Combination and Optimal Sequencing of Systemic and Locoregional Therapies in Hepatocellular Carcinoma: Proceedings from the Society of Interventional Radiology Foundation Research Consensus Panel.

Hepatocellular carcinoma, historically, has had a poor prognosis with very few systemic options. Furthermore, most patients at diagnosis are not surgical candidates. Therefore, locoregional therapy (LRT) has been widely used, with strong data supporting its use. Over the last 15 years, there has been progress in the available systemic agents. This has led to the updated Barcelona Clinic Liver Cancer (BCLC) algorithm's inclusion of these new systemic agents, with advocacy of earlier usage in those who progress on LRT or have tumor characteristics that make them less likely to benefit from LRT. However, neither the adjunct of LRT nor the specific sequencing of combination therapies is addressed directly. This Research Consensus Panel sought to highlight research priorities pertaining to the combination and optimal sequencing of LRT and systemic therapy, assessing the greatest needs across BCLC stages.

TACE Combined with HIFU Versus Surgical Resection for Single Hepatocellular Carcinoma with Child-Pugh B Cirrhosis in Overall Survival and Progression-Free Survival: A Retrospective Study.

Objective: To compare the effectiveness, safety and survival outcome of transcatheter arterial chemoembolization (TACE) combined with high-intensity focused ultrasound (HIFU) versus surgical resection for treating single hepatocellular carcinoma (HCC) with Child-Pugh B cirrhosis. Methods: A hospital-based retrospective study with 146 patients diagnosed with single HCC with Child-Pugh B cirrhosis from July 2010 to July 2018 was conducted in a tertiary teaching hospital. A total of 49 patients underwent TACE combined with HIFU (the combined group), and 97 patients underwent surgical resection (the resection group). Of them, 22 patients undergoing TACE combined with HIFU and 45 patients undergoing surgical resection had small HCC (tumor diameter ≤3 cm). The overall survival (OS) time, progression-free survival (PFS) time and postoperative complications were compared between the two groups. Results: In the single HCC tumor cohort, there was no significant difference in OS between the two groups [hazard ratio (HR) = 0.6379; 95% confidence interval (95% CI) = 0.3737 to 1.089; P = .0995], while the resection group showed an obvious superiority to the combined group regarding PFS (HR = 0.3545; 95% CI = 0.2176-0.5775; P < .0001). The 1-year, 3-year and 5-year recurrence rates were 30.9%, 55.7%, 86.6% in the resection group and 53.1%, 77.6%, 89.8% in the combined group, respectively. In the small HCC tumor cohort, there was also no difference in OS between the two groups (HR = 0.8808; 95% CI = 0.3295-2.355; P = .06396), while the resection group showed an obvious superiority to the combined group regarding PFS (HR = 0.4273; 95% CI = 0.1927-0.9473; P = .0363). The 1-year, 3-year and 5-year recurrence rates were 28.9%, 53.3%, 93.3% in the resection group and 40.9%, 68.2%, 81.8% in the combined group, respectively. Furthermore, the incidence of complications of the combined group was 38.8%, which was significantly less than the 56.7% of the resection group (P = .041), and the duration of general anesthesia in the combined group was shorter than that in the resection group (P = .001). Therein, there was no difference in the incidence of grade I complications (Clavien-Dindo classification) between the two groups (P = .866). Conclusion: For patients with single or single small HCCs, TACE combined with HIFU may not be inferior to surgical resection in terms of the long-term survival rate, while surgical resection still has a definite advantage in terms of delaying recurrence. In addition, the combination of TACE and HIFU has higher safety than surgical resection.

Evaluating the predictive power of circulating tumor cells for the prognosis of transarterial chemoembolization treatment on patients with advanced hepatocellular carcinoma.

ABSTRACT: Explore the predictive power of Circulating Tumor Cells (CTCs) for evaluating the prognosis of transarterial chemoembolization (TACE) treatment on advanced hepatocellular carcinoma (HCC) patients, and use it to construct a prediction model.We retrospectively analyzed 43 patients with Barcelona Clinic Liver Cancer stage C HCC who underwent TACE treatment.The survival time of 43 advanced HCC patients were 2 to 60 months, with the median survival time of 12 months, 1-, 3-, and 5-year survival rates were 42.9%, 9.0%, and 3.6%, respectively. The OS of patients with high level of CTCs before TACE (CTC1 > 2) was significantly lower than that of patients with low level of CTCs (8 vs 12 months, P = .040), but there was no significant difference in PFS between the 2 groups (P = .926). Meanwhile, there was no significant difference in OS and PFS between patients with high level CTCs and those with low level CTCs at 1 week and 4 weeks after TACE (P all > .05). In univariate and multivariate Cox regression analysis, the number of lesions and CTC before TACE were the independent influencing factors for prognosis in these patients, and the HR was 3.01 and 1.20, respectively (all P < .05). The area under curve of COX regression model to predict OS increased with the increase of follow-up time, ranging from 0.56 to 0.85.The CTCs number before TACE is an effective biomarker for predicting the OS of advanced HCC patients. The joint prediction model based on CTCs and tumor number can effectively predict the prognosis of patients with advanced HCC.

What Should Be the Rules for Downstaging for Hepatocellular Carcinoma?

INTRODUCTION: Liver transplantation remains the main curative treatment method for hepatocellular carcinoma. There are several criteria for hepatocellular carcinoma to be eligible for liver transplantation, and it depends on main transplantation centers worldwide. Locoregional treatments and downstaging protocols are used for either to achieve these criteria or to prevent drop outs on the transplant waiting lists. But who can benefit from these bridging therapies effectively for the main purpose of curative treatment? Main contraindications are known for locoregional treatments like cirrhosis or low hepatic function, total main portal vein occlusion, and extrahepatic metastasis. HCCs, which are confined to liver but have high tumor burden, remains the main controversial issue. AIM: On this aspect, we reviewed the literature for downstaging protocols for hepatocellular carcinoma with their effect on survival and recurrence rates after liver transplantation. CONCLUSION: Although candidates for downstaging is still controversial, with the absence of main contraindications, LRT can be applied to selected HCCs, which have a certain degree of tumor burden.

Tumor Diameter for Hepatocellular Carcinoma: Why Should Size Matter?

PURPOSE: There are two main goals in hepatocellular carcinoma management, the first is long term survival and the second is the low recurrence rate after the treatment. Therefore, a lot of selection criteria defined for each treatment method and tumor size is one of the most important parameter in almost all of them. METHODS: In this review, importance of diamater in hepatocellular carcinoma is reviewed. RESULTS: Many reports showed a significant association between increase in maximum tumor diameter and microvascular invasion. Patients with larger tumors are more likely to have poorly differentiated tumors. Increased regional and distant metastasis of tumors were observed in the larger size hepatocellular carcinoma. Liver transplantation represents the best treatment option for patients with decompensated liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Combined with biological, inflammatory, radiological, pathological and genetic markers that predict the biological behavior of the tumor, today, tumor size is one of the best aggressiveness markers until new markers are found. So, tumor size is matter.

Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma.

The efficacy of sorafenib in combination with transarterial chemoembolization (TACE) or multiple-line therapies in patients with advanced hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the overall survival (OS) of patients with advanced HCC in response to different combination therapies.We analyzed the treatment and OS of 401 patients with Barcelona clinic liver cancer stage C HCC between 2012 and 2017. Mortality was analyzed using multivariate Cox regression, and OS was analyzed by the Kaplan-Meier method.The mean age was 59 years and males were predominant. During a median follow-up time of 8.6 months (range, 1-80 months), 346 (86.2%) patients died. In the multivariate Cox regression analysis, primary tumor size ≥5 cm, serum alpha-fetoprotein ≥200, and serum albumin ≥3.5 were significantly associated with mortality. In addition, compared with sorafenib alone, multiple-line treatments with sorafenib and multiple-line treatments without sorafenib yielded significantly decreased mortality. In the Kaplan-Meier analysis, sorafenib with TACE, multiple-line treatments with sorafenib, third-line treatments with sorafenib, and multiple-line treatments without sorafenib yielded a significantly better median OS than sorafenib alone.Sorafenib with concurrent multiple-line therapies significantly improved OS. These combination therapies will provide important information for immunotherapy combination with locoregional therapies in advanced HCC.

Pretransplant Intra-arterial Liver-Directed Therapy Does Not Increase the Risk of Hepatic Arterial Complications in Liver Transplantation: A Single-Center 10-Year Experience.

PURPOSE: To investigate the association between pretransplant intra-arterial liver-directed therapy (IAT) for hepatocellular carcinoma (HCC) and hepatic arterial complications (HAC) in orthotopic liver transplantation (OLT) [namely hepatic artery thrombosis (HAT) and/or the need for hepatic arterial conduit]. METHODS: A total of 175 HCC patients (mean age: 60 years) underwent IAT with either transarterial chemoembolization or yttrium-90 (90Y) transarterial radioembolization prior to OLT between 2003 and 2013. A matched control cohort of 159 HCC patients who underwent OLT without prior IAT was selected. Incidence of HAC in both cohorts was investigated. The categorical differences between both cohorts were calculated by chi-square test. RESULTS: Among the 175 patients (chemoembolization, n = 82; radioembolization, n = 93), 8 (5%) required conduits due to HA disease (chemoembolization, n = 6; radioembolization, n = 2), 3 (2%) developed HAT (chemoembolization, n = 2; radioembolization, n = 1). Eleven of 175 patients (6.7%) had HAC. Of the 159 control patients, 6 (4%) needed conduits for HA disease and 3 (2%) developed HAT. Nine of 159 patients (5.7%) had HAC. Chi-square analysis between the IAT cohort and the control group yielded a p value of 0.810. When comparing chemoembolization to radioembolization, p = 0.076 (not significant at p < 0.05). CONCLUSION: Although aggressive pretransplant radioembolization and chemoembolization are both utilized in most liver transplant centers, neither appears to increase the risk of peri-transplant hepatic arterial complications in HCC patients.

Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a poor 5-year survival rate. Many HCCs are not amenable to surgical resection, because of tumor size, location, or because of the patient's poor liver function, a common obstacle to HCC therapy, because HCCs almost always develop in chronically inflamed livers. SUMMARY: In recent years, many efforts have been made to improve patient survival by conducting clinical trials investigating local and systemic treatment options for patients with unresectable tumors. These treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), selective internal radiotherapy with yttrium-90 (SIRT), stereotactic body radiation therapy (SBRT), proton beam therapy, molecular targeted therapy, and checkpoint inhibition. In this "to-the-point" article, we review the current standard and summarize the most recent findings in unresectable HCC treatment. KEY POINTS: (1) RFA is currently the preferred treatment for patients with tumor burden restricted to the liver and not eligible for surgical resection; (2) TACE is utilized in patients who are not eligible for RFA because of tumor location and/or number of tumor lesions; (3) SIRT might improve treatment responses achieved by TACE and is feasible in patients with portal vein thrombosis; (4) new radiation therapy treatment modalities such as SBRT and proton beam therapy show promising results for local tumor control; and (5) sorafenib remains the first-line systemic treatment option after several large clinical trials have failed to show superiority of other molecular targeted therapies in HCC patients.

Early response evaluation using CT-perfusion one day after transarterial chemoembolization for HCC predicts treatment response and long-term disease control.

PURPOSE: To determine the value of CT perfusion (CTP) for early response assessment after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between April 2013 and April 2015, 41 HCC (16 patients) were included in this study. CT perfusion was performed before and one day after TACE. Blood flow (BF), blood volume (BV), time to start (TTS), arterial liver perfusion (ALP), portal liver perfusion (PVP) and hepatic perfusion index (HPI) were measured. Quantitative perfusion values before and after TACE were compared to the response assessed using mRECIST criteria six weeks after TACE and long-term outcome was assessed. RESULTS: Twenty-one lesions (51%) had complete remission (CR) and five (12%) had partial response (PR) six weeks after TACE. CTP parameters were significantly reduced after TACE in responders (PR, CR, p<0.001) while no difference was observed in non-responders. ALPpost was superior in the prediction of CR compared to BFpost and BVpost (p<0.001) with a sensitivity, specificity, PPV, NPV, and accuracy of 90%, 90%, 91%, 90%, and 91%, respectively. Only 3/21 lesions with CR recurred, with a mean local-recurrence-free survival of 19.6 months. CONCLUSION: CT perfusion detects lesions with complete response one day after TACE, and is a feasible tool for early response assessment.

HKLC Triages More Hepatocellular Carcinoma Patients to Curative Therapies Compared to BCLC and Is Associated with Better Survival.

BACKGROUND AND AIMS: The Hong Kong Liver Cancer (HKLC) system proposes to triage hepatocellular carcinoma (HCC) patients to more aggressive treatment and may be associated with superior survival compared with the Barcelona Clinic Liver Cancer (BCLC) system. We aimed to identify the influence of adherence to HKLC or BCLC treatment recommendations on survival and time to progression. METHODS: We examined a prospectively enrolled cohort of 292 patients undergoing 532 treatment episodes from a single clinical center. RESULTS: The BCLC and HKLC systems accurately predicted overall survival and time to progression after each treatment episode (BCLC: p < 0.001; HKLC: p < 0.001). Adherence to treatment recommendations was higher for HKLC than for BCLC (55.6 vs. 47.9%, p = 0.01). Survival was superior with adherence to HKLC recommendations compared to non-adherence (45.3 vs. 27.1 months, p < 0.001). There was no difference in survival in BCLC with adherence compared to non-adherence (34.6 vs. 32.3 months, p = 0.96). The survival benefit was limited to early- and very early stage disease for both HKLC (p < 0.001) and BCLC (p = 0.007). More patients were triaged to curative therapies by HKLC than BCLC (p = 0.004). The use of transarterial chemoembolization instead of ablation or resection in early- and very early stage disease for technical reasons was the major cause for non-recommended treatment and was associated with worse survival (p < 0.001). CONCLUSIONS: These data support the use of HKLC in early- and very early stage HCC. Efforts should be made to overcome technical reasons for not performing ablation in early- and very early stage disease.

ACR Appropriateness Criteria Radiologic Management of Hepatic Malignancy.

Management of primary and secondary hepatic malignancy is a complex problem. Achieving optimal care for this challenging population often requires the involvement of multiple medical and surgical disciplines. Because of the wide variety of potential therapies, treatment protocols for various malignancies continue to evolve. Consequently, development of appropriate therapeutic algorithms necessitates consideration of medical options, such as systemic chemotherapy; surgical options, such as resection or transplantation; and loco-regional therapies, such as thermal ablation and transarterial embolization techniques. This article provides a review of treatment strategies for the three most common subtypes of hepatic malignancy treated with loco-regional therapies: hepatocellular carcinoma, neuroendocrine metastases, and colorectal metastases. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Management of Postembolization Syndrome Following Hepatic Transarterial Chemoembolization for Primary or Metastatic Liver Cancer.

BACKGROUND: Transarterial chemoembolization (TACE) is an established treatment in managing liver primary neoplasms or liver metastases. Postembolization syndrome (PES) is a common adverse event defined as fever without associated sepsis, pain in the right upper quadrant, and nausea and/or vomiting. OBJECTIVE: This integrative review aims to identify effective management strategies for PES or one of its characterizing symptoms (fever, pain, and nausea and/or vomiting). METHODS: Searches of electronic databases MEDLINE, EMBASE, and CINAHL were conducted. Fifteen articles were identified for inclusion. Seven addressed all symptoms of PES, and 8 studies focused on individual symptoms of PES. RESULTS: Interventions identified are intra-arterial lidocaine, oral and intravenous analgesics, steroids, wrist-ankle acupuncture, antibiotics, and 5-HT3 receptor antagonists. Findings are explicated according to individual symptoms of PES. Intra-arterial lidocaine, steroids, and a 5-HT3 receptor antagonist are found to offer potential benefit in the management of PES symptoms. CONCLUSION: A number of interventions have shown potential benefit in the management of PES. A systemic approach using combination therapy is necessary to effectively manage characterizing symptoms. Further research is needed to determine the impact of primary disease site, TACE technique, and chemotherapeutic agent on PES. IMPLICATIONS FOR PRACTICE: Oncology nurses are uniquely placed to undertake thorough patient assessment after TACE and implement early intervention to effectively manage PES.

Compliant neurovascular balloon catheters may not be compatible with liquid embolic materials: intraprocedural rupture of the protecting balloon during tumor embolization using n-butyl cyanoacrylate and lipiodol mixture.

BACKGROUND: Simultaneous use of balloon catheters with embolic materials can cause unwanted rupture of the balloon occlusion catheters, which might cause a serious problem. Therefore, knowledge of the compatibility of occlusion balloon catheters with liquid embolic materials is important in various interventional procedures. OBJECTIVE: To determine the compatibility of occlusion balloon catheters with commonly used embolic materials in vitro. METHODS: We used three types of occlusion balloon catheters (Scepter C, Microvention, Tustin, California, USA; Hyperform, Covidien, Irvine, California, USA; and Ascent, Codman Neurovascular, Raynham, Massachusetts, USA) to test their tolerances to Lipiodol, n-butyl cyanoacrylate (NBCA; Histoacryl; B Braun, Melsungen, Germany), and dimethyl sulfoxide (DMSO) with Onyx. The balloon was inflated just as it is in an endovascular procedure, then put on a Petri dish to observe its morphological change after one drop of liquid embolic material was added using a 1 mL syringe. The presence of rupture and the time to rupture were evaluated by constant video monitoring. Additionally, we observed morphological changes of the balloon catheter surface after contact with embolic materials with a scanning electron microscope. RESULTS: Lipiodol or a 33% NBCA-Lipiodol mixture dropping onto the three types of balloon catheter resulted in ruptures of all three. All three types of balloon catheter were tolerant to NBCA and to DMSO followed by Onyx. CONCLUSIONS: Glue embolization should not be performed with all three kinds of balloon catheter on the market, but DMSO and Onyx are compatible with those balloon catheters.

Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference.

OBJECTIVES: Liver metastasis from a neuroendocrine tumour (NET) represents a significant clinical entity. A multidisciplinary group of experts was convened to develop state-of-the-art recommendations for its management. METHODS: Peer-reviewed published reports on intra-arterial therapies for NET hepatic metastases were reviewed and the findings presented to a jury of peers. The therapies reviewed included transarterial embolization (TAE), transarterial chemoembolization (TACE) and radioembolization (RE). Two systems were used to evaluate the level of evidence in each publication: (i) the US National Cancer Institute (NCI) system, and (ii) the GRADE system. RESULTS: Eighteen publications were reviewed. These comprised 11 reports on TAE or TACE and seven on RE. Four questions posed to the panel were answered and recommendations offered. CONCLUSIONS: Studies of moderate quality support the use of TAE, TACE and RE in hepatic metastases of NETs. The quality and strength of the reports available do not allow any modality to be determined as superior in terms of imaging response, symptomatic response or impact on survival. Radioembolization may have advantages over TAE and TACE because it causes fewer side-effects and requires fewer treatments. Based on current European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, RE can be substituted for TAE or TACE in patients with either liver-only disease or those with limited extrahepatic metastases.

Treatment of hepatocellular carcinoma: beyond international guidelines.

The management of hepatocellular carcinoma (HCC) is decided according to evidence-based recommendations generated by international societies: according to these recommendations, the tumour stage, as determined by the Barcelona clinical liver cancer (BCLC) score, divides patients into five prognostic categories, each with a distinct treatment indication. Radical therapies such as hepatic resection, orthotopic liver transplantation and percutaneous local ablation are strongly indicated in patients with very early and early stage tumours (BCLC O and A), a choice which mainly depends on a combination of tumour volume, status of underlying liver disease, the presence of comorbidities and the patient's age. Although radical therapies provide a survival rate of between 50% and 75% at year five in well selected patients, tumour recurrence is frequent following resection and ablation compared to transplantation (70% vs. 10% respectively), which has the additional advantage of preventing morbidity and mortality from portal hypertension. Generally, while radical therapies are contraindicated in patients with a large tumour burden, such as those with intermediate stage BCLC B, survival in the subset of these patients with well compensated cirrhosis may improve from 16 to 20 months, on average, following repeated treatments with transarterial chemoembolization (TACE). Survival may also improve in patients who are in poor condition or who do not respond to TACE and in those with an advanced HCC (BCLC C) following oral therapy with the multikinase inhibitor sorafenib. However, because most recommendations are based on uncontrolled studies and expert opinions rather than well designed, high powered randomized controlled trials, treatment criteria need to be adapted to special groups because real life cohorts do not match the selection criteria suggested by the guidelines. Indeed, up to one-third of patients with early stage tumours who are unfit for radical therapy because of advanced age, the presence of significant comorbidities or a strategic location of the nodule, are forced to receive palliative care. BCLC A patients with moderate portal hypertension and certain BCLC B patients could still be eligible for hepatic resection if a chance for 50% survival at 5 years is still perceived as being cost-effective by both the patient and caregivers.

Transarterial embolization therapies for the treatment of hepatocellular carcinoma: CEPO review and clinical recommendations.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world and its incidence rate has consistently increased over the past 15 years in Canada. Although transarterial embolization therapies are palliative options commonly used for the treatment of HCC, their efficacy is still controversial. The objective of this guideline is to review the efficacy and safety of transarterial embolization therapies for the treatment of HCC and to develop evidence-based recommendations. METHOD: A review of the scientific literature published up to October 2013 was performed. A total of 38 studies were included. RECOMMENDATIONS: Considering the evidence available to date, the CEPO recommends the following: (i) transarterial chemoembolization therapy (TACE) be considered a standard of practice for the palliative treatment of HCC in eligible patients; (ii) drug-eluting beads (DEB)-TACE be considered an alternative and equivalent treatment to conventional TACE in terms of oncological efficacy (overall survival) and incidence of severe toxicities; (iii) the decision to treat with TACE or DEB-TACE be discussed in tumour boards; (iv) bland embolization (TAE) not be considered for the treatment of HCC; (v) radioembolization (TARE) not be considered outside of a clinical trial setting; and (vi) sorafenib combined with TACE not be considered outside of a clinical trial setting.

[Operative therapy of hepatocellular carcinoma]. / Operative Therapie des hepatozellulären Karzinoms.

BACKGROUND: Curative surgical strategies for hepatocellular carcinoma are liver resection and transplantation. METHODS: This overview is based on a selective literature search on therapeutic strategies for hepatocellular carcinoma. The new German S3 guidelines are outlined in detail but guidelines from other societies were also taken into consideration. RESULTS: The question of resectability is of utmost importance and should not only be evaluated in an interdisciplinary tumor board but also in an experienced liver center. Primary resectable hepatocellular carcinoma in patients without portal hypertension should be resected. Most patients without cirrhosis qualify for resection. In patients with Child grade A cirrhosis but without severe portal hypertension and a stable health status, a liver resection should be considered. At resection intraoperative ultrasound is standard. Intrahepatic tumor recurrences also can be re-resected or thermally ablated. New techniques for extended liver resections or minimally invasive liver resections are commonly used and have to be studied further. CONCLUSION: In addition to liver resection, liver transplantation now represents a standard therapy for hepatocellular carcinoma in cirrhosis. Observing the Milan selection criteria 5-year survival rates of 70-90 % can be achieved; however, increasing organ shortage leads to longer waiting times and thus higher risk of tumor progression. Therefore, patients on the waiting list should have follow-up imaging and bridging with surgical resection, radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) by interventional radiology. Living donor liver transplantation should be considered in all these patients with expected longer waiting times.