Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma

Chapter 4: Chemotherapy and radiotherapy

Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.

Focus

Quality Improvement Guidelines for Transhepatic Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic Malignancy

How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated?

Advanced hepatocellular carcinoma (HCC) has a very low resectable rate. This meta-analysis aimed to compare efficacy of three combination strategies in treatment of advanced unresectable HCC with a view of guiding future selection of the best combination therapy for sorafenib and local therapy. A search was conducted to identify relevant literature published between April 2013 and May 2022, and then compared efficacy of sorafenib combined with external radiotherapy (SOF + RT), sorafenib with transarterial chemoembolization (SOF + TACE), sorafenib with hepatic artery infusion chemotherapy (SOF + HAIC), sorafenib (SOF), external radiotherapy (RT), transarterial chemoembolization (TACE), and hepatic artery infusion chemotherapy (HAIC) were studied and analyzed. Finally, the results were statistically analyzed using R 3.5.3 software and Stata/SE 15.0 software. A total of 46 studies, involving 7595 patients, were included in the meta-analysis. Analysis of overall survival (OS) and progression-free survival (PFS) of seven related treatment interventions revealed that the combination therapy had significantly higher efficacy than monotherapies. Among the combination therapies, SOF + RT was associated with the best OS and PFS rates, and the least adverse events compared to the other treatment modalities. The efficacy of combination therapy was better than monotherapy. In combination therapy, the overall survival time and progression-free survival time of SOF + RT were longer, and the adverse reactions were less. Therefore, SOF + RT may be the best choice for sorafenib combined with local therapy.

To study the expression and significance of GPC3, CD10 and CD34 in hepatocellular carcinoma (HCC), dysplastic nodules (DN), cirrhotic regenerative nodules (CRN), focal nodular hyperplasia (FNH) and hepatocellular adenoma (HA). Immunohistochemical study for GPC3, CD10, CD34 and AFP was performed on 80 cases of HCC (30 cases of well-differentiated HCC and 50 cases of advanced HCC), 30 cases of DN (18 cases of high-grade DN and 12 cases of low-grade DN), 36 cases of CRN, 20 cases of FNH and 20 cases of HA. (1) The positive expression rate of GPC3 was 92% (46/50) in advanced HCC, 66.7% (20/30) in well-differentiated HCC, 2/18 in high-grade DN, and 0 in low-grade DN, CRN, FNH and HA. The expression rate of GPC3 in well-differentiated HCC was lower than that in advanced HCC and higher than that in high-grade DN (P < 0.05). (2) The negative expression rate of CD10 was 78% (39/50) in advanced HCC, 43.3% (13/30) in well-differentiated HCC, 20% (4/20 and 4/20) in both FNH and HA, 2.8% (1/36) in CRN and 0 in both high-grade DN and low-grade DN. The occurrence of CD10-strongly positive cells was 2% (1/50) in advanced HCC, 16.7% (5/30) in well-differentiated HCC, 15/18 in high-grade DN, 11/12 in low-grade DN, 80.6% (29/36) in CRN and 60% (12/20 and 12/20) in both FNH and HA. The positive expression rate of CD10 in well-differentiated HCC was higher than that in advanced HCC and lower than that in high-grade DN, low-grade DN, CRN, FNH and HA (P < 0.05). (3) The positive expression rates of CD34 in advanced HCC and well-differentiated HCC ranged from 25% to 100% [and strongly positive in 76% (38/50) and 70% (21/30), respectively]. The rates in high-grade DN and low-grade DN ranged from 5% to 25% (and weakly positive in 16/18 and 10/12, respectively). In CRN, the rate ranged from 0 to 5% [and weakly positive in 27.8% (10/36)]. In FNH and HA, the positive rates ranged from 25% to 50%. The positive expression rate of CD34 in well-differentiated HCC was significantly higher than that in high-grade DN, low-grade DN, CRN, FNH and HA (P < 0.05). (4) The positive expression rate of AFP was 44% (22/50) in advanced HCC, 20% (6/30) in well-differentiated HCC, no expression in DN, LCN, LCN, FNH and HA. The positive expression rate of AFP in well-differentiated HCC was lower than that in advanced HCC and higher than that in LCN, FNH and HA. The different expression had statistical significance (P < 0.05). GPC3 is a relatively sensitive and specific marker in pathologic diagnosis of HCC. When coupled with immunohistochemical results of CD34, CD10 and AFP, GPC3 is useful in differentiating HCC from DN, LCN, FNH and HA.

Rethinking future development of molecular therapies in hepatocellular carcinoma: A bottom-up approach

Treatment for Hepatocellular Carcinoma in South Asia

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.

Atezolizumab plus bevacizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a cost-effectiveness analysis.

Hepatocellular Carcinoma Radiation Therapy: Review of Evidence and Future Opportunities

Year in review: Liver cancer research in 2022: tumor microenvironment takes the central stage.

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

New Developments in the Treatment of Hepatocellular Carcinoma: The Concept of Adjuvant and Neoadjuvant Chemotherapy