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1.
Molecular therapies for HCC: Looking outside the box.
Faivre, S, Rimassa, L, Finn, RS
Journal of hepatology. 2020;(2):342-352
Abstract
Over the past decade, sorafenib has been the only systemic agent with proven clinical efficacy for patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib was shown to be non-inferior to sorafenib, while regorafenib, cabozantinib, and ramucirumab were shown to be superior to placebo in patients failing sorafenib. In addition, trials of immune checkpoint inhibitors reported encouraging efficacy signals. However, apart from alpha-fetoprotein, which is used to select patients for ramucirumab, no biomarkers are available to identify patients that may respond to a specific treatment. Different synergisms have been postulated based on the potential interplay between antiangiogenic drugs and immunotherapy, with several clinical trials currently testing this hypothesis. Indeed, encouraging preliminary results of phase I studies of bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab have led to the design of ongoing phase III trials, including both antiangiogenics and immune checkpoint inhibitors in the front-line setting. Other important phase II studies have tested molecular therapies directed against different novel targets, such as transforming growth factor-beta, MET (hepatocyte growth factor receptor), and fibroblast growth factor receptor 4. These studies integrated translational research with the aim of better defining the biological tumour profile and identifying tumour and blood biomarkers that select patients who may really benefit from a specific molecular therapy. Importantly, good safety profiles make these drugs suitable for future combinations. In this review, we discuss the most recent data on novel combination strategies and targets, as well as looking ahead to the future role of molecular therapies in the treatment of patients with advanced HCC.
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2.
Targeted Molecular Therapeutic Options for Hepatocellular Carcinoma.
Sridhar, S, Sharma, I, Sankpal, UT, Ghabach, B, Narra, K, Neerukonda, L, Basha, R
Critical reviews in oncogenesis. 2020;(1):47-55
Abstract
Liver cancer is the 6th leading cause of cancer related deaths in the US even though it ranks 14th in incidence. More men are diagnosed with liver cancer than women, and the number of projected deaths among men (20,020) is almost double that among women (10,140) in the US. Infections like hepatitis and metabolic conditions like obesity are believed to be major risk factors for the onset of liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for 75% of all cases. Chemotherapy has not been effective in treating HCC. Targeted therapies are being used in advanced HCC patients due to a better survival and less side effects when compared to traditional chemotherapy. Therapeutic agents targeting the regulators of growth factor signaling pathways and the mediators of downstream signaling-for example, inhibitors of the tyrosine kinase receptor-are used as targeted molecular therapies. Kinase inhibitors that modulate growth signals, such as sorafenib and lenvatinib, are commonly employed in targeted molecular therapy for HCC patients. This review covers these agents, highlighting modes of action and providing details on clinical trials.
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3.
Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial.
Kudo, M, Okusaka, T, Motomura, K, Ohno, I, Morimoto, M, Seo, S, Wada, Y, Sato, S, Yamashita, T, Furukawa, M, et al
Journal of gastroenterology. 2020;(6):627-639
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Abstract
BACKGROUND The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.
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Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma.
Briggs, A, Daniele, B, Dick, K, Evans, TRJ, Galle, PR, Hubner, RA, Lopez, C, Siebert, U, Tremblay, G
British journal of cancer. 2020;(12):1754-1759
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Abstract
BACKGROUND In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. METHODS Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model. RESULTS Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. CONCLUSIONS Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm. TRIAL REGISTRATION Trial number: NCT01761266 (Submitted January 2, 2013).
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Sorafenib in pediatric hepatocellular carcinoma from a clinician perspective.
Pearson, H, Marshall, LV, Carceller, F
Pediatric hematology and oncology. 2020;(5):412-423
Abstract
Hepatocellular Carcinoma (HCC) is a rare tumor in children and normally carries poor outcomes. The most frequently employed chemotherapy regimen includes cisplatin and doxorubicin (PLADO), but this combination offers limited efficacy. Sorafenib is a multi-tyrosine kinase inhibitor which, following positive studies in adults with HCC, has begun to be introduced in conjunction with PLADO in pediatric oncology with some encouraging results. Based on these findings, the use of sorafenib is become more common in children with unresectable and/or metastatic HCC. The care of patients receiving sorafenib requires appropriate expertise and standardized pediatric guidelines are lacking. An increasing number of children with HCC are expected to receive sorafenib in the years to come. Pediatric oncology clinicians have a key role in identifying side effects early and clinicians caring for children receiving sorafenib need to be familiar with these. This review article provides suitable and practical information on sorafenib for educational development to optimize clinical care and facilitate enhanced patient/parent education. The article addresses specific areas including mechanisms of action, pre-clinical and clinical evidence, dosing and drug administration and toxicities of sorafenib. Clinical research and recommendations for managing sorafenib-related side effects are discussed. Underpinned by research, this article provides pediatric oncology clinicians with the knowledge required to deliver optimal care to children receiving sorafenib.
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Hepatic uptake index in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced magnetic resonance imaging estimates functional liver reserve and predicts post-hepatectomy liver failure.
Donadon, M, Lanza, E, Branciforte, B, Muglia, R, Lisi, C, Pedicini, V, Poretti, D, Famularo, S, Balzarini, L, Torzilli, G
Surgery. 2020;(3):419-425
Abstract
BACKGROUND Recent evidence suggests that gadolinium ethoxybenzyl diethylenetriamine penta acetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance imaging may be used to evaluate liver function. The aim of this study was to assess whether the signal intensity of Gd-EOB-DTPA magnetic resonance imaging may be used to predict functional liver reserve and posthepatectomy liver failure in patients undergoing hepatectomy for liver tumors. METHODS This is an observational retrospective study on 137 preoperative Gd-EOB-DTPA magnetic resonance imaging of patients undergoing hepatectomy between 2015 and 2018. Mean signal intensity of liver (L20) and spleen (S20) were measured on T1-weighted single-breath-hold 3-dimensional fat-saturated gradient echo sequences acquired 20 minutes after Gd-EOB-DTPA administration. The hepatocellular uptake index of liver volume (VL) was calculated with the formula VL([L20/S20] - 1) and was tested with several score systems for liver diseases and to the occurrence of post-hepatectomy liver failure. RESULTS Patients with diseased liver had significantly lower values of hepatic uptake index in comparison with those with normal function. This was found for a Model for End-Stage Liver Disease score ≤9 versus >9 (P = .04), combination of bilirubin and cholinesterases levels score ≤2 versus >2 (P = .02), albumin to bilirubin grades (P = .03), and Humanitas score ≤6 versus >6 (P = .03). Twenty-two patients (16%) developed posthepatectomy liver failure, and 2 (1.4%) died within 90 days. The hepatocellular uptake index was significantly lower in those patients with posthepatectomy liver failure (P < .01). Receiver operating characteristics curve analysis revealed valuable hepatocellular uptake index ability in predicting post-hepatectomy liver failure (area under the curve = 0.84; 95% confidence interval, 0.71-0.92; P < .01), with a cutoff value of 574.33 (98% sensitivity; 83% specificity). CONCLUSION The hepatocellular uptake index hepatocellular uptake index measured on preoperative Gd-EOB-DTPA magnetic resonance imaging identifies patients with diseased liver and predicts posthepatectomy liver failure. This index could be used to discern those patients at higher risk of complications after hepatectomy.
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Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer.
Kumar, S, Fayaz, F, Pottoo, FH, Bajaj, S, Manchanda, S, Bansal, H
Current topics in medicinal chemistry. 2020;(22):1999-2024
Abstract
Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines' profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.
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Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.
Kudo, M, Ueshima, K, Ikeda, M, Torimura, T, Tanabe, N, Aikata, H, Izumi, N, Yamasaki, T, Nojiri, S, Hino, K, et al
Gut. 2020;(8):1492-1501
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Abstract
OBJECTIVE This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE. DESIGN Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination 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 (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing. RESULTS Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities. CONCLUSION TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials. TRIAL REGISTRATION NUMBER NCT01217034.
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BCL9/BCL9L in hepatocellular carcinoma: will it or Wnt it be the next therapeutic target?
Moghe, A, Monga, SP
Hepatology international. 2020;(4):460-462
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Astaxanthin Encapsulated in Biodegradable Calcium Alginate Microspheres for the Treatment of Hepatocellular Carcinoma In Vitro.
Zhang, X, Li, W, Dou, X, Nan, D, He, G
Applied biochemistry and biotechnology. 2020;(2):511-527
Abstract
Astaxanthin (AST) has attracted great interests in the scientific world because of its anti-oxidative, anti-inflammatory properties. And biodegradable materials, like chitosan, have been employed as the AST carrier to protect it from degradation and promote its bioavailability. However, the lack of pH responsiveness of these materials usually could not protect AST from the strong acidic gastric juices. In this study, calcium alginate (CA) microspheres, a pH responsive and biodegradable material, were prepared by a modified double emulsion technology and used as the AST encapsulation agent. Experimental results showed that the microparticles formed had a good degree of roundness, dispersity, encapsulation efficiency, and pH responsiveness. Cellular studies demonstrated that AST encapsulated in CA could inhibit hepatoma cells (HepG2 cell line) but it has relatively small or no impact on control hepatocytes (THLE-2 cell line). Furthermore, investigation of the underlying mechanism indicated that recovery of disorder of glucose metabolism by inhibiting aerobic glycolysis and promoting tricarboxylic acid cycle played an important part in the cell proliferation inhibition of hepatoma cells. As suggested above, AST could be a very promising therapeutic agent of liver cancer in clinical trials.