Intermediate-stage Hepatocellular Carcinoma Research Articles

Clinical values of Barcelona Clinic Liver Cancer subgroup and up-to-7 criteria in intermediate stage hepatocellular carcinoma with transcatheter arterial chemoembolization.

BACKGROUNDTransarterial chemoembolization (TACE) is a recommended treatment for patients with intermediate stage hepatocellular carcinoma (HCC) but with variable treatment outcomes.AIMTo determine factors for predicting outcomes of TACE in patients with intermediate stage B HCC.METHODSPatients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC who underwent TACE as the primary treatment were enrolled at Taichung Veterans General Hospital from January 2005 to December 2009. Patients were assigned to either the objective responder (OR) group or the non-OR group according to mRECIST criteria. Clinical and radiological characteristics were compared between the 2 groups. The overall survival of enrolled subjects was analyzed.RESULTSIn 128 enrolled patients, 66 (51.6%) were in the OR group and 62 (48.4%) in the non-OR group. Compared with the non-OR group, the OR group had a significantly smaller HCC size (6.55 cm vs 9.50 cm, P = 0.001) and was within the up-to-7 criteria (50% vs 26.7%, P = 0.001). After multivariable analyses, these significant associations still existed. Overall survival rate of all the subjects averaged 20.65 ± 13.26 mo. The survival rate at 1-year was 64.8%, 2-year was 46.9%, and 3-year was 31.2%. For those patients with OR to TACE, smaller tumor size and within up-to-7 criteria were associated with significantly better overall survival. Those patients with subgroup B1 had the highest OR ratio (75%) and better overall survival (26.70 ± 12.07 mo) after TACE.CONCLUSIONBCLC stage B HCC patients with smaller tumor size or within up-to-7 criteria had better survival outcomes to TACE. BCLC stage B subgroup is useful to predict refractoriness to TACE.

Impact and Novel Perspective of Immune Checkpoint Inhibitors in Patients with Early and Intermediate Stage HCC.

Simple SummaryThe prognostic evaluation and therapeutic management of hepatocarcinoma (HCC) is based on the Barcelona Liver Cancer Clinic (BCLC). In the past years, immunotherapy has become a mainstay of first-line treatment in advanced HCC and further treatment options are underway. Beyond this, the scientific community is more and more focusing on immunotherapeutic approaches in earlier HCC stages. The purpose of this review is to describe the rationale for immunotherapeutic approaches and the studies conducted with immunotherapy in patients with early and intermediate stage HCC.Surgery and radiofrequency ablation remain the gold standard to achieve cure in patients with hepatocellular carcinoma (HCC). After a decade in which only sorafenib was available for advanced and metastatic HCC, the emergence of other molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has significantly improved the patients` prognosis. In particular, the use of ICIs has shown promising results and has revolutionized the treatment algorithm in HCC patients. Indeed, preclinical and clinical data have documented a high density of immunosuppressive cells and an increased expression of the programmed death-1 (PD-1) receptor and cytotoxic T-cell associated protein-4 (CTLA-4) in HCC. However, despite these observations, no validated biomarker is available and the molecular groundwork responsible for response to ICIs remains elusive. The anti-CTLA4 monoclonal antibody tremelimumab and the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab were the first ICIs to be tested in HCC. Recently, the combination of the anti-programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab demonstrated an improvement in patient outcome compared to sorafenib, becoming the standard of care in the frontline setting of advanced disease. Other immunotherapeutic agents such as pembrolizumab or the combination nivolumab-ipilimumab have shown promising results that have to be confirmed in phase III studies. Currently, the combination of different ICIs (i.e., ipilimumab, durvalumab) and anti-angiogenic agents (i.e., regorafenib, lenvatinib) is currently being tested in several trials and will hopefully revolutionize the treatment of HCC. To date, numerous studies are underway evaluating ICIs in adjuvant and neoadjuvant settings to improve survival in early and intermediate stages. Thus, this review focuses on the rationale for ICIs and their potential use for early or intermediate HCC stages.

Efficacy Investigation of TACE Combined with Lenvatinib and Sintilimab in Intermediate-Stage Hepatocellular Carcinoma.

Objective To evaluate the effectiveness of transarterial chemoembolization (TACE) combined with lenvatinib and sintilimab in treating patients with midstage hepatocellular carcinoma (HCC). Methods Sixty-two patients with midstage HCC were enrolled in this study. All of them were firstly treated in our hospital between September 1, 2019, and March 1, 2020. According to different treatment regimens, they were divided into the control group (31 cases, TACE group) and the observation group (31 cases, TACE combined with lenvatinib and sintilimab group). Each patient was followed up for at least 30 months to compare the short-term clinical efficacy and survival rate between the two groups. Results The objective response rate (ORR) and disease control rate (DCR) of the observation group at 3 months were 77.4% and 93.5%, respectively, which were higher than those of the control group (P < 0.05). The 2-year cumulative overall survival rate of the observation group was 64.5%, which was significantly higher than that of the control group (P < 0.05). The survival curve of the disease-free survival rate in the observation group was higher than that in the control group, and the difference was statistically significant (X2 = 4.313, P < 0.05). Conclusion TACE combined with lenvatinib and sintilimab in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma can effectively control the tumor progression and prolong the survival time of patients. Those preliminary findings need validation in larger studies, with a prospective design and longer follow-up.

Transarterial chemoembolization in patients with hepatocellular carcinoma beyond Barcelona-Clinic Liver Cancer- B and portal vein tumor thrombosis: Experience from a tertiary care center.

Transarterial chemoembolization (TACE) is the preferred treatment for patients with intermediate-stage hepatocellular carcinoma (HCC) without portal vein tumor thrombosis (PVTT). However, select patients with advanced HCC and with PVTT have shown improved survival with TACE. This study was undertaken to evaluate the outcome of TACE in patients with HCC beyond Barcelona-Clinic Liver Cancer- B (BCLC - B) and those with HCC and PVTT. Patients with unresectable HCC, subjected to TACE were included. HCC patients with PVTT involving main portal vein and, poor performance status were excluded from the study. Patients were stratified according to performance status, alpha feto protein (AFP) values, and up-to-seven criteria. Individually and using various combinations, the influence of these variables on survival was also estimated. A total of 50 patients were included in the study. PVTT was present in 12 patients. Clinically, significant liver failure was observed in two patients. The average overall survival of patients beyond BCLC-B following TACE was 13 months. Survival was not influenced by tumor invasion into the portal vein. Patients with higher AFP levels had comparable survival provided their tumor load was satisfying up-to-seven criteria. We conclude that TACE could improve survival in selective HCC patients beyond BCLC-B and with PVTT not extending to the main portal vein.

Enhanced Tumoricidal Immune Responses by Transarterial Chemotherapy Using Novel Nanocomplexes in a Rat Liver Cancer Model.

Locoregional treatments for hepatocellular carcinoma (HCC) induce immunogenic cell death and a tumor-specific immune response, but infiltration and activation of immune cells in the liver have not been clearly described. Transarterial chemoembolization (TACE) or transarterial chemotherapy (TAC) without embolization have been used to treat intermediate or advanced stage HCC patients. The identification of intrahepatic immune cell changes after locoregional therapy provides a theoretical basis for the combination with immune checkpoint inhibitors (ICIs) in HCC. This study aimed to determine the anticancer effect and changes in the liver immune cell population and function after direct injection of polymerized phenylboronic acid-conjugated doxorubicin (pPBA-Dox) nanocomplexes into the liver through TAC. pPBA-Dox nanocomplexes were delivered directly to the liver cancer in a rat model by transarterial methods. Anticancer effect was confirmed by magnetic resonance imaging (MRI), and the immune cell population and functional changes were confirmed by flow cytometry (FACS). We first established a rat liver cancer model by implanting McA-RH7777 into rats and confirmed the formation of liver cancer through MRI, pathological examinations, and biochemical tests. Transarterial injection of pPBA-Dox nanocomplexes had a stronger anticancer effect than conventional Dox alone. Higher numbers of CD8+ and CD4+ T cells with activated phenotypes were infiltrated into the tumor microenvironment after transarterial pPBA-Dox treatments than after Dox alone treatment, suggesting the induction of stronger local immune responses by pPBA-Dox than Dox alone. This study provides a theoretical basis for TAC combined with ICIs and insight into novel targeted therapies using nanocomplexes for the treatment of HCC.

Impact of alcohol consumption on treatment outcome of hepatocellular carcinoma patients with viral hepatitis who underwent transarterial chemoembolization.

BACKGROUNDAlcohol consumption increases the risk of hepatocellular carcinoma (HCC) in patients with pre-existing liver disease, including viral hepatitis. However, studies on the impact of alcohol consumption on the outcomes of HCC are limited. We hypothesized that alcohol had an additional effect with chronic viral hepatitis infection on treatment outcomes after transarterial chemoembolization (TACE) in patients with intermediate-stage HCC (Barcelona Clinical Liver Cancer [BCLC] -B).AIMTo evaluate the additional effect of alcohol on treatment outcomes of TACE among HCC patients with viral hepatitis.METHODSThis study, conducted at Hatyai Hospital in Thailand, included HCC patients over 18 years of age with chronic viral hepatitis. Records of HCC patients with viral hepatitis classified as BCLC-B who underwent TACE as the first treatment modality between 2014 and 2019 were retrospectively reviewed. Patients with chronic viral hepatitis only were categorized under group A, and those with chronic viral hepatitis and concurrent alcohol consumption were categorized under group B. Both groups were compared, and the Cox proportional-hazards model was used to identify the survival-influencing variables.RESULTSOf the 69 patients, 53 were categorized in group A and 16 in group B. There were no statistically significant differences in tumor characteristics between the two patient groups. However, Group A had a statistically significantly higher proportion of complete response (24.5% vs 0%, P = 0.030) and a higher median survival rate (26.2 mo vs 8.4 mo; log-rank P = 0.012) compared to group B. Factors associated with decreased survival in the proportional-hazards model included alcohol consumption (hazards ratio [HR], 2.377; 95% confidence interval [CI], 1.109-5.095; P = 0.026), presence of portal hypertension (HR, 2.578; 95%CI, 1.320–5.037; P = 0.006), largest tumor size > 5 cm (HR, 3.558; 95%CI, 1.824-6.939; P < 0.001), and serum alpha-fetoprotein level > 100 ng/mL (HR, 2.536; 95%CI, 1.377-4.670; P = 0.003).CONCLUSIONIn HCC BCLC B patients with chronic viral hepatitis, alcohol consumption is an independent risk factor for increased mortality and decreases the rate of complete response and survival after TACE.

Transarterial chemoembolization failure/refractoriness: A scientific concept or pseudo-proposition.

Multi-session transarterial chemoembolization (TACE) is usually needed for the treatment of intermediate-stage hepatocellular carcinoma (HCC), but it may not always have a positive influence on prognosis due to high heterogeneity of HCC. To avoid ineffective repeated TACE, the concept of TACE failure/refractoriness has been proposed by several organizations and is being addressed using tyrosine kinase inhibitors. The concept of TACE failure/refractoriness is controversial due to ambiguous definitions and low evidence-based data. To date, only a few studies have examined the rationality concerning the definition of TACE failure/refractoriness, although the concept has been introduced and applied in many TACE-related clinical trials. This review focuses on some of the issues related to different versions of TACE failure/refractoriness, the rationality of related definitions, and the feasibility of continuing TACE after so-called failure/refractoriness based on published evidence. A suggestion to re-define TAEC failure/refractoriness is also put forward.

Up to seven criteria in selection of systemic therapy for hepatocellular carcinoma.

Barcelona clinic liver cancer (BCLC) intermediate stage hepatocellular carcinoma is a heterogenous disease. Transarterial chemoembolization is offered as the first line therapy in this disease stage. Recent advances in systemic therapy have markedly improved outcomes even in advanced stage disease. The use of systemic therapy in BCLC intermediate stage disease may now be of therapeutic benefit in selected patients. We will focus on “the up to seven” criteria and its utility in selecting systemic therapy.

Immune Checkpoint Inhibitors for Advanced Hepatocellular Carcinoma: Monotherapies and Combined Therapies.

Hepatocellular carcinoma (HCC) is an important cause of cancer death and is considered the 3rd most lethal around the world. Hepatectomy, liver transplantation, and ablation therapy are considered curative treatments for early-stage HCC. Transarterial chemoembolization is the preferred therapy for intermediate stage HCC. Ssystemic therapy is recommended for advanced HCC. For more than a decade, sorafenib and lenvatinib were used as the first-line treatment for the advanced HCC. For the great success of immunotherapy in melanoma and lung cancer, some immune-based treatments, such as immune checkpoint inhibitors (ICIs), have been applied in the treatment of HCC. The anti-programmed cell death protein 1 (PD1) antibodies, including nivolumab and pembrolizumab, have been approved by the Food and Drug Administration for sorafenib-pretreated patients. Moreover, due to the results of durable antitumor responses attained from the phase 3 trials, atezolizumab in combination with bevacizumab is now the standard therapy for advanced HCC. Recently, there are a lot of clinical trials involving the ICIs, as monotherapy or combination therapy, with tyrosine kinase inhibitors, antiangiogenic drugs, cytotoxic agents, and locoregional treatments, providing a promising outcome for advanced HCC. Thus, this review summarized the role of ICIs for HCC patients with monotherapy or combination therapy. The success and failures of monotherapy and combination therapy involving ICIs have provided advanced insights into HCC treatment and led to novel avenues to improve therapy efficacy in HCC.

Validation and prognostic value of EZ-ALBI score in patients with intermediate-stage hepatocellular carcinoma treated with trans-arterial chemoembolization

BackgroundHeterogeneity of liver function and tumor burden in intermediate-stage hepatocellular carcinoma (HCC) results in different outcomes after transarterial chemoembolization (TACE). Easy albumin-bilirubin (EZ-ALBI), a simplified albumin-bilirubin (ALBI) score, has recently been proposed as a new prognostic score for HCC. This study aimed to validate the EZ-ALBI score and evaluate the impact of dynamic changes in patients with intermediate-stage HCC undergoing TACE.MethodsAll patients with HCC treated with TACE at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between January 2015 and December 2019 were prospectively enrolled. Intermediate-stage HCC was defined as Barcelona Clinic Liver Cancer (BCLC) stage B or unresectable single HCC with size > 5 cm in BCLC stage A. EZ-ALBI and ALBI scores were calculated and stratified into three different grades. Overall survival (OS) and prognostic factors were assessed using the Kaplan–Meier curve and Cox proportional hazard model. Decision analysis curves were used to evaluate the clinical utility of the predictive scores.ResultsAmong 672 patients with HCC treated with TACE, 166 patients with intermediate-stage HCC who met the eligibility criteria were enrolled. The median OS of all patients in the cohort was 21 months. A good correlation between the EZ-ALBI and ALBI scores was observed (correlation coefficient 1.000, p < 0.001). The baseline EZ-ALBI grades 1, 2, and 3 were 24.5%, 70%, and 5.5%, respectively. EZ-ALBI grade can stratify patients with significantly different prognoses (p = 0.002). Baseline EZ-ALBI grade 2, 3, and serum alpha-fetoprotein > 20 ng/ml were significantly associated with OS [hazard ratio (HR) 2.20 (95% confidence interval [CI] 1.24–3.88, p = 0.007), 3.26 (95% CI 1.24–8.57, p = 0.016), and 1.77 (95% CI 1.10–2.84, p = 0.018), respectively]. Following TACE, 42 (29.6%) patients had a worsening EZ-ALBI grade. However, the EZ-ALBI grade migration was not significantly correlated with OS. EZ-ALBI and ALBI score provided improved discriminatory ability (Harrell’s concordance index 0.599 and 0.602, respectively) and better net benefit compared with Child-Turcotte-Pugh and Model for End-stage Liver Disease scores.ConclusionsThe baseline EZ-ALBI score demonstrated good predictive performance for survival and a strong correlation with conventional ALBI scores. Both the EZ-ALBI and ALBI scores outperformed other prognostic models in patients with intermediate-stage HCC receiving TACE. However, the dynamic change in the EZ-ALBI grade after TACE was not associated with postprocedural survival.

A randomised phase II clinical trial of low-dose cyclophosphamide and transarterial chemoembolization (TACE) with or without vaccination with dendritic cells (DC) pulsed with HepG2 lysate ex vivo in patients with hepatocellular carcinoma (HCC): The ImmunoTACE trial.

4012 Background: A previous study by our group using autologous monocyte-derived DC pulsed ex vivo with HepG2 cell lysate showed some clinical benefit with evidence of antigen-specific T-cell responses in patients with advanced HCC. The current trial reports the activity of this vaccine in combination with TACE in patients with HCC. All patients also received low-dose cyclophosphamide to deplete regulatory T cells and thereby enhance vaccination. Methods: Patients with intermediate stage HCC (performance status 0-2, Child Pugh A/B7) were randomised 1:1 to TACE plus low-dose cyclophosphamide (Group 1) or TACE plus low-dose cyclophosphamide plus dendritic cell vaccination (Group 2). Cyclophosphamide was administered on Day 1 and 29 followed by TACE on Day 31 (+/- DC infusion), with further cyclophosphamide on Days 60, 90 and 120 (+/- additional DC infusions on Days 62, 92 and 122). The primary endpoint was progression free survival (PFS) by RECIST v1.1. Secondary endpoints included radiological response by RECIST v1.1, PFS and radiological response according to modified (m) RECIST, overall survival (OS), immune response and toxicity. Target recruitment was 48 evaluable patients (24 patients in each arm) to detect a 20% increase in PFS rate at 1 year (30% vs 50%) with a relaxed one-sided statistical significance level of 20% and 80% power using a logrank test. Results: Between March 2016 and October 2019, 55 patients from 3 UK centres were randomised of whom 48 were evaluable (24 each arm). Median PFS by RECIST criteria was significantly longer in Group 2 compared to Group 1 (18.6 vs 10.4 months: hazard ratio (HR) 0.43, 80% CI -∞-0.59; one-sided p = 0.02). Median PFS using mRECIST criteria showed a similar magnitude of benefit (18.6 vs 10.8 months: HR 0.48, 95% CI 0.22-1.02). Median OS was 25.7 months in Group 2 vs 21.5 months in Group 1 (HR 0.61, 95% CI 0.27-1.38). Group 2 showed a higher overall response rate (complete and partial response) by RECIST (54% vs 29%) and mRECIST (75% vs 54%) and a higher disease control rate (complete and partial response and stable disease) by RECIST (92% vs 67%) and mRECIST (88% vs 67%). Treatment with DC infusions was well tolerated; the most common adverse events were chills (30%), fatigue (22%) and nausea (22%), all of which were low grade. Immune response analyses are currently ongoing. Conclusions: The addition of tumour lysate pulsed DC infusions to treatment with TACE plus low-dose cyclophosphamide significantly increased PFS in patients with HCC. To the best of our knowledge, this is the first randomised study to demonstrate efficacy using DC in HCC. Further investigation of the role of DC infusions in the treatment of HCC are warranted but will need to take into account the current evolving immunotherapy landscape. Clinical trial information: 11889464.

Efficacy and safety of transcatheter arterial chemoembolization in combination with camrelizumab and targeted agents in intermediate-stage unresectable hepatocellular carcinoma: A single-arm, prospective, real-world study.

e16190 Background: The prognosis for advanced hepatocellular carcinoma (HCC) is still very poor. This study aimed to explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with camrelizumab plus targeted therapy for the treatment of patients with advanced HCC. Methods: In this single-arm, prospective, real-world study, patients with intermediate-stage unresectable HCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive comprehensive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a tyrosine kinase inhibitor (TKI) agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight &lt; 60 kg), sorafenib 400 mg twice-daily or donafenib 200 mg twice-daily until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) assessed by an independent review committee per modified RECIST. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: From September 2020 to November 2021, 49 patients were enrolled. Among them, 45 (91.8%) patients were male, 41 (83.7%) patients were aged ≤65 years, 30 (61.2%) patients had extrahepatic metastases, and 41 (83.7%) patients had HBV infection. The ORR and DCR were 69.4% (34/49) and 87.8% (43/49), respectively. Five (10.2%) patients were assessed as eligible for surgery, and one of them already received surgery successfully and achieved pathological complete response. The median OS was not reached, and the median PFS was 6.1 months (95%CI, 1.4 -10.8). After 3 months, the alpha-feto-protein decreased compared with before treatment (p &lt; 0.05). All patients had adverse events (AEs) of any grade. The most common AEs were reactive cutaneous capillary endothelial proliferation (30, 61.2%), abdominal pain (25, 51.0%), thyroid dysfunction (20, 40.8%) and fever (18, 36.7%). The majority of treatment-related AEs (TRAEs) were mild or moderate. Grade 3 TRAEs occurred in 3 (6.1%) patients, grade 4 TRAEs occurred in 1 (2.0%) patient, and no deaths occurred. Conclusions: TACE combined with camrelizumab plus targeted therapy in the treatment of advanced HCC shows good efficacy in controlling tumor progression and may provide opportunity of resection. Clinical trial information: ChiCTR2000039508.

Lenvatinib combined with hepatic arterial infusion of modified FOLFOX regime as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria.

e16154 Background: Transcatheter arterial chemoembolization (TACE) is not effective for intermediate-stage hepatocellular carcinoma (HCC) beyond up-to-seven criteria (substage B2) and also impairs the hepatic functional reserve, resulting in poor prognosis. This study aimed to investigate the efficacy and safety of lenvatinib combined transarterial infusion chemotherapy with FOLFOX regimen (FOLFOX-HAIC) for substage B2 HCC. Methods: This study retrospectively enrolled and analyzed 18 patients with substage B2 HCC from Nov. 2019 to Nov. 2021. Patients were orally administered with 8 mg(≤60kg) or 12mg(&gt; 60kg) lenvatinib once daily initially, and FOLFOX-HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2,400 mg/m2 for 46 hours) was performed every 3 weeks and up to 6 sessions. Then patients were treated with lenvatinib alone. Patients with downsizing HCC was allowed for potential curative therapies (surgical resection or ablation). Best response according to the RECIST 1.1 and mRECIST criteria, progression-free survival (PFS) and treatment-related adverse events (TRAE) were evaluated. Results: 18 patients (median age: 63.0 years) underwent a total of 77 cycles of HAIC therapy (mean: 4.3; range: 2-6). All patients were classified as Child-Pugh A class. The ORR were 83.3% (RECIST 1.1) and 94.4% (mRECIST), the disease control rate (DCR) was 100% (RECIST1.1/mRECIST). With a median follow-up period of 12.9 months, the median PFS was 10 months. During the follow-up period, no patient died, and 8 of 18 (44.4%) patients experienced progression. 6-, 9-, and 12-months PFS rates were 94%, 74%, and 55%, respectively. TRAE occurred in 15 of 18 patients (83.3%). Two grade 3 TRAE (hepatic encephalopathy and hypertension) was observed. Conclusions: Lenvatinib combined with FOLFOX-HAIC was well tolerated and had shown promising ORR, PFS rates in patients with intermediate-stage HCC beyond up-to-seven criteria. A prospective large-scale trial is needed to justify these results. [Table: see text]

Trial Designs for Integrating Novel Therapeutics into the Management of Intermediate-Stage Hepatocellular Carcinoma.

Intermediate-stage hepatocellular carcinoma (HCC) consists of heterogeneous groups of patients in terms of tumor burden and organ function reserves. Although liver-directed therapy (LDT), including trans-catheter arterial chemoembolization, radiofrequency ablation or even surgical resection, is the recommended frontline treatment modality, intrahepatic and distant failures are common. The recent advances in systemic treatment, notably the introduction of immune checkpoint inhibitor (ICI)-based therapy, have significantly improved the objective tumor response rate, quality of response and overall survival in patients with recurrent and advanced HCC. Whether the combination of systemic treatment and LDT can further improve the outcome of patients with intermediate-stage HCC is currently being extensively evaluated. In this article, the recent clinical trials incorporating different ICI-based combinations with different LDT for intermediate-stage HCC were reviewed focusing on trial design issues, including patient selection, endpoint definition, and biomarker development. The strength and caveats of different combination strategies and novel biomarker development were discussed.

A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL.

e16195 Background: Trans-arterial chemoembolization (TACE) is the gold-standard for intermediate stage HCC. We hypothesised the ischemic and cytotoxic effect of TACE to boost anti-cancer immunity and to synergise with the anti PD-1 pembrolizumab (pembro). We designed a phase Ib study to test the safety and preliminary efficacy of pembro after TACE in intermediate HCC. Methods: PETAL study will enroll up to 32 patients with intermediate HCC to receive pembro 200 mg every 3 weeks for up to 1 year or until disease progression or unacceptable toxicity. The first safety-run-in phase includes 6 patients: if no dose limiting toxicities (DLTs) emerge over a 21-day window after first pembro, the others are enrolled in the expansion phase. Pembro is given within 30 days after 1 or 2 TACEs. The first phase includes 1 patient scoring Child-Pugh (CP)-B7 and the remaining have to be CP-A. Safety is the primary endpoint and is measured as the incidence of treatment-related adverse events (TRAEs), graded according to NCI CTCAEv4. Efficacy is the secondary endpoint and is evaluated as progression free survival (PFS) from first TACE, according to mRECIST criteria. Survival is estimated using Kaplan-Meier method. All the patients who have received at least one dose of pembro are evaluable for safety. Results: At the time of data cut-off, on the 14th of January 2022, 14 patients had received at least one dose of pembro. The median age was 72 (IQR: 63.3-74.6), 79% were male, 71% were cirrhotic, 29% had viral hepatis and 43% ECOG PS 1. One patient had Child-Pugh (CP) class B7 and 13 had A. The median number of nodules was 1.5 (IQR:1-2.8), and 4.1 cm (IQR: 3.7-4.5) the median diameter. Overall, 5 patients received 2 TACEs and 9 had 1. Patients received a median of 4.5 cycles (IQR: 2.3-6.5) of pembro. No DLTs emerged in the first phase. Treatment-related adverse events (TRAE) of any grade (G) were reported in 86% of participants, 21% of participants experienced G3 TRAEs, and there were no G4 or G5 TRAEs. Specific skin-related toxicity was the most frequently reported (35%) TRAE. No patients had treatment-related liver toxicity. Causes of treatment discontinuation were PD (n=7), TRAEs (n=1), clinical deterioration in the CP B patient (n=1), COVID pandemic (n=2) and withdrawal of consent (n=1); at the time of data cut-off, mPFS from first TACE was 10.8 months (95%CI: 6.63-14.97). Conclusions: Adjuvant pembro following TACE is manageable and tolerable with signs of activity. These results prompt the investigation in larger trials. Clinical trial information: NCT03397654. [Table: see text]

IMMUTACE: A biomarker-orientated phase II, single-arm, open-label AIO study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate-stage hepatocellular carcinoma (HCC; AIO-HEP-0217)—Updated efficacy results.

4116 Background: Immunotherapy based combinations recently revolutionized the treatment of patients (pts) with advanced HCC, but its significance in earlier stages remains to be determined. TACE is commonly used as first line treatment in intermediate HCC, but outcome of patients treated with TACE in real-life cohorts is still poor with a median overall survival (OS) below 20 months. The aim of this study was to determine the safety and efficacy of TACE combined with nivolumab. Methods: This is a phase II trial, that recruited 59 patients at 10 sites in Germany between 06/2018 and 06/2020. Pts received up to two TACE treatments followed by nivolumab (240 mg/ Q2W), initiated on day 2-3 after the first TACE session and continued until progression for a maximum treatment duration of two years. Primary endpoint was ORR (mRECIST; with ORR exceeding 55% (power = 80%; actual beta 0.17) as promising for further investigations). Secondary endpoints include mPFS, mTTFS (median time to failure of strategy), mOS, QoL, and safety/tolerability. Tumor tissue was obtained at baseline and blood samples were collected longitudinally for translational research. Results: 49 pts (14.3% HCV and 8.2% HBV) were enrolled and received at least one dose of nivolumab, median tumor size was 4.5 cm (0.9 – 15 cm) and median number 3 (1 – 12). ORR by mRECIST was 71.4% (CR: 16.3%, PR: 55.1%, SD 4.1%, PD: 14.3%). At a median follow-up of 20 months, mPFS was 7.2 mo (95% CI; 5.3 – 11.2; 40 events), mTTFS was 11.2 mo (95% CI; 7.2, 13.5; 42 events) and mTTSST (median time to subsequent systemic therapy) was 24.9 mo (95% CI; 12.2, - ; 21 events). Median duration of Nivolumab was 8.3 months and mOS was 28.3 mo (95% CI; 20 – not estimable; 23 events). Grade ≥3 treatment-related adverse events occurred in 34.7% of patients. Correlative analysis of efficacy with genetic alterations, gene expression signatures and changes of immune cell populations will be reported soon. Conclusions: The study met its primary endpoint and provides evidence for the efficacy of TACE in combination with nivolumab without new safety signals in pts with intermediate HCC and no prior systemic therapy. Our findings support further evaluation of nivolumab-based combinations for the treatment of intermediate HCC. Disclaimer: This study was supported with drug and funding by Bristol-Myers-Squibb. Clinical trial information: NCT03572582.

Abstract No. 193 ▪ FEATURED ABSTRACT Comparison of radioembolization versus chemoembolization in a propensity matched multi-center large database veteran cohort for early and intermediate stage hepatocellular carcinoma

To examine the differences in overall survival and repeat treatments in patients with early and intermediate stage hepatocellular carcinoma (HCC) receiving first-line yttrium-90 radioembolization (TARE) versus chemoembolization (TACE) treatment

Abstract No. 556 Cost-effectiveness of radioembolization with Y-90 glass microspheres versus transarterial chemotherapies in the treatment of intermediate stage hepatocellular carcinoma: a U.S. hospital perspective

Transarterial radioembolization with Y-90 glass microspheres (“Y-90”) is a safe and effective alternative to transarterial chemoembolization (TACE) in patients with intermediate stage hepatocellular carcinoma (HCC). A previous economic evaluation from the UK National Health Service perspective found Y-90 to be cost-effective compared with TACE and transarterial bland embolization (TAE) in a population of unresectable HCC patients. This economic evaluation assessed the cost-effectiveness of Y-90 across the same patient population in the U.S.

Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma.

Transarterial chemoembolization (TACE) combined with a PD-1 inhibitor and TACE combined with a PD-1 inhibitor and lenvatinib have recently been reported as promising treatments to improve the prognosis of hepatocellular carcinoma (HCC) patients. This study aims to compare the efficacy of these two treatments. A retrospective study was conducted, and patients were recruited from two centers in China. Progression-free survival (PFS) and overall survival (OS) were compared, and the objective response rate (ORR) and disease control rate (DCR) were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment-related adverse events (AEs) were analyzed to assess safety. The median follow-up for the entire cohort was 11.4months. Of the 103 patients included in this study, 56 received triple therapy, and 47 received doublet therapy. PFS was significantly higher in the triple therapy group than in the doublet therapy group (mPFS 22.5 vs. 14.0months, P<0.001). Similar results were obtained in terms of OS (P=0.001). The ORR and DCR were also better in the triple therapy group (64.3% vs. 38.3%, P=0.010; 85.7% vs. 57.4%, P=0.002). The most common AEs in the triple therapy group were decreased albumin (55.3%), decreased platelet count (51.8%) and hypertension (44.6%). The combination of TACE with a PD-1 inhibitor and lenvatinib in patients with BCLC stage B HCC might result in significantly improved clinical outcomes with a manageable safety profile compared with TACE with a PD-1 inhibitor.

Treatment for Intermediate-Stage Hepatocellular Carcinoma: Current Practice and Outcome in Real World Study

Background: Intermediate-stage hepatocellular carcinoma (HCC) is a very heterogeneous disease. The first line treatment for this group is transarterial chemoembolization (TACE), however, in clinical practice, not all patients are suitable for TACE. We aim to evaluate current treatment practice and outcome of patients with intermediate-stage HCC.Methods: HCC patients database from 2013 to 2016 in Cipto Mangunkusumo Hospital and Dharmais Cancer Hospital were retrospectively analyzed. Patients with intermediate-stage HCC were included in this study.Results: A total of 456 patients were diagnosed with HCC, but only 151 (33.1%) patients with intermediate-stage HCC were included. Men outnumbered women in a ratio of 3:1. The most common etiology for HCC was hepatitis B virus (HBV) infection, which accounted for 55% of patients. Fifty-two patients (34.4%) were treated with TACE as first-line treatment. Sixty-seven patients (44%) were given best supportive care due to ineligibility for TACE. Frequency of TACE varied from one to eleven times. Overall median survival was 617 days (1.7 years). One-year survival for patients undergoing TACE and liver resection was 47% and 60%, respectively. We did not compare the survival between any treatment groups because the number of patient in each group is not sufficient to be statistically analyzed.Conclusion: Only 34.4% of patients with intermediate-stage HCC was treated with TACE as first-line treatment. An improvement in the treatment strategy should be done for HCC patients in Indonesia.