Current status and prospect of treatments for recurrent hepatocellular carcinoma

Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.     

Sorafenib suppresses postsurgical recurrence and metastasis of hepatocellular carcinoma in an orthotopic mouse model

Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase-labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. CONCLUSION: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention.     

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.     

Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model

The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag-expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen-specific immune-directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8(+) T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8(+) T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance. CONCLUSION: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.     

Peretinoin as an adjuvant therapy for hepatocellular carcinoma

Introduction: The current curative treatment modalities for hepatocellular carcinoma (HCC) are unfortunately fraught with high rates of HCC recurrence. Hence there is a need to prevent or reduce HCC recurrence after initial curative therapy. Peretinoin is a synthetic oral retinoid showing significant reduction in the incidence of recurrent or new HCC in patients who had received curative HCC therapy.

Areas covered: Peretinoin is analysed against the background of molecular pathogenesis of the different causes of HCC. Publications related to peretinoin since 1996 are reviewed, covering clinical characteristics, safety and tolerance profile as well as the current status of clinical development.

Expert commentary: Early phase studies are promising but we need to await the results of the ongoing phase III study of peretinoin in hepatitis C related HCC. Long term impact of peretinoin may be diminished by the foreseeable near eradication of hepatitis C by the direct acting antivirals.     

Treatment of hepatocellular carcinoma

Opinion statement The incidence of hepatocellular carcinoma (HCC) is increasing in the United States. Several modalities are available for the treatment of HCC, and decisions regarding the optimal choice of therapy are based on tumor burden and severity of liver disease. Classification systems are helpful for prognostic purposes and to guide in the choice of therapy. Surgical resection is a mainstay of therapy for patients with solitary small tumors and preserved liver function (noncirrhotic or Child-Pugh class A cirrhotic patients without portal hypertension). Unfortunately, a minority of patients is eligible for resection, and postoperative recurrence or de novo HCC is common. Liver transplantation offers the best chance of curing HCC in cirrhotic patients. Patients with a solitary tumor less than 5 cm or no more than three tumors each 3 cm or less have a survival rate of 70% with less than 20% recurrence at 5 years. Access to liver transplantation is limited by organ availability, and tumor progression during the waiting period can lead to ineligibility. Ethanol injection and radiofrequency ablation are effective modalities to ablate small tumors (generally <5 cm) in patients who are not candidates for resection or liver transplantation. These modalities can also be used to treat HCC prior to liver transplantation. Transarterial chemoembolization is used to treat patients with multifocal or large HCC who are ineligible for other therapies. Chemotherapeutic agents are infused into the tumor via the hepatic artery along with embolic material in order to induce tumor necrosis. This technique should be used in selective patients with relatively preserved liver function, absence of portal vein thrombosis, or encephalopathy. Limited data exist to support the use of this modality as a primary treatment option for small HCC. Chemotherapeutic or hormonal therapies have a limited role in the management of patients with HCC. Despite mixed outcomes, we routinely use the somatostatin analog octreotide in advanced, multifocal HCC. Emerging therapies should focus on treatment of small tumors and targeted pharmacologic therapy for advanced disease.     

Chinese expert consensus on neoadjuvant and conversion therapies for hepatocellular carcinoma

The low resection and high recurrence rates in hepatocellular carcinoma (HCC) are the major challenges to improving prognosis. Neoadjuvant and conversion therapies are underlying strategies to overcome these challenges. To date, no guideline or consensus has been published on the neoadjuvant and conversion therapies in HCC. Recent studies showed that neoadjuvant therapy for resectable HCC and conversion therapy for unresectable HCC are safe, feasible, and effective. Neoadjuvant and conversion therapies have the following advantages in treating HCC: R0 resection with sufficient volume of future liver remnant, relatively simple operation, and wide applicability. Therefore, it was necessary to conduct a widely accepted consensus among the experts in China who have extensive expertise and experience in treating HCC using neoadjuvant and conversion therapies, which is important to standardize the application of neoadjuvant and conversion therapies for the management of HCC. The strategies of neoadjuvant therapy include the selection of the eligible patients, therapy regimen, cycles, effect evaluations, and multidisciplinary treatment. The management of patients with insufficient volume of future liver remnant and patients who cannot achieve R0 resection is the key to the strategies of conversion therapy. Here, we present the resultant evidence- and experience-based consensus to guide the application of neoadjuvant and conversion therapies in clinical practice.     

Targeting of circulating hepatocellular carcinoma cells to prevent postoperative recurrence and metastasis

Currently,the main treatment for hepatocellular carcinoma(HCC)involves the surgical removal of tumors or liver transplantation.However,these treatments are often not completely curative,as they are associated with a risk for postoperative recurrence and metastasis.Circulating tumor cells(CTCs)are increasingly recognized as the main source for recurrence and metastasis after radical hepatectomies are performed.Many studies have demonstrated the association between the presence of either pre-or postoperative CTCs and an increased risk for HCC recurrence.To improve the therapeutic outcome of HCC,a personalized,comprehensive and multidisciplinary approach should be considered,involving the application of appropriate diagnostic and therapeutic measures targeting HCC CTCs in different stages throughout the course of treatment.This article proposes some HCC CTC-based strategies for the treatment of HCC,including the monitoring of HCC CTCs before,during and after radical hepatectomy,therapeutic targeting of HCC CTCs,prevention of the generation and colonization of CTCs,as well as the use of CTC indexes for the selection of indications,prediction of prognoses,and planning of individualized therapeutic regimens.Innovation and technological development of therapies targeting CTCs,as well as their translation into clinical practice,will help to effectively reduce postoperative recurrence and metastasis,and significantly prolong the survival of HCC patients.     

Combined interventional therapies of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, responsible for an estimated one million deaths annually. It has a poor prognosis due to its rapid infiltrating growth and complicating liver cirrhosis. Surgical resection, liver transplantation and cryosurgery are considered the best curative options, achieving a high rate of complete response, especially in patients with small HCC and good residual liver function. In nonsurgery, regional interventional therapies have led to a major breakthrough in the management of unresectable HCC, which include transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave coagulation therapy (MCT), laser-induced thermotherapy (LITT), etc. As a result of the technical development of locoregional approaches for HCC during the recent decades, the range of combined interventional therapies has been continuously extended. Most combined multimodal interventional therapies reveal their enormous advantages as compared with any single therapeutic regimen alone, and play more important roles in treating unresectable HCC.     

Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy

A better understanding of signaling pathways in HCC pathogenesis has led to targeted therapies against HCC. Identification of liver cancer stem cell markers and their related pathways is one of the most important goals of liver cancer research. New therapies should ideally target cancer stem cells and not normal stem/progenitor cells, because the latter are very important in regeneration and repair. Individualized HCC therapy will require better definition of patient subgroups that benefit most or should be protected from therapy failure and unwanted side effects. Tumor tissue acquisition should be mandatory, reversing the practice that was established years ago when targeted HCC therapy was but a pipe dream.     

Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.     

Treatment for hepatocellular carcinoma in Japan over the last three decades: Our experience and published work review

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related mortality worldwide. In the last few decades, there has been a marked increase in therapeutic options for HCC and epidemiological characteristics at HCC diagnosis have also significantly changed. With these changes and advances in medical technology and surveillance program for detecting earlier stage HCC, survival in patients with HCC has significantly improved. Especially, patients with liver cirrhosis are at high risk of HCC development, and regular surveillance could enable early detection of HCC and curative therapy, with potentially improved clinical outcome. However, unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation, surgical resection or ablative therapies). Locoregional therapies such as radiofrequency ablation, percutaneous ethanol injection, microwave coagulation therapy and transcatheter arterial chemoembolization play a key role in the management of unresectable HCC. Currently, molecular‐targeted agents such as sorafenib have emerged as a promising therapy for advanced HCC. The choice of the treatment modality depends on the size of the tumor, tumor location, anatomical considerations, number of tumors present and liver function. Furthermore, new promising therapies such as gene therapy and immunotherapy for HCC have emerged. Approaches to the HCC diagnosis and adequate management for patients with HCC are improving survival. Herein, we review changes of epidemiological characteristics, prognosis and therapies for HCC and refer to current knowledge for this malignancy based on our experience of approximately 4000 HCC cases over the last three decades.     

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.
DATA SOURCES: PubMed database was searched for relevant articles in English on the issue of HCC management.
RESULTS: Surgical resection represents a potentially cura-tive option for appropriate candidates with tumors detected at earlier stages and with well-preserved liver function. The long-term outcome of surgery is impaired by a high rate of recurrence. Surgical approaches are being challenged by local ablative therapies such as radiofrequency ablation and micro-wave ablation in selected patients. Liver transplantation offers potential cure for HCC and also correction of underlying liver disease, and minimizes the risk of recurrence, but is reserved for patients within a set of criteria proposed for a prudent allocation in the shortage of donor organs. Transcatheter locoregional therapies have become the palliative standard allowing local control for intermediate stage patients with noninvasive multinodular or large HCC who are beyond the potentially curative options. The signiifcant survival beneift with the multikinase inhibitor sorafenib for advanced HCC has shifted the direction of research regarding systemic treat-ment toward molecular therapies targeting the disregulated pathways of hepatocarcinogenesis. Potential beneift is sug-gested from simultaneous or sequential multimodal therapies, and optimal combinations are being investigated. Despite the striking progress in preclinical studies of HCC immuno-therapy and gene therapy, extensive clinical trials are required to achieve successful clinical applications of these innovative approaches.
CONCLUSION: Treatment decisions have become increasing-ly complex for HCC with the availability of multiple surgical and nonsurgical therapeutic options and require a compre-hensive, multidisciplinary approach.     

Strategy for improving survival and reducing recurrence of HCV-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer and the third leading cause of cancerrelated death in the world.With advances in imaging diagnostics,accompanied by better understanding of high-risk patients,HCC is now frequently detected at an early stage;however,the prognosis remains poor.The recurrence rate after treatment of HCC is higher than that associated with cancers of other organs.This may be because of the high incidence of intrahepatic distant recurrence and multicentric recurrence,especially with hepatitis C virus(HCV)-related hepatocellular carcinoma.The Barcelona Clinic Liver Cancer(BCLC)classification has recently emerged as the standard classification system for the clinical management of patients with HCC.According to the BCLC staging system,curative therapies(resection,transplantation,transcatheter arterial chemoembolization,percutaneous ethanol injection therapy,percutaneous microwave coagulation therapy and percutaneous radiofrequency ablation)can improve survival in HCC patients diagnosed at an early stage and offer a potential long-term cure.However,treatment strategies for recurrent disease are not mentioned in the BCLC classsification.The strategy for recurrence may differ according to the recurrence pattern,i.e.,intrahepatic distant recurrence vs multicentricrecurrence.In this article,we review recurrent HCC and the therapeutic strategies for reducing recurrent HCC,especially HCV-related HCC.     

Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma

Primary liver cancer, hepatocellular carcinoma (HCC), is the fifth most common cancer and the third leading cancer killer in the world. There is no effective therapeutic option for most HCC patients. A new therapeutic strategy is essential. Granulin-epithelin precursor (GEP, also called progranulin, acrogranin, or PC-derived growth factor) was identified as a potential therapeutic target for HCC from our earlier genome-wide expression profiles. We aimed to conduct a detailed investigation with in vitro and animal experiments. We developed the anti-GEP monoclonal antibody (mAb), and examined its effect on hepatoma cells and normal liver cells in vitro. A nude mice model transplanted with human HCC was used to investigate if anti-GEP mAb can inhibit tumor growth in vivo. We demonstrated that anti-GEP mAb inhibited the growth of hepatoma cells but revealed no significant effect on normal liver cells. In the nude mice model transplanted with human HCC, anti-GEP mAb decreased the serum GEP level and inhibited the growth of established tumors in a dose-dependent manner. The anti-GEP mAb reduced tumor cell proliferation via the p44/42 MAPK and Akt pathways, and reduced tumor angiogenesis to deprive the nutrient supply with reduced microvessel density and tumor vascular endothelial growth factor level. CONCLUSION: We have shown that anti-GEP antibody can inhibit HCC growth, providing evidence that GEP is a therapeutic target for HCC treatment.     

Surgical treatment of intra hepatic recurrence of hepatocellular carcinoma

Recurrence after hepatocellular carcinoma(HCC) is frequent.Currently,there are no recommendations on therapeutic strategy after recurrence of HCC.Whereas the 5 year-recurrence rate after resection of HCC is 100%,this drops to 15% after primary liver transplantation.Repeat hepatectomy and salvage liver transplantation(SLT) could be performed in selected patients to treat recurrent HCC and enable prolonged overall survival after treatment of recurrence.Other therapies such as local ablation,chemoembolization or sorafenib could be proposed to those patients unable to benefit from resection or SLT.A clear definition of the place of SLT and "prophylactic" liver transplantation is required.Indeed,identifying risks factors for recurrence at time of primary liver resection of HCC may help to avoid recurrence beyond Milan criteria and non-resectable situations.In this review,we summarize the recent data available in the literature on the feasibility and outcomes of repeat hepatectomy and SLT as treatment for recurrent HCC.     

Molecular imaging and therapy targeting copper metabolism in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Significant efforts have been devoted to identify new biomarkers for molecular imaging and targeted therapy of HCC. Copper is a nutritional metal required for the function of numerous enzymatic molecules in the metabolic pathways of human cells. Emerging evidence suggests that copper plays a role in cell proliferation and angiogenesis. Increased accumulation of copper ions was detected in tissue samples of HCC and many other cancers in humans. Altered copper metabolism is a new biomarker for molecular cancer imaging with position emission tomography (PET) using radioactive copper as a tracer. It has been reported that extrahepatic mouse hepatoma or HCC xenografts can be localized with PET using copper-64 chloride as a tracer, suggesting that copper metabolism is a new biomarker for the detection of HCC metastasis in areas of low physiological copper uptake. In addition to copper modulation therapy with copper chelators, short-interference RNA specific for human copper transporter 1 (hCtr1) may be used to suppress growth of HCC by blocking increased copper uptake mediated by hCtr1. Furthermore, altered copper metabolism is a promising target for radionuclide therapy of HCC using therapeutic copper radionuclides. Copper metabolism has potential as a new theranostic biomarker for molecular imaging as well as targeted therapy of HCC.     

Effects of branched‐chain amino acid‐enriched nutrient for patients with hepatocellular carcinoma following radiofrequency ablation: A one‐year prospective trial

Background and Aim: This prospective control study examined whether supplementation with branched‐chain amino acid (BCAA)‐enriched nutrients can help maintain and improve residual liver function and nutritional status in cirrhotic patients with hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Methods: Subjects were 49 patients with hepatitis C‐related HCC who underwent RFA. Two groups were formed: BCAA group (BCAA‐enriched nutrient, aminoleban EN) and controls (standard diet only). Event‐free survival rate, liver function tests, and Short Form (SF)‐8 scores were evaluated in both groups before and one year after RFA. Energy metabolism using indirect calorimetry was measured before and after 3 months. Results: Complete data were obtained from 35 patients (BCAA group, n = 20; controls, n = 15). Six events (death, recurrence of HCC, rupture of esophageal varices and liver failure) occurred during the observation period, but frequencies of these events did not differ between groups. Event‐free survival rate tended to be higher in the BCA group than in controls. Among the parameters of liver function, serum albumin level was only significantly increased over 6 months, and remained at similar values for one year (P < 0.05). SF‐8 scores for general health, physical functioning, and social functioning were significantly elevated in the BCAA group (P < 0.05). Non‐protein respiratory quotient was significantly improved in the BCAA group (P < 0.01). Conclusion: Supplementation with BCAA‐enriched nutrients for one year in cirrhotic patients with HCC after RFA therapy can perform safety and improve both nutritional state and quality of life.