Treatment Of Advanced Hepatocellular Carcinoma Patients Research Articles

Advanced hepatocellular carcinoma with major portal vein invasion: Therapeutic outcomes of hepatic arterial infusion chemotherapy vs concurrent radiotherapy.

Hepatocellular carcinoma (HCC) with major portal vein invasion (MPVI) presents very poor outcomes. Hepatic artery infusion chemotherapy (HAIC) and radiation therapy (RT) have both been found to be effective for advanced HCC. In this retrospective study, we compared the therapeutic outcomes of our "new" HAIC regimen with and without concurrent RT, before and after propensity score matching (PSM) in treating HCC patients with MPVI. One hundred forty patients with MPVI received HAIC alone and 35 patients underwent concurrent HAIC and RT during a 16-year period. The left subclavian artery was adopted as the entry site for a temporary catheter placement for a 5-day chemoinfusion. The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was adopted to assess the objective response rate (ORR). The Kaplan-Meier curve was used to calculate progression-free survival (PFS) and overall survival (OS) between the two groups. Univariate and multivariate analyses by Cox regression model were used to assess hazard ratios. Of the 140 patients with Child-Pugh A liver function, the median OS was 17.0 months. In the initial cohort, higher ORR and PFS were found in the concurrent RT group than in the HAIC alone group (80% vs 66.4% and 9 vs 8 months, respectively) but shorter OS (10.5 vs 14.5 months, p = 0.039) was observed. After PSM, the OS was 10 and 15 months ( p = 0.012), respectively. Multivariable Cox regression analysis revealed that the significant factors for adjusting hazard ratios for OS were Child-Pugh classification, alpha fetal protein (AFP) level, and hepatic vein invasion. HAIC is an effective treatment for advanced HCC patients with MPVI. Concurrent HAIC and full-dose RT were associated with worse clinical outcomes.

Evaluation of the Clinical Efficacy of Intensity-Modulated Radiotherapy Combined with Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma with Extrahepatic Oligometastasis and Prognostic Factors for Patient Survival.

To investigate the clinical efficacy of intensity-modulated radiotherapy (IMRT) combined with transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) patients with extrahepatic oligometastasis and the prognosis of patients receiving this treatment. Twenty-one HCC patients with extrahepatic oligometastasis were retrospectively analyzed; seven patients received IMRT only, and 14 received IMRT plus TACE. TACE treatment was administered before IMRT (50 mg epirubicin, oxaliplatin 100 mg, and mitomycin 10 mg). The short-term efficacy of this treatment and patient prognosis were evaluated. Complete response (CR) and partial response (PR) in the intrahepatic region were achieved in three and 14 patients, respectively. The objective response rate (ORR) approached 81%. CR and PR were achieved in six and 10 patients with extrahepatic metastases, respectively, for an ORR of 100%. Pain was completely relieved in all patients with bone metastases. The median overall survival (OS) and progression-free survival (PFS) were 21 months and 9.1 months, respectively. The 1-year PFS rate was 43%, and the 1-, 2-, 3-, and 4-year OS rates were 83%, 35%, 9%, and 4%, respectively. Univariate analysis showed that the prognostic factors for patient survival included Child-Pugh class, vascular thrombus, Karnofsky performance status (KPS), radiotherapy dose, ascites, combination therapy, and pattern of progression. Multivariate analysis showed that vascular thrombus, combination therapy, and pattern of failure were prognostic factors for PFS, and the KPS was the only prognostic factor for OS. No grade 3-4 adverse reactions were observed. IMRT combined with TACE is safe and feasible without major toxicities for the treatment of advanced HCC patients with extrahepatic oligometastasis and results in excellent objective efficacy and a potential survival benefit. The KPS is the only predictive factor for OS. This approach is expected to be a useful palliative option for selected HCC patients with extrahepatic metastases.

The upregulation of CLGN in hepatocellular carcinoma is potentially regulated by hsa-miR-194-3p and associated with patient progression.

Patients with hepatocellular carcinoma (HCC) have poor prognosis, especially in advanced stages. Targeted therapy is the main treatment for advanced HCC patients, but the optimal targets for HCC remain poorly understood. The main purpose of this study was to identify potential novel prognostic markers and therapeutic targets. Firstly, differentially expressed genes (DEGs) in HCC were identified from the Gene Expression Omnibus (GEO) database. The expression, significance in prognosis, and potential mechanisms of DEGs were analyzed using GEPIA, TIMER, HPA, Kaplan Meier Plotter, CBioPortal, miRWalk, TargetScan, and ENCORI databases. Immunohistochemical staining was used to determine the protein expression levels of potential candidate genes. The mRNA levels of MND1, STXBP6, and CLGN were significantly increased in HCC (p< 0.01). HCC patients with elevated CLGN mRNA levels had poorer overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS) (p < 0.05). Higher MND1 mRNA levels significantly correlated with poorer DFS in HCC patients (p< 0.05). However, there was no significant correlation between STXBP6 expression and prognosis of HCC (p> 0.05). Further analysis revealed that patients with elevated CLGN mRNA expression in advanced pathology stages had poorer prognosis (p< 0.01). In addition, CLGN protein levels were elevated in HCC compared to their levels in normal tissues. The mRNA levels of CLGN had no significant correlation with the abundance of six common tumor infiltrating lymphocytes in HCC (COR < 0.5). Moreover, the mutation rate of CLGN was less than 1% in HCC patients (10/1089). Finally, the expression level of hsa-miR-194-3p in HCC was significantly lower than that in normal tissues (p < 0.05), and prognosis of HCC with low expression of hsa-miR-194 was poor (p < 0.05). The upregulation of CLGN in HCC is significantly associated with poor patient prognosis, especially in the advanced stages, and may be regulated by hsa-miR-194-3p. These findings suggest that CLGN may be closely related to the progression of HCC, and is a potential therapeutic target and prognostic indicator for patients with advanced HCC.

Regorafenib Combined with PD-1 Blockade Immunotherapy versus Regorafenib as Second-Line Treatment for Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Study.

PurposeTo evaluate the safety and efficacy of regorafenib combined with anti-PD-1 antibody sintilimab (rego-sintilimab) as a second-line treatment for advanced hepatocellular carcinoma (HCC).MethodsThis multicenter retrospective study evaluated consecutive patients with advanced HCC who received rego-sintilimab (rego-sintilimab group) or regorafenib alone (regorafenib group) as a second-line treatment from January 2019 to December 2020. Adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Uni- and multi-variable analyses of prognostic factors for OS and PFS were performed using Cox proportional hazard regression models.ResultsIn total, 113 patients were included in the study: 58 received rego-sintilimab and 55 received regorafenib. The rego-sintilimab group had higher ORR (36.2% vs 16.4%, P = 0.017), longer PFS (median 5.6 vs 4.0 months; P = 0.045), and better OS (median 13.4 vs 9.9 months; P = 0.023) than the regorafenib group. Regorafenib alone, Child-Pugh B, and neutrophil-to-lymphocyte ratio (NLR) > 3.6 were independent prognostic factors for poor OS. Regorafenib alone, α-fetoprotein level, and NLR > 3.6 were independent prognostic factors for poor PFS. Subgroup analyses showed a survival benefit of rego-sintilimab in patients with NLR ≤ 3.6 (hazard ratio 0.518 [95% CI, 0.257–0.955]) but not in those with NLR > 3.6 (0.852 [0.461–1.572]); P = 0.002 for interaction. The difference in incidence of grade 3/4 adverse events between the two groups was not statistically significant (39.7% vs 30.9%; P = 0.331).ConclusionRego-sintilimab was tolerated and led to better OS than regorafenib as a second-line treatment for advanced HCC patients, especially in those with NLR ≤ 3.6.

Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.

e16159 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P &lt; 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.

Autologous dendritic cells pulsed with lysate from an allogeneic hepatic cancer cell line as a treatment for patients with advanced hepatocellular carcinoma: A pilot study

ObjectivesThis is a randomized trial adopted to evaluate the safety and efficacy of immunization with specific anti-hepatocellular carcinoma dendritic cells (DCs) in Egyptian patients with advanced hepatocellular carcinoma (HCC) as a treatment or adjuvant therapy in comparison with the traditional therapy. MethodsThis study was conducted on 20 HCC patients who were assigned to four groups according to BCLC staging; group I: HCC patients (stage B) received trans-arterial chemoembolization (TACE) and DCs as an adjuvant therapy; group II: HCC patients (stage B) received TACE only; group III: advanced HCC patients (stage D) received DCs vaccine; group IV: advanced HCC patients (stage D) received supportive treatment. DCs were generated from peripheral blood monocytes and pulsed with a lysate of an allogeneic hepatic cancer cell line (HepG2). Toxicity and immunological response were reported as primary outcomes whereas clinical biochemical and radiological responses were reported as secondary outcomes. ResultsOur study detected that patients who received DCs vaccine (group III) showed mild decrease in Child-Pugh score as well as AFP and PIVKA II levels and developed 20% partial response [PR] 40% stable disease [SD] and 40% progressive disease [PD] compared to the patients of group IV on supportive treatment who developed 100% PD. Although group I patients developed PR (60%) SD (20%) and PD (20%) no significant difference was detected in the clinical biochemical or radiological response between group I and group II patients. DCs vaccine had minimal adverse effects with no autoimmunity and elicited a better immunological response such as increased CD8 cells percentage and number as well as decreased TGFβ levels in the vaccinated patients. ConclusionDCs vaccine is safe as it is not associated with significant toxicity. However due to the small number of included patients the efficacy and immune response of using DCs vaccine in the treatment of advanced HCC patients need to be justified by testing of a large cohort.

Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy.

Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.

3:00 PM Abstract No. 81 Radioembolization for hepatocellular carcinoma patients with portal vein thrombosis: a single-center 14-year experience

To report overall survival (OS) outcomes for advanced stage hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) treated with yttrium-90 radioembolization (Y90). With IRB approval we searched our prospectively acquired database for patients treated with Y90. Patients who had advanced stage HCC with tumor PVT were included. Patients who had simultaneous hepatic vein invasion and extrahepatic metastases were excluded. Clinical and laboratory data were collected at baseline and 1 month post-Y90. Toxicity was assessed using CTCAE v4.0. OS outcomes were reported and stratified by Child-Pugh (CP) and location of PVT. OS was calculated using Kaplan Meier method. Multivariate analysis was conducted using Cox-proportional hazards. A subanalysis for patients with high alpha-fetoprotein (AFP) (>100 ng/dl) was conducted. 185 patients with HCC and tumor PVT had Y90. 43(23%) patients had segmental, 65(35%) had lobar, and 77(42%) had main PVT. 74 patients (40%) were CPA, 51(28%) were CPB7 and 60(32%) were CP≥B8. New grade 3/4 toxicities were seen in 29(16%) patients for bilirubin, 23(13%) for albumin, and 5(2.6%) for alkaline phosphatase. Median OS(months) (95% CI) for CPA, CPB7, and CP≥B8 patients was 13.3(8.7-15.7), 6.9(5.3-10.1), and 3.9(2.9-5.0), respectively. For CPA patients, median OS(months) (95% CI) was 14.3(12.0-17.8) for segmental, 14.2(7.3-19.5) for lobar and 7.7(4.6-13.8) for main [P = 0.78]. For CPB7 patients, median OS (months) (95% CI) was 6.5(3.4-38) for segmental, 6.9(4.6-13.3) for lobar and 7.7(4.8-11.1) for main [P = 0.82]. For CP≥B8 patients, median OS (months) (95% CI) was 8.4(1.2-75.2) for segmental, 4.4(2.5-9.7) for lobar and 3.4(2.5-4.6) for main [P = 0.015]. Multivariate analysis showed baseline bilirubin, ascites, and AFP to be significant OS prognosticators. Out of 123 patients with high AFP, 12(10%) patients normalized their AFP levels (<13) with a median OS of 23.9 months (CI:20.1-124.1). Y90 can serve as a safe and effective treatment for advanced HCC patients with tumor PVT, particularly for those with preserved liver function. OS is affected by baseline liver function, tumor size, and AFP level. Location of PVT had a significant effect on OS in CP≥B8.

GALNT14 genotype-guided, sorafenib in combination with transarterial chemoembolization in hepatocellular carcinoma: An interim report of a prospective randomized controlled trial.

e15657 Background: Sorafenib is the only approved targeted agent for treatment of unresectable hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) is the mainstay of treatment for advanced HCC patients in Barcelona Clinical Liver Cancer (BCLC) stage B. Previous randomized controlled trials did not show definite beneficial effect for TACE + sorafenib combination therapy in Asian HCC patients. Recently, an SNP marker on GALNT14gene, rs9679162, was found associated with therapeutic outcomes in HCC patients receiving chemotherapy or chemoembolization, wherein rs9679162-TT genotype was associated with a favorable therapeutic response. In this study, we examined whether this marker could be used as a guide for TACE + sorafenib therapy. Methods: From 2015-Aug, HCC patients in BCLC stage B were genotyped for GALNT14-rs9679162. Patients with genotype TT were treated with TACE alone. Patients with non-TT (CT or CC) were randomized 1:1 to receive TACE + sorafenib treatment or TACE treatment alone (NCT02504983). Results: Interim analysis was performed on 2017-Jan. Totally 40 patients were enrolled. Of them, 16 and 24 patients had GALNT14-TT and non-TT genotypes, respectively. Of the non-TT patients, 11 and 13 patients were randomized into TACE alone (TACEA) and TACE + sorafenib (TACE+S) group. TACEA patients had significant shorter time-to-tumor progression compared with TACE+S (P = 0.019) and GALNT14-TT patients (P &lt; 0.001). No significant difference was found for time-to-therapeutic response (CR + PR) between the three groups. However, when evaluating the time-to-therapeutic response occurring &gt; 3 m of the first TACE (excluding early response), it was found that TACEA patients had significant longer time-to-therapeutic response compared with TACE+S (P = 0.046) and GALNT14-TT patients (P = 0.034). Conclusions: The interim analysis confirmed that patients with GALNT14-TT genotype had a favorable TACE response compared with the non-TT genotype. In addition, in patients with non-TT genotype, TACE + sorafenib combination therapy had a significantly better therapeutic response compared with TACE alone. Clinical trial information: NCT02504983.

Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study.

Sorafenib, an oral multikinase inhibitor, is approved for advanced hepatocellular carcinoma (HCC) treatment. However, its therapeutic effect in advanced HCC patients with extrahepatic metastasis remains uncertain. This study aimed to prospectively assess the efficacy, safety, and survival risk factors and evaluate the prognostic impact of sorafenib treatment in advanced HCC patients with or without extrahepatic metastasis. Between May 2009 and March 2014, 312 consecutive advanced HCC patients who received sorafenib were enrolled in this study. We evaluated their characteristics and compared the clinical outcomes of those with and without extrahepatic metastasis. Of the enrolled patients, 245 (81%) received sorafenib treatment for more than 1 month, with a median duration of 3.6 months. Eighteen patients demonstrated partial response to sorafenib therapy, 127 had stable disease, and 134 had progressive disease at the first radiologic assessment. The median survival time (MST) and progression‐free survival (PFS) were 10.3 and 3.6 months, respectively. Multivariate analysis identified gender, Child‐Pugh class, baseline serum des‐gamma‐carboxy prothrombin level, and treatment duration as independent risk factors for survival. Extrahepatic metastasis was detected in 178 patients. However, the MST, PFS, and therapeutic effect were comparable between patients with and without extrahepatic metastasis. The independent risk factors for decreased overall survival in patients with extrahepatic metastasis were similar to those affecting all patients. Our results indicated that sorafenib could be administered for hepatic reserve and as long‐term treatment for advanced HCC patients regardless of their extrahepatic metastasis status.

Phase 2 open‐label study of single‐agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B–endemic Asian population

The current study was a phase 2 open-label study to evaluate the efficacy and tolerability of single-agent sorafenib in the treatment of advanced HCC patients in a hepatitis B-endemic Asian population. Patients with advanced hepatocellular carcinoma (HCC) received sorafenib at a dose of 400 mg twice daily in 4-week cycles. Tumor response was assessed every 3 cycles using Response Evaluation Criteria in Solid Tumors criteria. Fifty-one patients were enrolled in the study and were treated with sorafenib for at least 12 weeks. The median age was 56 years (range, 28-79 years). Approximately 90% had hepatitis B virus-related HCC. Thirty-six (71%) patients had underlying Child-Pugh A cirrhosis, 13 (26%) Child-Pugh B, and 2 (3%) Child-Pugh C. Four (8%) patients achieved partial responses, and 9 (18%) patients had stable disease for at least 12 weeks. The median overall survival was 5 months (range, 4-17 months). Patients without extrahepatic spread, particularly without lung metastasis (P<.01), are more likely to benefit from sorafenib treatment. The most common toxicities were diarrhea (67%), malaise (55%), and hand-foot-skin reaction (54%). The majority of patients had transient liver function derangement. Patients with and without underlying portal vein thrombosis had similar therapeutic benefits and likewise shared a similar treatment-related toxicity profile with sorafenib treatment. Single-agent sorafenib demonstrates good efficacy and acceptable tolerability in treating an advanced HCC patient population in a hepatitis B-endemic area. The presence of lung metastasis predicts poor response to sorafenib in advanced HCC patients.

Molecular targeting for treatment of advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major global health problem, which has a grave morbidity and mortality. Over the past few decades, no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage. Sorafenib is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of Raf-1 and B-Raf serine-threonine kinases, and exerts an anti-angiogenic effect by targeting the vascular endothelial growth factor receptor-1, 2 and 3, and platelet-derived growth factor receptor-beta tyrosine kinases. Recently, two clinical successful applications, SHARP and Asia-Pacific trial, of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance. However, because the results of clinical trials show diverse responses in a subset of HCC patients, a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity, ultimately leading to the most suitable individualization of molecular targeted therapy in HCC.

Future perspectives on the treatment of hepatocellular carcinoma with cisplatin

Hepatocellular carcinoma (HCC) is the commonest primary liver malignancy. Its incidence is increasing worldwide. Surgery, including transplantation resection, is currently the most effective treatment for HCC. However, recurrence rates are high and long-term survival is poor. Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. Cisplatin (CDDP) is a key drug for the standard regimens of various cancers in the respiratory, digestive and genitourinary organs. Recently, several encouraging results have been shown in using CDDP in the treatment of advanced HCC patients. This review examines current knowledge regarding the chemotherapeutic potential of CDDP.

Evolution of systemic therapy of advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) commonly occurs in hepatitis B endemic areas, especially in Asian countries. HCC is highly refractory to cytotoxic chemotherapy. This resistance is partly related to its tumor biology, pharmacokinetic properties, and both intrinsic and acquired drug resistance. There is no convincing evidence thus far that systemic chemotherapy improves overall survival in advanced HCC patients. Other systemic approaches, such as hormonal therapy and immunotherapy, have also disappointing results. Recently, encouraging results have been shown in using sorafenib in the treatment of advanced HCC patients. In this review, we concisely summarize the evolution of developments in the systemic therapy of advanced HCC.