred after LT, in whom PEI and RFA had been performed before LDLT. The disease free survival after LDLT was comparable to that of cases without pre-LT therapy. Conclusion  Half of the preoperatively “thought-to-be” necrotic lesions still contained viable HCC cells after the pre-LT treatment. Overall, the history of pre-LT therapy does not preclude or interfere with subsequent LT, although percutaneous treatment may spread disseminated tumor cell growth under immunosuppression.     

Multicenter validation of a score to predict prognosis after the development of HCC recurrence following liver transplantation

BackgroundHCC recurrence after LT impacts negatively on survival. A recent study detected late recurrence (≥12 months), alpha-fetoprotein (AFP) <100 ng/mL at recurrence and being amenable for curative-intent treatments as good prognostic factors. With these variables a prognostic score was proposed. The objective of this study was to validate the prognostic score for hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT).MethodsData from the University of California, San Francisco, the University Hospital of Birmingham and Instituto Nazionale dei Tumori, Milan including patients with HCC recurrence after LT were analyzed. The previous reported score was applied to this cohort.ResultsFrom June 2002–December 2014, 1328 patients had a confirmed HCC in their explanted liver. The study group comprised 130 patients (9.8%) diagnosed with HCC recurrence after LT. Overall median survival after HCC recurrence was 12.4 (95% CI 10.2–16.3) months. Application of the previously reported score showed a significantly superior survival for the good prognosis group compared to moderate and poor prognosis groups (p < 0.0001).ConclusionThe score continues to identify a group of patients who would benefit from aggressive treatment and experience significant improved survival following recurrent HCC after LT.     

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.     

Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation： A case report

INTRODUCTION Strict criteria developed to select patients with hepatocellular carcinoma (HCC) for liver transplantation have increased the survival and decreased the recurrence of tumor after transplantation[1]. However, tumor recurrence and subsequent mo…     

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.     

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 radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis

Background

This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization (TACE) on post-hepatectomy recurrence.

Methodology

From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for Hepatocellular carcinoma (HCC). 102 patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumor size ≤5 cm and number of lesion ≤3 when tumors were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. Primary outcome was overall survival, which was determined using log-rank test and Kaplan Meier plots performed. Categorical data were analyzed using Chi-square test and continuous variable were analyzed using Mann-U Whitney test.

Results

Demographics and primary tumor characteristics were similar in both groups (p > 0.05). Overall survival after initial hepatectomy and salvage treatment for recurrence was similar (p > 0.05) in both groups with 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (p < 0.05).

Conclusions

RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when tumor size is ≤5 cm and ≤3 lesion when re-resection or salvage transplantation is not considered feasible.