Efficacy and Safety of Chemoradiation Therapy Using One- Shot Cisplatin via Hepatic Arterial Infusion for Advanced Hepatocellular Carcinoma with Major Macrovascular Invasion: a Single-arm Retrospective Cohort Study

Background: Patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) who receive systemic chemotherapy have a poor prognosis. This study aimed to determine if one-shot cisplatin (CDDP) chemotherapy via hepatic arterial infusion (HAI) combined with radiation therapy (RT) prior to systemic chemotherapy could improve the outcomes of these patients. Methods: This study consisted of 32 HCC patients with the following eligibility criteria: (i) portal vein invasion 3/4 and/or hepatic vein invasion 2/3; (ii) received one-shot CDDP via HAI; (iii) received RT for MVI, (iv) a Child-Pugh score ≤7; and (v) an Eastern Clinical Oncology Group Performance Status score of 0 or 1. To determine the therapeutic effect, we collect the information of patients’ characteristics and took contrast-enhanced computed tomography at the start of the therapy and every 2 to 4 months after the therapy initiated. We evaluated the overall response of the tumor and tumor thrombosis according to modified Response Evaluation Criteria in Solid Tumors. We assessed the patient’s data statistically by the Mann-Whitney U-test, fisher’s exact test, and evaluated overall survival and progress-free survival by log-ranked test, and analyzed the predictive factors by as appropriate. Results: The overall response rate at the first evaluation performed a median of 1.4 weeks after HAI was 16% of the main intrahepatic tumor and 59% of the MVI. The best responses were the same as those of the first-time responses. The duration of median survival was 8.6 months, and for progression-free survival of the main intrahepatic tumor was 3.2 months. The predictive factor of overall survival was the relative tumor volume in the liver and the first therapeutic response of MVI. There were no severe adverse events or radiation-induced hepatic complications. Conclusions: One-shot CDDP via HAI and RT were well tolerated and showed immediate and favorable control of MVI. Thus, this combination shows potential as a bridging therapy to systemic chemotherapy.

Hepatic arterial infusion chemotherapy of oxaliplatin plus fluorouracil versus sorafenib in advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase 3 trial (The FOHAIC-1 study).

4007 Background: Advanced hepatocellular carcinoma (HCC) with mega liver masses and macrovascular invasion were commonly observed at the first diagnosis, while with less extrahepatic metastases (77.5% vs. 37.9%). However, in clinical trials IMbrave150, SHARP, and Asia-Pacific SHARP, the percentage of extrahepatic metastases reached 63%, 53%, and 68.7%, respectively, while macrovascular invasion only accounted for 38%, 36%, and 36%. Unlike the previous and ongoing phase 3 clinical trials exploring the optimal systemic medication in the first-line treatment of advanced HCC, this study mainly focused on a population with a heavy intrahepatic tumor burden. Methods: In this open-label, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo hepatic arterial infusion chemotherapy (HAIC) of FOLFOX regimens (HAIC-FO) or sorafenib treatment. Patients in the HAIC-FO group were recommended to receive tumor and normal tissue biopsy to search for the potential genomic biomarkers in predicting the response to treatment. Results: Between May 2017 and May 2020, 551 patients were recruited. Two hundred sixty eligible patients were randomly assigned to receive HAIC-FO (n = 130) or sorafenib (n = 132) and were included in the intention-to-treatment population. Macrovascular invasion with or without extrahepatic metastasis was present in 82.8% of patients (84.6% and 81.1%; P = 0.446). The median tumor diameter was 11.7 cm (IQR 8.3-14.0) of the HAIC-FO group and 10.8 cm (8.7-13.6) of the sorafenib group (P = 0.439). The percentage of patients with > 50% tumor volume involvement of the liver was 41.5% and 39.4%, respectively (P = 0.724). At the time of data cutoff (Oct 31, 2020, at 190 deaths [79 of HAIC-FO and 111 of sorafenib]), patients receiving HAIC-FO had a median overall survival of 13.9 months (95%CI 10.6-17.2), compared with 8.2 months (7.5-9.0) for those receiving sorafenib (HR 0.408 [95%CI 0.301-0.552], P < 0.001). Tumor downstaging occurred in 16 (12.3% of 130) patients of the HAIC-FO group, including 15 (93.8%) receiving curative surgery or ablation and finally achieving a median overall survival (progression-free survival) of 20.8 (16.4) months (95%CI 9.1-32.5 [7.5-25.3]) with a 1-year rate of 93.8% (68.8%). Analyses of predictive biomarkers based on the whole genome sequencing were ongoing in the HAIC-FO group. Conclusions: This randomized phase 3 study proved that HAIC-FO had superior efficacy and survival outcome than sorafenib in the first-line treatment of primary diagnostic, advanced HCC, indicating that patients with heavy intrahepatic tumor burden, HAIC-FO monotherapy might be a better strategy than sorafenib. Clinical trial information: NCT03164382.

Predictive Factors for the Effectiveness of Repeated Lines of Transarterial Chemoembolization in the Treatment of Localized Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-related death in the world. The progression of HCC after previously effective TACE is quite often local. This article describes our experience with repeated TACE in patients with local progression of HCC. We analyzed 125 patients with HCC, for the period from 2009 to 2015. TACE was performed for intrahepatic manifestations of HCC. Progression of HCC after TACE-1 was observed in 88.8 % (n = 111) patients. Disease progression after TACE‑2 was registered in 40 (32 %) patients. TACE‑3 was performed in 8 (6.4 %) patients. The analysis showed that isolated local intrahepatic progression of HCC with the growth of intrahepatic tumor nodes previously subjected to TACE‑1 (without new foci) does not affect OS. The efficiency of re-embolization (TACE‑2) is somewhat lower than for TACE of the first stage. Independent factors of overall survival increase in patients receiving TACE: satisfactory objective status according to ECOG, efficacy of the first stage of TACE, late progression and objective effect after re-embolization.

Distant Metastases in Patients with Intrahepatic Cholangiocarcinoma: Does Location Matter? A Retrospective Analysis of 370 Patients

Background. Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor entity, and distant metastases are common. However, studies investigating patterns and clinical relevance of distant metastases are rare. Therefore, we aimed to analyze occurrence, location, and prognostic impact of distant metastases on overall survival (OS). Methods. Between 1997 and 2018, 417 patients with ICC were treated at our tertiary care center. Distant metastases and intrahepatic tumor burden were retrospectively evaluated in a longitudinal approach using volumetric assessment of cross-sectional imaging studies and all available medical/histopathological reports. Results. Finally, 370 patients with histopathologically confirmed ICC were included. Of these, 186 showed distant metastases, either initially (n = 59) or during follow-up (n = 127). The most common metastatic sites were the lung (n = 105), peritoneum (n = 81), and bone (n = 50). After detection of lung metastases, the residual median OS was 5.3 months; followed by peritoneal metastases, 4.5 months, and bone metastases, 4.4 months (P=0.17). At the time of first metastatic occurrence, residual OS according to intrahepatic tumor burden of <25%, 25–50%, and >50% was 6.5 months, 4.9 months, and 1.2 months, respectively (P<0.001). In multivariate hazard regression, hepatic tumor burden, liver function, and subsequent treatment were significant predictors of survival. Conclusions. During the disease course, every second patient developed extrahepatic metastases. While the presence of distant metastases was associated with poor patient outcomes, there was no significant difference between metastatic sites. However, hepatic tumor burden was the life-limiting risk factor in a majority of patients at the time of distant metastatic disease.

Different organ-specific response to nivolumab to determine the survival outcome of patients with advanced hepatocellular carcinoma (aHCC).

4584 Background: Previously, two phase III clinical trials of immune checkpoint inhibitors (ICI) failed to meet their primary endpoints, leading to doubts regarding the clinical activity of ICI monotherapy in patients with aHCC. Here, we comprehensively examined clinicopathological factors and estimated their association with survival outcomes in aHCC patients treated with nivolumab. Methods: A total of 261 eligible patients from 5 high-volume centers who were treated with nivolumab between June 9, 2012 and March 14, 2018 and had measurable diseases were reviewed. We reviewed more than 80 clinicopathological factors and categorized them into 6 areas: 1) demographics (n = 16); 2) baseline laboratory values (n = 19); 3) tumor burden (n = 12); 4) previous treatment (n = 12); 5) treatment response (n = 5); 6) toxicity profiles (n = 18). Their association with survival outcomes were evaluated, and organ-specific response evaluation, adapted from RECIST 1.1, was conducted. Results: Of the 261 patients, 218 (84%) had extrahepatic spread. The median follow-up time was 4.5 months. The median progression-free survival (PFS) and overall survival (OS) were 2.3 months (95% CI, 1.8-2.8) and 6.3 months (95% CI, 5.0-8.2). Objective response rate was 15%. Subgroup analyses revealed that compensated liver function (Child-Pugh score A5/6), surrogate markers for low tumor burden (low AFP, low PIVKA, and low LDH level), inflammatory markers (low C-reactive protein [CRP], low erythrocyte sedimentation rate [ESR], low neutrophil-to-lymphocyte ratio [NLR], high lymphocyte-to-monocyte ratio [LMR]), and low intrahepatic tumor burden were significantly associated with longer OS. A total of 456 individual lesions (liver, n = 249; lung, n = 124; lymph node, n = 35; others such as boner soft tissues, n = 48) were examined. Organ-specific response rates (hepatic tumor, 9%; lung, 25%; lymph node, 37%; others metastasis, 15%) were different, of which intrahepatic tumor was the least responsive organ to ICI treatment in aHCC. Conclusions: Underlying liver function, the tumor extent and burden, and the degree of plasma lymphocytes are crucial for determining tumor response to ICI in aHCC. Antitumor immune response to ICI differs in an organ-specific manner. The hepatic tumors of HCC may be less responsive to nivolumab than extrahepatic lesions.

Clinical Significance of Hepatectomy for Hepatocellular Carcinoma Associated with Extrahepatic Metastases

Background: This study evaluated the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases who can undergo hepatectomy. Methods: A total of 32 patients who underwent hepatectomy for HCC with extrahepatic metastases, including lymph node and/or distant metastases were recruited for this study. Results: Fourteen patients had lymph node metastasis only, 16 had distant metastasis only, and 2 had both metastasis types during preoperative diagnosis. The 3-year overall survival (OS) rate of all patients was 17.9%, and the median survival time (MST) was 11.8 months. Univariate analysis revealed that intrahepatic maximal tumor size, intrahepatic tumor number, and intrahepatic tumor control after hepatectomy were significant factors influencing OS (p < 0.05). Multivariate analysis revealed that independent risk factors for OS were intrahepatic maximal tumor size and intrahepatic tumor number (p < 0.05). The MST and 3-year OS rate of patients with maximal tumor size <100 mm and intrahepatic tumor number ≤2 were 39.0 months and 51.9%, respectively. Conclusions: Hepatectomy is not recommended for HCC patients with extrahepatic metastasis with ≥3 intrahepatic tumors, even when all intrahepatic tumors can be eliminated via hepatectomy. Aggressive surgery may be justified for HCC patients with ≤2 intrahepatic tumors and maximal tumor size <100 mm, irrespective of vascular invasion.