Advances in locoregional therapy for hepatocellular carcinoma combined with immunotherapy and targeted therapy

Locoregional therapies(LRTs)of hepatocellular carcinoma(HCC)represented by ablation and TACE has become the main means for the clinical treatment of unresectable HCC.Among these,TACE is used throughout the stageⅠb toⅢb of HCC treatment.In recent years,immunotherapy led by immune checkpoint inhibitors has become a hot direction in clinical research.At the same time,targeted drugs such as Sorafenib and Apatinib have played an important role in the treatment and complementary therapy of advanced HCC,and their clinical application has been quite mature.HCC is the sixth most common malignant tumor in the world.When it comes to its treatment,different therapies have different indications,and their individual efficacies are not satisfactory,which makes the exploration of the use of combination therapy in HCC treatment become a new trend.In this paper,the status of the three therapies and the progress of their combined application are briefly reviewed.

New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization(TACE)being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors(TKIs) and immune checkpoint inhibitors(ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

Salvage locoregional therapies for recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the second most common cause of cancerrelated death worldwide.Despite the advent of screening efforts and algorithms to stratify patients into appropriate treatment strategies,recurrence rates remain high.In contrast to first-line treatment for HCC,which relies on several factors,including clinical staging,tumor burden,and liver function,there is no consensus or general treatment recommendations for recurrent HCC(R-HCC).Locoregional therapies include a spectrum of minimally invasive liver-directed treatments which can be used as either curative or neoadjuvant therapy for HCC.Herein,we provide a comprehensive review of recent evidence using salvage loco-regional therapies for R-HCC after failed curative-intent.

Hepatocellular carcinoma locoregional therapies:Outcomes and future horizons

Hepatocellular carcinoma(HCC)is the most common primary cancer of the liver and has an overall five-year survival rate of less than twenty percent.For patients with unresectable disease,evolving liver-directed locoregional therapies provide efficacious treatment across the spectrum of disease stages and via a variety of catheter-directed and percutaneous techniques.Goals of locoregional therapies in HCC may include curative intent in early-stage disease,bridging or downstaging to surgical resection or transplantation for early or intermediate-stage disease,and local disease control and palliation in advanced-stage disease.This review explores the outcomes of chemoembolization,bland embolization,radioembolization,and percutaneous ablative therapies.Attention is also given to prognostic factors related to each of the respective techniques,as well as future directions of locoregional therapies for HCC.

Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies

BACKGROUND:Locoregional therapies(LRTs) are treatments to achieve local control of hepatocellular carcinoma(HCC).Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood.The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant(LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology.METHODS:Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT.Radiologic response was evaluated to predict tumor necrosis in the explanted liver.Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors(RECIST),and European Association for the Study of the Liver(EASL) guidelines.LRT was repeated as needed until time of LT.Histological tumor necrosis was graded as complete(100%),partial(50%-99%),or poor(【50%).RESULTS:Between 2002 and 2011,128 patients(97 men and 31 women) received pre-LT LRT including transarterial therapy(93),radiofrequency ablation(20),or combination of both(15).The mean age of the patients was 58±9 years.Their mean follow-up was 35±27 months.The median waitlist time was 55 days.One hundred(78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis.Nineteen(15%) of the patients had complete tumor necrosis on histopathology analysis.Fifty(39%) of the patients exhibited partial necrosis,52(41%) showed poor or no necrosis and 7(5%) showed progressive disease.The overall pre-LT radiologic staging was correlated with explant pathology in 73(57%) of the patients.Underestimated tumor stage was noted in 49(38%) patients,and overestimated tumor stage in 6(5%) patients.The post-LT 3-year overall survival and disease free survival were 82% and 80%,and the rates for complete and partial tumor necrosis were 100% vs 78%(P=0.02) and 100% vs 75%(P=0.03),respectively.CONCLUSIONS:In the current era,interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis.Total tumor necrosis is the goal of LRT;therefore,evolution in its performance is needed.Similarly,ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

Treatment of recurrent hepatocellular carcinoma following liver resection,ablation or liver transplantation

Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and causes one third of cancer related deaths world-wide.Approximately one third of patients with HCC are eligible for curative treatments that include hepatic resection,liver transplantation or imaging guided tumor ablation.Recurrence rates after primary therapy depends on tumor biology and pre-treatment tumor burden with early recurrence rates ranging from 30%-80%following surgical resection and ablation.HCC recurs in over ten percent following liver transplantation for HCC.Treatment modalities for tumor recurrence following resection and ablation include repeat liver resection,salvage liver transplantation,locoregional therapies,and systemic chemotherapy/immunotherapy.Locoregional and immune mediated therapies are limited for patients with tumor recurrence following liver transplantation given potential immune related allograft rejection.Given the high HCC recurrence rates after primary tumor treatment,it is imperative for the clinician to review the appropriate treatment strategy for this disease entity.This article will review the current literature regarding HCC recurrence after primary curative therapies and will discuss the relevant future trends in the HCC field.

Transarterial embolization is an acceptable bridging therapy to hepatocellular carcinoma prior to liver transplantation

BACKGROUND Hepatocellular carcinoma(HCC)is an aggressive malignant neoplasm that requires liver transplantation(LT).Despite patients with HCC being prioritized by most organ allocation systems worldwide,they still have to wait for long periods.Locoregional therapies(LRTs)are employed as bridging therapies in patients with HCC awaiting LT.Although largely used in the past,transarterial embolization(TAE)has been replaced by transarterial chemoembolization(TACE).However,the superiority of TACE over TAE has not been consistently shown in the literature.AIM To compare the outcomes of TACE and TAE in patients with HCC awaiting LT.METHODS All consecutive patients with HCC awaiting LT between 2011 and 2020 at a single center were included.All patients underwent LRT with either TACE or TAE.Some patients also underwent percutaneous ethanol injection(PEI),concom-itantly or in different treatment sessions.The choice of LRT for each HCC nodule was determined by a multidisciplinary consensus.The primary outcome was waitlist dropout due to tumor progression,and the secondary outcome was the occurrence of adverse events.In the subset of patients who underwent LT,complete pathological response and post-transplant recurrence-free survival were also assessed.RESULTS Twelve(18.5%)patients in the TACE group(only TACE and TACE+PEI;n=65)and 3(7.9%)patients in the TAE group(only TAE and TAE+PEI;n=38)dropped out of the waitlist due to tumor progression(P log-rank test=0.29).Adverse events occurred in 8(12.3%)and 2(5.3%)patients in the TACE and TAE groups,respectively(P=0.316).Forty-eight(73.8%)of the 65 patients in the TACE group and 29(76.3%)of the 38 patients in the TAE group underwent LT(P=0.818).Among these patients,complete pathological response was detected in 7(14.6%)and 9(31%)patients in the TACE and TAE groups,respectively(P=0.145).Post-LT,HCC recurred in 9(18.8%)and 4(13.8%)patients in the TACE and TAE groups,respectively(P=0.756).Posttransplant recurrence-free survival was similar between the groups(P log-rank test=0.71).CONCLUSION Dropout rates and posttransplant recurrence-free survival of TAE were similar to those of TACE in patients with HCC.Our study reinforces the hypothesis that TACE is not superior to TAE as a bridging therapy to LT in patients with HCC.

Liver transplantation for hepatocellular carcinoma:an update

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology.

Treatment strategies for hepatocellular carcinoma with extrahepatic metastasis

Extrahepatic metastasis(EHM)of hepatocellular carcinoma(HCC)has increasingly been seen due to improved survival with effective management of intrahepatic lesions.The presence of EHM indicates an advanced stage of HCC,for which systemic therapy serves as the standard treatment modality.Since the approval of Sorafenib as the first systemic agent in 2007,it took almost a decade to show its efficacy in both first and further lines of setting until the landscape of systemic drugs was finally expanded.Moreover,with inspiring results from immunotherapy trials in HCC,it appears that the introduction of immunotherapy may lead to an evolution in the portfolio of HCC treatment.Although the locoregional approach in the management of EHM is not recommended for advancedstage HCC,efforts have been made to demonstrate its efficacy in symptom relief and potential benefit for overall survival.This review provides a summary of recent updates of the systemic agents in the treatment of advanced HCC,with an emphasis on aggressive locoregional management of EHM by various treatment modalities.

Hepatocellular carcinoma Liver Imaging Reporting and Data Systems treatment response assessment: Lessons learned and future directions

Hepatocellular carcinoma(HCC)is a leading cause of morbidity and mortality worldwide,with rising clinical and economic burden as incidence increases.There are a multitude of evolving treatment options,including locoregional therapies which can be used alone,in combination with each other,or in combination with systemic therapy.These treatment options have shown to be effective in achieving remission,controlling tumor progression,improving disease free and overall survival in patients who cannot undergo resection and providing a bridge to transplant by debulking tumor burden to downstage patients.Following locoregional therapy(LRT),it is crucial to provide treatment response assessment to guide management and liver transplant candidacy.Therefore,Liver Imaging Reporting and Data Systems(LI-RADS)Treatment Response Algorithm(TRA)was created to provide a standardized assessment of HCC following LRT.LIRADS TRA provides a step by step approach to evaluate each lesion independently for accurate tumor assessment.In this review,we provide an overview of different locoregional therapies for HCC,describe the expected post treatment imaging appearance following treatment,and review the LI-RADS TRA with guidance for its application in clinical practice.Unique to other publications,we will also review emerging literature supporting the use of LI-RADS for assessment of HCC treatment response after LRT.

The Society for Immunotherapy of Cancer clinical practice guideline on immunotherapy for hepatocellular carcinoma

The Society for Immunotherapy of Cancer(SITC)published clinical practice guideline on immunotherapy for hepatocellular carcinoma(HCC)(1).Many clinical practice guidelines for HCC have been published by academic societies worldwide(2),but the SITC guideline is the first to focus exclusively on immunotherapy.

Progress in surgical and nonsurgical approaches for hepatocellular carcinoma treatment

BACKGROUND： Hepatocellular carcinoma （HCC） is a com- plex and heterogeneous malignancy, frequently occurs in the setting of a chronically diseased organ, with multiple con- founding factors making its management challenging. HCC represents one of the leading causes of cancer-related mortal- ity globally with a rising trend of incidence in some of the de- veloped countries, which indicates the need for better surgical and nonsurgical management strategies.

Role of locoregional therapies in the management of patients with hepatocellular carcinoma

Hepatocellular carcinoma(HCC)was the sixth most common cancer and the third cause of cancer-related deaths worldwide in 2020.Liver resection and transplantation remain the cornerstone for patients with early-stage disease and represent the only option for potential cure in HCC.However,fewer than 10%of patients are considered suitable for surgery at the time of diagnosis.Locoregional therapies,defined as minimally invasive image-guided liver tumour-directed procedures,are integral to in the management of HCC.This review discusses the role of locoregional therapies in HCC management in the emergence of immune and systemic treatments.

Activation of Anti-tumor Immune Response by Ablation of HCC with Nanosecond Pulsed Electric Field

Locoregional therapy is playing an increasingly important role in the non-surgical management of hepatocellular carcinoma(HCC).The novel technique of non-thermal electric ablation by nanosecond pulsed electric field has been recognized as a potential locoregional methodology for indicated HCC.This manuscript explores the most recent studies to indicate its unique anti-tumor immune response.The possible immune mechanism,termed as nano-pulse stimulation,was also analyzed.

Recurrence of hepatocellular carcinoma following deceased donor liver transplantation:case series

Aim:We aimed to study the clinical and pathological characteristics of liver transplant recipients with hepatocellular carcinoma recurrence.Methods:We reviewed the data for 26 patients who had tumor recurrence after deceased donor liver transplant for hepatocellular carcinoma at the Johns Hopkins Hospital from January 2005 to December 2015.Results:In total,88%of recipients were males.The mean age was 59 years.On explant,poor differentiation was detected in 43%,while 73%had microvascular invasion.Overall,62%were diagnosed to be outside of Milan criteria.Out of these,15%met the criteria for downstaging.Twenty(77%)patients had pre-transplant alpha fetoprotein levels≥20 ng/mL.In 54%of patients,the location of hepatocellular carcinoma(HCC)recurrence was extrahepatic,followed by intrahepatic in 31%and both intra-and extrahepatic in 15%.The post-transplant tumor recurrence was diagnosed at a mean of 427 days(range 34-1502).Fifty percent of HCC recurrences were diagnosed within one year following liver transplant.Twenty(77%)patients received treatment for their recurrent HCC:external radiation(n=10),surgical resections(n=8;brain 4,spine 2,bone 1,and Whipple surgery 1),sorafenib(n=7),locoregional therapy(n=5).Overall,24 out of 26(92%)recipients died within four years after the transplant.Conclusion:HCC recurrence after liver transplant is infrequent.More than fifty percent of HCC recurrences following liver transplant are extrahepatic.Despite better recipient selection for liver transplant,the curative options are limited in recurrent cases and associated with extremely poor outcomes.

Efficacy of percutaneous radiofrequency ablation for hepatocellular carcinoma treatment in patients aged≥80 years

Background:Although radiofrequency ablation(RFA)is a minimally invasive treatment for early-stage hepatocellular carcinoma(HCC),it remains unclear whether RFA achieves favorable outcomes in pa-tients aged≥80 years.This study aimed to determine the efficacy and safety of RFA for HCC in patients aged≥80 years.Methods:A total of 512 naïve patients with HCC who had undergone RFA from January 2001 to December 2016 were enrolled.They were categorized into the≥80-year-old group and the control group(aged<80 years).The primary endpoint was overall survival(OS),and the secondary endpoints were recurrence-free survival,complications associated with RFA,and cause of death.Propensity score matching was performed to adjust for patients’sex,liver function,tumor number,tumor diameter,and hepatitis C virus infection.Finally,the data of 68 patients in the≥80-year-old group and 68 in the control group were analyzed;their baseline characteristics,primary endpoint,and secondary endpoints were compared.Results:There were significant differences in the alanine aminotransferase level and prothrombin time between the groups.The cumulative OS rate was not significantly different between the groups(P=0.83):98.5%,87.9%,and 50.5%in the≥80-year-old group and 94.1%,72.8%,and 49.3%in the control group at 1,3,and 5 years,respectively.Age≥80 years was not significantly associated with OS in multivariate analyses.Liver-related death occurred in 17 patients in the≥80 year-old group and in 16 patients in the control group(P=1.00).Conclusions:RFA is safe and effective for the treatment of patients with HCC aged≥80 years.

Hepatocellular Carcinoma and the Role of Liver Transplantation:A Review

Hepatocellular carcinoma(HCC)is one of the leading causes of cancer deaths worldwide and liver transplantation(LT)is the only potentially curative treatment.Over the years,Milan criteria has been used for patient selection.There is ongoing research in this field with introduction of new biomarkers for HCC that can help guide future treatment.Furthermore,newer therapies for downstaging of the tumor are being implemented to prevent dropout from the transplant list.In addition,combination therapies for better outcome are under investigation.Interestingly,the concept of living-donor LT and possible use of hepatitis C virus-positive donors has been implemented as an attempt to expand the organ pool.However,there is a conflict of opinion between different centers regarding its efficacy and data is scarce.The aim of this review article is to outline the various selection criteria for LT,discuss the outcomes of LT in HCC patients,and explore future directions of LT for HCC.Therefore,a comprehensive PubMed/MEDLINE review was conducted.To expand our search,references of the retrieved articles were also screened for additional data.After selecting the studies,the authors independently reviewed them to identify the relevant studies.After careful evaluation 120 studies relevant to out topic are cited in the manuscript.Three tables and two figures are also included.In conclusion LT for HCC has evolved over the years.With the introduction of several expanded criteria beyond Milan,the introduction of bridging therapies,such as transcatheter arterial chemoembolization and radiofrequency ablation,and the approval of newer systemic therapies,it is evident that there will be more LT recipients in the future.It is promising to see ongoing trials and the continuous evolution of protocols.Prospective studies are needed to guide the development of a pre-LT criteria that can ensure low HCC recurrence risk and is not overly stringent,clarify the role of LDLT,and determine the optimal bridging therapies to LT.