Extrahepatic Spread Research Articles

Comparison of therapeutic outcomes of liver resection and transarterial chemoembolization in multifocal HCC: a propensity score-matched analysis

Background and Aims: Patients with multifocal hepatocellular carcinoma (HCC), preserved liver function, without cancer-related symptoms (PS 0), vascular invasion or extrahepatic spread represent a heterogeneous group. Although transarterial chemoembolization (TACE) is the most frequently employed treatment in this group of patients, previous data have indicated that liver resection (LR) could be a safe and effective procedure for multifocal HCC. Nevertheless, it is still debated whether better outcomes are achieved after surgery as compared to those obtained with TACE.

Combined treatment of unresectable hilar cholangiocarcinoma with subsequent liver transplantation

Objective: to demonstrate the experience of unresectable hilar cholangiocarcinoma treatment using neoadjuvant therapy followed by liver transplantation (LT).Materials and methods. From 2017 to 2021, six patients were included in the treatment protocol for unresectable Klatskin tumor followed by liver transplantation at Granov Russian Scientific Center for Radiology and Surgical Technology. The neoadjuvant therapy included endobiliary photodynamic therapy (PDT), as well as regional and systemic chemotherapy. Each method was used at least three times for 4 to 5 months with radiological evaluation and measurement of CA 19-9 levels. Patients were placed on the waiting list when the tumor marker reduced, or when there were no radiological signs of disease progression and there was no acute cholangitis. The recipients underwent laparoscopic abdominal revision for carcinomatosis and assessment of lymph nodes in the hepatoduodenal ligament with urgent morphological examination. Where there was no extrahepatic spread, LT was performed according to the classical technique with paracaval, para-aortic and hepatoduodenal lymphodissection, biliodigestive anastomosis by an isolated Roux loop of small intestine. The operation was performed in three patients, all of them were men aged 40 to 55 years (mean 48). The mean time from the start of treatment to transplantation was 9.3 months (range 6 to 14). Mean CA 19-9 level at the time of intervention was 81.3 IU/mL (8 to 212).Results. In three patients, CA 19-9 levels more than doubled on average over four months despite treatment. According to data from computed tomography RECIST assessment, two of the patients showed disease progression. In one patient, carcinomatosis was detected by diagnostic laparoscopy. In three patients, CA 19-9 levels decreased more than fourfold. Two of these patients were radiologically confirmed to have the disease stabilized, and one had a partial response. One patient died from sepsis three years after transplantation as a result of secondary biliary cirrhosis and biliary abscesses without signs of progression. Two patients are still alive after 6 and 21 months without signs of tumor progression.Conclusion. LT for unresectable Klatskin tumor is effective in controlling the bioactivity of the tumor through the use of neoadjuvant therapy

TALENTACE: A phase III, open-label, randomized study of on-demand transarterial chemoembolization combined with atezolizumab + bevacizumab or on-demand transarterial chemoembolization alone in patients with untreated hepatocellular carcinoma.

TPS487 Background: In 2020, there were ̃905,000 new cases and ̃830,000 deaths from liver cancer globally, and a respective 410,038 and 391,152 in China (5-year overall survival [OS]: 14.1%).1,2,3 Hepatocellular carcinoma (HCC) accounts for 75%–85% of liver cancers.1 Transarterial chemoembolization (TACE) is the preferred treatment for patients with intermediate-stage unresectable HCC (uHCC); however, there are issues with the need for repeated dosing and the heterogenous target population (median OS: 13–43 mo). Treatment with TACE + systemic therapy may improve this. Although several trials reported negative results for TACE + sorafenib (sor) vs TACE alone in patients with uHCC, the TACTICS trial showed improved untreatable (unTACEable) progression-free survival (PFS) (25.2 vs 13.5 mo; P= 0.006).4 While promising, the unmet need for combination therapies remains. The recent IMbrave150 trial showed significantly improved OS with atezolizumab (atezo) + bevacizumab (bev) vs sor (19.2 vs 13.4 mo; P= 0.0009) in patients with uHCC5, making it an attractive option for combination with TACE. Methods: TALENTACE (NCT047126430) is a phase III, open-label, randomized study to evaluate the efficacy and safety of TACE + atezo + bev or TACE alone in patients with uHCC. Key inclusion criteria are ≥18 years old, HCC diagnosis, no prior systemic treatment, no prior locoregional treatment of target lesions, eligible for TACE treatment, tumor max diameter + tumor number ≥6, and not a candidate for curative therapy. Patients with tumors that have macrovascular invasion (MVI) or extrahepatic spread (EHS) are excluded. Patients will be randomized (1:1) to receive TACE + atezo + bev or TACE alone. TACE will be performed by clinical demand; atezo (1200 mg) and bev (15 mg/kg) will be administered by intravenous infusion on Day 1 of each 21-day cycle. Co-primary endpoints are independent review committee-determined TACE-PFS (randomization to unTACEable progression, TACE failure/refractoriness, or death) and OS. Secondary endpoints include investigator-determined TACE-PFS; time to unTACEable progression, progression, MVI, EHS, and MVI/EHS; objective response rate, duration of response, patient reported outcomes, and incidence of adverse events.

Ramucirumab for patients with advanced hepatocellular carcinoma and elevated α-fetoprotein following a non-sorafenib based first-line therapy: Final results from an expansion cohort of REACH-2.

423 Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) and elevated α-fetoprotein (AFP) have poor prognosis, and need effective, well-tolerated treatment options. Ramucirumab has been shown to improve survival and is currently approved as second-line therapy for pts with a baseline elevated AFP that have progressed on prior sorafenib. However, new options now exist in the front-line setting. This global open-label expansion cohort of REACH-2 (NCT02435433) was initiated to study ramucirumab in pts with advanced HCC and baseline AFP ≥400 ng/mL following a non-sorafenib based systemic therapy, representing one of the first sequencing studies in HCC. Methods: This single-arm study investigated ramucirumab in pts with advanced HCC (BCLC stage C or B disease), Child-Pugh A, ECOG PS 0/1, and baseline AFP ≥400 ng/mL who received 1-2 prior systemic regimens for advanced HCC, excluding prior sorafenib or chemotherapy. Enrolled pts received ramucirumab 8 mg/kg IV once every 14 days. The primary endpoint was safety. Secondary endpoints included overall survival (OS), progression-free survival (PFS) objective response rate (RECIST 1.1) and time to progression (TTP). Final analysis occurred after all enrolled pts completed ≥ 3 treatment cycles or discontinued treatment. Results: 47 pts were treated at 21 investigative sites in the USA (n = 12), Taiwan (n = 10), mainland China (n = 8), Hong Kong (n = 8), Germany (n = 8), and Switzerland (n = 1). At baseline, these pts with 2nd to 3rd+ line advanced HCC had ECOG PS 1 (51%), with vascular invasion or extrahepatic spread (85%), viral hepatitis B (55%), BCLC stage C disease (92%), and a median AFP of 3236 ng/mL (IQR: 1332, 18210). Prior systemic regimens included lenvatinib (n = 20), checkpoint inhibitor (CPI) monotherapy (n = 11), CPI + antiangiogenic (n = 15), and CPI + CPI (n = 4). Grade ≥ 3 treatment-emergent adverse events (AEs) were reported in 27 (57%) pts and were deemed to be treatment-related in 11 (23%) pts. Grade ≥ 3 AEs occurring in ≥ 5% pts were hypertension (n = 5; 11%), proteinuria (n = 3; 6%), hyponatremia (6%) and AST increased (6%). Two deaths occurred due to treatment-related AEs on therapy or within 30 days of treatment discontinuation (myocardial infarction and upper GI hemorrhage). Median OS was 8.7 months (95% CI 4.6-12.2), median PFS was 1.7 months (95% CI 1.5-4.1), and median TTP was 2.8 months (95% CI 1.5-4.2). The number of pts achieving an objective response was 5 (10.6%, 95% CI 1.8-19.5), with a median duration of response of 8.3 months (95% CI 2.4-NR). Conclusions: This expansion cohort of REACH-2 represents a non-sorafenib sequencing study in pts with advanced HCC. The safety/efficacy profile of ramucirumab following a non-sorafenib based systemic therapy was consistent with that observed in pts who received prior sorafenib in the Ph3 REACH-2 study. Clinical trial information: NCT02435433.

ABC-HCC: A phase IIIb, randomized, multicenter, open-label trial of atezolizumab plus bevacizumab versus transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma.

TPS498 Background: Hepatocellular carcinoma (HCC) is among the most common and deadliest cancers worldwide. In the intermediate stage the current standard of care is locoregional treatment with transarterial chemoembolization (TACE). The IMbrave150 phase 3 study has demonstrated that the combination of atezolizumab, an anti-PD-L1 antibody, and bevacizumab, an anti-VEGF antibody (atezo/bev), extends survival in comparison to sorafenib in the first-line setting in advanced HCC[1] which has led to its approval for patients with unresectable HCC. However, it is unknown whether atezo/bev is more efficacious than TACE for the treatment of intermediate HCC. ABC-HCC (NCT04803994) is a phase 3b, randomized, multicenter, open-label, investigator-initiated trial of atezo/bev versus TACE in intermediate stage HCC with high tumor burden exceeding the Milan criteria. Methods: The ABC-HCC study is recruiting patients ≥18 years of age who have a confirmed diagnosis of HCC in the intermediate stage (multifocal, exceeding the Milan criteria, no extrahepatic spread, no macrovascular invasion) and no curative treatment option. In addition, patients must have an ECOG performance status of 0, preserved liver function (Child-Pugh A), and ≥2 untreated lesions with a diameter > 10 mm and arterial hyperenhancement on cross-sectional imaging. Those who have previously received locoregional or systemic treatment are excluded. 434 patients will be randomly assigned 1:1 to systemic treatment (atezo at 1200 mg IV plus bev at 15 mg/kg IV) once every three weeks or to TACE. Both conventional and DEB-TACE are allowed. Region, AFP level (< 200 ng/mL vs. ≥200 ng/mL), and ALBI (1 vs. 2) will be used for stratification. Cross-sectional imaging (CT/MRI) will be performed every 8 weeks to determine the time to failure of treatment strategy, a novel primary endpoint. Failure of strategy is reached in case of progressive disease and any of the following: loss of clinical benefit, unacceptable toxicity, liver function deterioration, and therapy not further applicable for other reasons. Secondary endpoints are overall survival (OS), OS rate at 24 months, objective response rate, time to progression, time to loss of systemic treatment options, progression-free survival, duration of treatment, duration of response, time to deterioration of liver function, safety, and quality of life (EORTC QLQ-C30 and HCC18). Patients will be followed for survival, quality of life and subsequent anti-cancer therapy every 12 weeks after the end of study treatment. Recruitment for this study began in July 2021. FF, RK, JB and PRG contributed equally.

Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.

420 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]

Longitudinal monitoring of circulating tumor DNA (ctDNA) during disease course of metastatic colorectal cancer (mCRC).

189 Background: ctDNA is an attractive alternative to tissue for its easy accessibility and real time representation of systemic tumor profile. We explored the utility of ctDNA profiling during the course of mCRC treatment. Methods: Serial blood samples were obtained from mCRC patients before and during first-line palliative chemotherapy at fixed intervals (after every four cycles) until confirmed disease progression. ctDNA was sequenced using targeted next-generation sequencing (NGS) platform with 106 genes. Changes of ctDNA profile and treatment outcome were comprehensively analyzed. Results: A total of 272 samples from 62 patients were analyzed. In the pre-treatment blood samples, 56 (90.3%) of patients had detectable ctDNA mutations including single nucleotide variants, short insertions/deletions and copy number changes (median 4.5 mutations/ patient, range 0 - 133). In 31 (50.0%) patients who had tissue NGS panel results performed in the clinic, overall concordance between mutations from ctDNA and tissue was 86.5%. In three patients, ctDNA mutational profiles were found to be completely different from tissue profiles. At further investigation, these patients were found to have a separate primary cancer in their colon. At the time of the first follow-up, most (98.0%) patients showed decrease of ctDNA from baseline, represented by average variant allele frequency (VAF) changes of all ctDNA mutations found. Clearance of ctDNA was achieved in 40 (78.4%) patients and was associated with longer progression-free survival (median PFS 11.8 moths in ctDNA clearance (+) vs. 4.7 months in ctDNA clearance (-), p < 0.001). The ctDNA clearance at the same time point was able to further discriminate the patients in same category by RECIST 1.1. Serial follow-up monitoring revealed three patterns of ctDNA changes at the time of clinical progressive disease (PD): 1) re-emergence or re-increase of baseline ctDNA mutations, 2) emergence of new resistance mutations, 3) radiologic PD without evidence of ctDNA progression. In the patients with detectable ctDNA at PD, the ctDNA progression preceded radiologic progression in 25 (58.1%) patients by median of 3.3 months. The patients in clinical PD without ctDNA progression showed different patterns of metastasis having mainly extrahepatic spread, while 77.8% of the patients with ctDNA progression had their progression confirmed in liver metastasis. Diverse resistant mutations and gene amplifications in PD patients were discovered by ctDNA sequencing. For seven (16.3%) of the PD patients, the newly identified mutations could be potential candidates of targeted therapy or clinical trial. Conclusions: ctDNA profile provided additional information to conventional evaluation methods and reflected dynamic changes. ctDNA monitoring may improve precise treatment decision-making for individual patients.

Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma: A Real-life Multicentric Weighted Comparison.

The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario. The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial. BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups. Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1-3-5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19-6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06-1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1-3-5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007). In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.

Liver Transplantation for Intrahepatic Cholangiocarcinoma: What Are New Insights and What Should We Follow?

Intrahepatic cholangiocarcinoma (iCCA) is a complex malignancy carrying poor prognosis. Liver transplantation (LT) was historically contraindicated for iCCA, due to poor outcomes after LT. However, an increasing number of studies have challenged this premise, because LT alone or combined with neoadjuvant chemotherapy has achieved relatively satisfactory transplant outcomes in well selected iCCA cases. This current review based on existing clinical researches, evinced that LT might serve as a viable option in iCCA cases as follows: ① unresectable tumor restricted to 2 cm, along with context of chronic liver diseases; and ② unresectable tumor locally advanced within the liver (without extrahepatic metastasis or vascular invasion) but responses to tumor down-staging treatments (namely, systemic neoadjuvant therapy and/or locoregional therapy). On the contrary, it is recommended as contraindications in iCCA cases as follows: ① patients with tumor progression while waiting for a transplant (increase of diameter, macrovascular invasion, new nodules, escalation of carbohydrate antigen 19-9, or extrahepatic spread); ② patients with iCCA recurrence. Conclusively, tumor burden, tumor biology, and response to down-staging strategies should be taken into consideration before LT. Whereas, the concept of “locally advanced stage” remains to be defined in the future, especially the optimized combination of “maximum size of largest lesion”, “number of lesions”, with/without “tumor differentiation”, just like the Milan criteria which is widely used for hepatocellular carcinoma. Given the scarcity of donor organ, and also the debate about LT in iCCA, accurate consensus about LT for iCCA patients is still urgently warranted.

Efficacy of Different Treatments for Patients with Advanced Hepatocellular Carcinoma: A System Review and Network Meta-Analysis

ABSTRACT Background: Over the past decade, the treatment landscape for advanced hepatocellular carcinoma (HCC) has expanded considerably. Therefore, this network meta-analysis aimed to compare the efficacy of combination treatment versus sorafenib. Materials and Methods: A systematic literature review was conducted to select eligible studies. A network meta-analysis was performed to compare the overall survival (OS) and objective response rate (ORR) among anti- programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) plus anti-vascular endothelial growth factor (VEGF), hepatic arterial infusion chemotherapy (HAIC) plus sorafenib and sorafenib in patients with advanced HCC. Furthermore, for patients without extrahepatic spread, the comparison of the OS among transarterial chemoembolization (TACE) plus radiotherapy (RT), anti-PD-1/PD-L1 plus anti-VEGF, HAIC plus sorafenib and sorafenib was conducted. Results: A total of 1182 articles were screened through database searching, among which 7 studies involving 1639 patients were included in the analysis. By comparison of 6-month OS, 12-month OS and ORR, anti-PD-1/PD-L1+anti-VEGF was considered the best intervention in advanced HCC anti-PD-1/PD-L1 plus anti-VEGF versus sorafenib: 12-month OS: HR, 0.64; 95% CI, 0.47–0.88; ORR: odd ratio, 0.53; 95% CI, 0.38–0.74). While for patients without extrahepatic spread, the above four interventions showed similar OS; however, TACE plus RT rank the best with a P-score of 57.07%. Conclusions: In patients with advanced HCC, anti-PD-1/PD-L1+anti-VEGF was associated with highest ranking of OS compared with HAIC plus sorafenib and sorafenib. TACE plus RT might be a more favorable choice than other treatments in advanced HCC without extrahepatic spread. Highlights:

Characteristics of patients with hepatocellular carcinoma: A multicenter study.

Background and AimThe aim of the present study was to examine the etiology of hepatocellular carcinoma (HCC) by underlying cause and determine the characteristics and clinical features of patients with HCC.Materials and MethodsThe study comprised 1802 HCC patients diagnosed and followed up by Liver Diseases Outpatient Clinics in 14 tertiary centers in Turkey between 2001 and 2020.ResultsThe mean age was 62.3±10.7 years, and 78% of them were males. Of the patients, 82% had cirrhosis. Hepatitis B virus (HBV) infection was the most common etiology (54%), followed by hepatitis C virus (HCV) infection (19%) and nonalcoholic fatty liver disease (NAFLD) (10%). Of the patients, 56% had a single lesion. Macrovascular invasion and extrahepatic spread were present in 15% and 12% of the patients, respectively. The median serum alpha-fetoprotein level was 25.4 ng/mL. In total, 39% of the patients fulfilled the Milan Criteria. When we compared the characteristics of patients diagnosed before and after January 2016, the proportion of NAFLD-related HCC cases increased after 2016, from 6.6% to 13.4%.ConclusionChronic HBV and HCV infections remain the main causes of HCC in Turkey. The importance of NAFLD as a cause of HCC is increasing.

Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2–3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607–1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466–0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

Real-life data on the impact of successful downstaging in patients with hepatocellular carcinoma: A Dutch Multicenter Study

Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country.We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value <100 ng/ml, successful downstaging and liver transplantation (all ≤p = 0.01) were positively associated to overall survival.In conclusion, our results demonstrate that LRT is not routinely offered to intermediate stage HCC patients in the Netherlands. Nevertheless, we showed that patients with intermediate stage HCC who are successfully downstaged have a survival benefit compared to those who were not.

Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib

BackgroundHepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes.Patients and methodsWe conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed.ResultsAmong the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin–bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047).ConclusionNASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial

Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.

The Immunology of Hepatocellular Carcinoma.

Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.

From the Editor’s desk…

From the Editor’s desk…

Hepatocellular Carcinoma in Non-cirrhotic Liver Arises with a More Advanced Tumoral Appearance: A Single-Center Cohort Study.

A small proportion of all hepatocellular carcinomas (HCCs) arise in a non-cirrhotic liver (NCL). However, our knowledge about the HCCs developing in a NCL is scarce. This study was undertaken to investigate the characteristics and survival course of this patient group. We retrospectively analyzed the database of patients with HCC at a tertiary center during a 10-year period (2009-2019). All demographic, clinical, laboratory, and tumoral features with survival outcomes were compared between the HCC-CL and HCC-NCL groups. Out of 384 HCC cases, 11.2% (n = 43) had no cirrhosis. The dominant etiology in the HCC-NCL group was hepatitis B virus (n = 26, 60.5%), followed by non-alcoholic fatty liver disease (n = 10, 23.2%), and hepatitis C virus (n = 7, 16.3%). The maximum tumor diameter was approximately 2 times larger in the HCC-NCL group (HCC-NCL: 90 mm vs. HCC-CL: 46.5 mm, P < .001). The proportion of patients with vascular (HCC-NCL: 27.9% vs. HCC-CL: 8.6%, P < .001) and extrahepatic invasion (HCC-NCL: 14% vs. HCC-CL: 3%, P = .001) were prominently higher in the HCC-NCL group. Patients with HCC-NCL were less often detected in early-curable stages (BCLC 0-A) than those in the HCC-CL group (HCC-NCL: 16.3% vs. HCC-CL: 34.9%, P = .004). The overall survival was not different between the 2 groups (HCC-NCL: 19.4 ± 9.8 months vs. HCC-CL: 17.5 ± 2.3 months, P = .581). HCC in NCL is diagnosed at more advanced tumoral stages with larger tumor size and more often with vascular and extrahepatic spread. Despite the preserved liver functions, the overall survival is not prolonged in HCCs without cirrhosis, due to the late recognition.

932P IMbrave150: Exploratory efficacy and safety results in patients with hepatocellular carcinoma without macrovascular invasion (MVI) or extrahepatic spread (EHS) treated with atezolizumab (atezo) + bevacizumab (bev) or sorafenib (sor)

First-line atezo + bev has been approved in >70 countries based on significantly longer overall and progression-free survival (OS/PFS) vs sor in patients (pts) with unresectable hepatocellular carcinoma (HCC) at the primary analysis of IMbrave150 (NCT03434379). We report exploratory efficacy and safety in pts without MVI or EHS after 12 mo additional follow-up.