Sorafenib For Advanced Hepatocellular Carcinoma Research Articles

Outcomes of hepatocellular carcinoma patients treated with sorafenib: a meta-analysis of Phase III trials.

Aim: To benchmark overall survival (OS) and time to radiological progression (TTP) of patients enrolled in randomized controlled trials (RCTs) assessing sorafenib in advanced hepatocellular carcinoma using individual participant survival data, and to meta-analyze prognostic factors for OS and TTP. Methods: RCTs were identified through literature search until December 2018. Individual participant survival was reconstructed with an algorithm from published Kaplan-Meier curves. Results: Ten RCTs were included. Median OS was 10.0 months (95% CI: 9.6-10.5), and median TTP was 4.1 months (95% CI: 3.8-4.3). Multivariable analyses showed HCV positivity, absence of macrovascular invasion and extra-hepatic disease as predictors of longer OS. Conclusion: We provided a benchmark for future studies on sorafenib. The present results can be used in the decision making for the early shift to second-line strategy.

Phase 2 HEPANOVA trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma

Phase 2 HEPANOVA trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma

Sorafenib for advanced hepatocellular carcinoma (HCC) in the public health setting in Brazil: a cost-effectiveness analysis

Sorafenib for advanced hepatocellular carcinoma (HCC) in the public health setting in Brazil: a cost-effectiveness analysis

Mutation profiles in circulating tumor DNA (ctDNA) to predict the efficacy of sorafenib treatment in patients with advanced hepatocellular carcinoma (HCC).

e15648 Background: To find biomarkers from blood samples through ctDNA and leucocyte genomic DNA sequencing to predict the efficacy of sorafenib. Methods: CtDNA and leucocyte genomic DNA were extracted from patients with advanced hepatocellular carcinoma for sequencing analysis before and after targeted therapy with sorafenib. Mutation profiles were obtained by deep sequencing of 620 selected genes for further bioinformatics analysis. Gene mutation frequency and status were further integrated with clinical data to dynamically monitor and predict the efficacy of sorafenib. Results: Twelve patients with advanced hepatocellular carcinoma admitted to our hospital from March 2017 to September 2018 were enrolled. A total of 27 blood samples were collected for further analysis. The results showed that there were significant differences in BRD4 and FANCG gene mutation abundance between therapeutic effect group and poor effect group (p = 0.014). The mutations of BRD4, FANCG and TP53 were associated with shorter PFS (BRD4 mutation type vs wild type: 12 weeks vs 32 weeks, p = 0.0011; FANCG mutation type vs wild type: 16 weeks vs 32 weeks, p = 0.0103; TP53 mutation type vs wild type: 8 weeks vs 32 weeks, p = 0.0095). Furthermore, we found another 19 genes (SDHA, OTUD7A, TMPRSS2, NAV3, AKT1, EIF2S2, DICER1, MAP3K1, RAD9A, TCF3, IRS1, PIK3C2G, CTCF, TSHZ2, ITPKB, KDM5C, STAG2, AMER1, CDC27) associated with therapeutic efficacy, and dynamic changes of these 19 genes mutation alleys could predict therapeutic efficacy. Conclusions: Our results showed that mutations in ctDNA could predict the efficacy and prognosis of sorafenib for advanced hepatocellular carcinoma, and that dynamic monitoring of mutation frequency in ctDNA of peripheral blood samples could be an additional method to monitor therapeutic efficacy of sorafenib. The clinical significance of the mutations of BRD4, FANCG, TP53 and another 19 genes we found needs to be confirmed on a larger scale.

Nemesis: Non-inferiority meta-analysis of selective internal radiation therapy with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma: A preliminary analysis.

e15604 Background: No survival benefit has been observed for selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres versus (vs.) sorafenib in patients with advanced hepatocellular carcinoma (HCC). In NEMESIS, we assessed by an individual patient data meta-analysis whether SIRT, either as monotherapy or followed by sorafenib, is non-inferior to sorafenib and compared safety profiles. Here we present preliminary data. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library, up to 6 December 2018, found three randomized trials comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with advanced HCC. The main outcomes were overall survival (OS) and frequency of adverse events (AEs). Survival data were pooled (fixed effect analysis). The primary population for non-inferiority analysis was the per-protocol (PP) population. The non-inferiority margin for the hazard ratio (HR) upper boundary was set at 1.08 as specified in EASL guidelines. Results: The three included trials compared sorafenib to SIRT (SIRveNIB and SARAH) or to SIRT followed by sorafenib (SORAMIC) in 1243 patients. After randomization, 23.3% vs. 7.1% of patients (p < 0.0001) did not receive the allocated intervention, and 542/608 (89.1%) vs. 418/635 (65.8%), (odds ratio [OR] 4.3, 95% CI: 3.2-5.8, p < 0.0001) completed the study without major protocol deviations (PP population), in the SIRT and sorafenib arms, respectively. Baseline characteristics of the PP population did not differ between the two comparison groups. Median OS with SIRT followed or not by sorafenib was non-inferior to sorafenib (HR 0.90, 95% CI 0.78–1.02). Treatment-related AEs grades ≥3 were reported in 109/356 (30.6%) patients who received SIRT and 197/378 (52.1%) patients in the sorafenib arm (SIRveNIB and SARAH only, p = 0.0002). Conclusions: SIRT as initial therapy for advanced HCC is non-inferior to sorafenib in OS, and offers a better safety profile.

Efficacy of on-demand intrahepatic arterial therapy in combination with sorafenib for advanced hepatocellular carcinoma.

PurposeThe purpose of this study was to evaluate the effectiveness and tolerability of “on-demand” combination therapy with sorafenib and hepatic arterial treatments, such as transarterial chemoembolization and hepatic arterial infusion chemotherapy, in patients with hepatocellular carcinoma (HCC).Patients and methodsEighty consecutive patients with advanced HCC, 58 administered sorafenib monotherapy and 22 administered on-demand combination therapy, were retrospectively evaluated.ResultsThe disease control rate was significantly higher in the combination group than in the monotherapy group (86.3% vs 51.7%, p=0.01). Elevated alanine aminotransferase levels were significantly more frequent in the combination group (40.9% vs 12.1%, p=0.01), but it was tolerable. Progression-free survival (180 vs 45 days, p=0.045) and overall survival (983 vs 452 days, p=0.004) were significantly longer in the combination group, as was the duration of sorafenib treatment (367 vs 66 days, p<0.001). Multivariate analysis showed that hepatitis C virus infection, disease control, and combination therapy were positive independent prognostic factors for survival, whereas alpha-fetoprotein >400 ng/mL was negatively prognostic. In patients receiving combination therapy, male sex, hepatitis B virus infection, performance status deterioration, Barcelona clinic liver cancer-B, and major vascular invasion were prognostic of survival.ConclusionOn-demand combination therapy was tolerated and may be a therapeutic option for patients with advanced HCC.

Phase II HEPANOVA trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma.

TPS470 Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC. Methods: Patients (N = 25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg twice daily). TTFields (150 kHz) will be delivered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions. Clinical trial information: NCT03606590.

Hepatocellular carcinoma’s 100 most influential manuscripts: A bibliometric analysis

Aims: A bibliometric analysis identifies the major publications that influence the clinical management of Hepatocellular Carcinoma (HCC). Within this study, the 100 most cited HCC articles are noted and analysed. Methods: The search terminology “Hepatocellular carcinoma” and “HCC” were used to search through the Thomson Reuters Web of Science database. The inclusion criteria consisted of English language full articles. The subject matter, author and institution details, year of publication and journal were recorded for the 100 most cited HCC articles. Citation rate index was calculated by dividing the number of citations by the number of years since publication. Results: The search through the Thomson Reuters Web of Science database identified 39,518 eligible papers. The median (range) citation number was 909 (4419 to 458). The most cited article (produced by Llovet et al) discussed the role of Sorafenib in advanced HCC (4419 citations). Hepatology published the most articles (n=20, 20,533 citations), however the Lancet had the overall highest citation number of 39219, across 9 published articles. The most discussed topic was HCC management (n=31), followed by prognosis (n=18) and aetiology (n=15). Conclusion: This bibliometric analysis has identified the 100 most cited HCC articles. Through integrating new knowledge into clinical practice, this has enabled novel treatment strategies to be utilised for patients with HCC. This study highlights what makes a citable article and may aid in the development for future HCC research themes.

Dynamic contrast enhanced perfusion CT imaging: A diagnostic biomarker tool for survival prediction of tumour response to antiangiogenetic treatment in patients with advanced HCC lesions

PurposeTo investigate whether perfusion-CT (p-CT) imaging could depict the inhibition of tumor neoangiogenesis induced by Sorafenib in advanced hepatocellular carcinoma (HCC), and whether it could be useful in predicting survival during treatment. Materials and methodsNinety-eight p-CT examinations were performed among 29 cirrhotic patients, with advanced HCC, before and every 2 months after Sorafenib administration, on a 256-slice MDCT scanner. Perfusion parameters were considered and statistically compared, at baseline and follow-up, between non-progressor (complete response, stable disease or partial response) and progressor (progressive disease) group. Kaplan-Meier analyses estimated the time-to-survival in overall population, after stratifying patients according to mRECIST. ResultsThe group that responded to Sorafenib showed a significant reduction of values in HCC target lesions after anti-angiogenic therapy (p < 0.01), in comparison with progressor group that demonstrated an increase or no significant variation. When patients were stratified into mRECIST, higher survival rate was observed in the non-progressor group compared to the progressor (48.6% vs 28.6%), and statistically significant correlation (p=0.01) was found between percentage variation of perfusion parameters, from baseline to follow-up, and overall survival rate. ConclusionQuantitative analysis of perfusion parameters, represents prognostic indicators useful in assessment of response to anti-angiogenic therapy, allowing for optimization of individualized treatment.

Abstract 4600: Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma

Abstract Purpose: We evaluated the potential role of Vascular Endothelial Growth Factor-A (VEGFA) amplification and genome-wide copy number variations (CNVs) using circulating cell-free DNA (cfDNA) as predictors of treatment outcome in hepatocellular carcinoma (HCC) patients treated with first-line sorafenib. Methods: Among 184 patients from a prospective biomarker cohort, who had started sorafenib between April 2015 and May 2016, 151 eligible patients were included in the analysis. Plasma cfDNA was extracted from peripheral blood in patients before starting sorafenib or healthy donors. Plasma VEGFA-to-EIF2C1 ratios (the VEGFA ratios) were determined using droplet digital polymerase chain reaction. We applied low depth whole genome sequencing in cfDNA to find CNVs and developed I-score to express genomic instability, which was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; p&amp;lt;0.0001). Patients who had progressive disease with sorafenib as best tumor response had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; p=0.006) and I-scores (3,405 vs.1,024; p=0.0017) than those who achieved disease control. The disease control rate was 52.0% for the cfDNA-high group (above the median) vs. 75.0% for the cfDNA-low group (p=0.003), and 49.3% for the I-score-high group (above the median) vs. 77.6% for the I-score-low group (p=0.0003). The cfDNA-high group also had significantly worse TTP (median, 2.2 vs. 4.1 months; HR=1.71; p=0.002) and OS (median, 4.1 vs. 14.8 months; HR=3.50; p&amp;lt;0.0001) than the cfDNA-low group. Similarly, the I-score-high group had poorer TTP (median, 2.2 vs. 4.1 months; HR=2.09; p&amp;lt;0.0001) and OS (median, 4.6 vs. 14.8 months; HR=3.35; p&amp;lt;0.0001). In the multivariate analyses, cfDNA remained an independent prognostic factor for OS (p&amp;lt;0.0001), and I-score for both TTP (p=0.011) and OS (p=0.010). Although the VEGFA ratio was significantly higher in HCC patients than in healthy controls (2.50 vs. 2.17; p&amp;lt;0.0001), it was not significantly associated with treatment outcomes. Conclusions: Pretreatment cfDNA concentration and genome-wide CNVs in cfDNA are potential biomarkers predicting treatment outcomes in advanced HCC patients receiving first-line sorafenib. Citation Format: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4600.

Efficacy and Safety of Sorafenib in a Racially Diverse Patient Population with Advanced Hepatocellular Carcinoma.

There are few efficacy and toxicity data on sorafenib for patients treated for hepatocellular carcinoma (HCC) who are not Caucasian or Asian. A retrospective analysis was carried out on 67 patients treated with sorafenib for advanced HCC at an urban referral center. Patients were categorized by race, age, sex, status, stage, and dose. Primary outcomes were time to progression (TTP), toxicity, and treatment discontinuation by race. African-Americans and Caucasians had significantly shorter TTP than patients of other races (Hispanic, Asian, and unidentified) [African-Americans: hazard ratio (HR)=5.01, p=0.0068; Caucasians: HR=8.25, p=0.0008). There were no significant differences in time to toxicity (p=0.99). Caucasians had the shortest time to therapy discontinuation (p=0.0298). TTP was shorter for males (HR=3.51, p=0.028), and longer for patients experiencing toxicity (HR=0.47, p=0.046). Among patients treated with sorafenib for advanced HCC, non African-American/non-Caucasian race, female sex, and toxicity were associated with significantly longer time to progression.

Abstract CT084: HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma

Abstract Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC. Trial Design: Patients (N=25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg daily). TTFields (150kHz) will be deilvered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions. Citation Format: Anca-Ligia Grosu, Josif Strouthos, Thomas Brunner, Uri Weinberg. HEPANOVA: A phase II trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT084.

Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma

Background: Upon FDA/EMEA registration for hepatocellular carcinoma (HCC), sorafenib received a broader therapeutic indication than the eligibility criteria of the landmark SHARP trial. This allowed treatment of SHARP non-eligible patients in daily clinical practice.Aim: To assess sorafenib efficacy and safety in SHARP eligible and non-eligible patients, and determine the validity of the current therapeutic indication as described by the FDA/EMEA.Patients and methods: Consecutive patients treated with sorafenib for advanced HCC at two Dutch tertiary referral centers between 2007 and 2016 were analyzed retrospectively. Primary outcome was overall survival (OS). Secondary outcomes were time to progression (TTP), response rate, adverse events and reasons for discontinuation. Outcomes were compared between SHARP eligible and non-eligible patients.Results: One hundred and ninety-three of 257 (75%) patients were SHARP eligible. SHARP eligible patients (9.5 months, 95% CI 7.7–11.3) had a longer median OS than non-eligible patients (5.4 months, 95% CI 3.6–7.1) (log-rank p < .001). SHARP non-eligible patients were more often Child–Pugh B, had higher AST and ALT levels and developed more grade 3–4 liver dysfunction (44 versus 23%, p < .001) during treatment. SHARP ineligibility remained the strongest predictor of OS (HR 1.78, 95% CI 1.32–2.41) and an independent predictor of TTP (HR 1.45, 95% CI 1.05–2.00) in multivariable analysis.Conclusions: Landmark trial outcomes of sorafenib for HCC are reproducible in daily practice, provided that the SHARP eligibility criteria are respected. Based on the findings of this and previous studies, sorafenib usage should be restricted to Child–Pugh A patients.

Exploring the role of oncolytic viruses in hepatobiliary cancers.

The standard of care for early hepatobiliary cancers (HBC) includes surgical resection. Liver transplantations or locoregional therapies are beneficial in early hepatocellular carcinoma (HCC) under certain circumstances. Systemic treatments have some benefit in advanced HBC, though long-term prognosis remains poor. We evaluated the role of oncolytic viruses in the treatment of HBCs through a systematic literature review. The recombinant vaccinia virus JX-594 improved median survival in patients with local/metastatic HCC more strongly at high dose than at low dose (14.1 vs 6.7 months; p=0.08) in a Phase II study. A Phase III study with JX-594 and sorafenib in advanced HCC is ongoing. No survival benefit in HCC was seen with two other recombinant adenoviruses (Ad-TK and DL1520). Several preclinical trials using oncolytic viruses in HBC showed promising results, warranting clinical studies.

P-101 - HEPANOVA: A phase 2 trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma - Trial in progress

P-101 - HEPANOVA: A phase 2 trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma - Trial in progress

Liver computed tomographic perfusion for monitoring the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients.

Sorafenib is the only approved treatment for advanced hepatocellular carcinoma (HCC). However, it is a diagnostic challenge to monitor its early treatment effects on HCC. The purpose of this study is to investigate the effects of sorafenib on HCC with liver computed tomography perfusion (CTP) and investigate its efficacy in assessing the early therapeutic response of sorafenib for advanced HCC. A total of 23 HCC patients were included in this study. Sorafenib was continuously administered orally at a dose of 400 mg twice daily. CTP was performed before and after 2 weeks of sorafenib treatment, and the changes of perfusion parameters were obtained with a 320-detector row CT scanner including hepatic artery flow (HAF), portal vein flow (PVF), and perfusion index. The modified response evaluation criteria in solid tumor (mRECIST) assessment were performed after two and 4 months of treatment. According to the result of mRECIST, three patients (13%) showed partial response, eight patients (34.7%) showed stable disease (SD) and 12 patients (52.2%) showed progressive disease (PD) after 2 months of treatment, whereas 10 patients (43.5%) showed SD and 13 (56.5%) showed PD after 4 months of treatment. The group that responded to sorafenib showed a significantly decreased HAF value after 2 months compared to that of baseline, whereas nonresponder group showed a significant increase in HAF. The patients with PD showed significantly higher HAF compared to that of SD patients. CTP might be applied to evaluate therapeutic effects of sorafenib in advanced HCC, where HAF could potentially serve as imaging biomarkers for monitoring early therapeutic effects after treatment.

Abstract LB-A08: Differential alteration of IL-8 in response to Sorafenib and PI3K/Akt/mTOR inhibitors in liver cancer cells and in liver cancer stem cells

Abstract Liver cancer stem cells (LCSCs) are derived from damaged and transformed Hepatic progenitor cells (HPCs) during precancerous cirrhosis stage. Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways are significantly deregulated during this process. The activation of PI3K/Akt/mTOR pathway in LCSC population is one of the reasons for acquired resistance to Sorafenib in advanced Hepatocellular carcinoma (HCC). Therefore, identifying novel inhibitors against LCSCs is highly essential. We elucidated the bioactivities of 10 different kinase inhibitors acting through PI3K/Akt/mTOR pathway on HCC cells and identified their potential for an inhibitory action on the LCSC population. We compared the LCSC inhibitory bioactivities of the inhibitors to that of DAPT (CSC inhibitor), DNA intercalators and Sorafenib. For this purpose, CD133+/EpCAM+ cells originated from HCC cells were analyzed by flow cytometry and effective inhibitors on LCSCs were further tested for their use in combination with Sorafenib. Treatment of cells with Sorafenib, and DNA intercalators resulted in enrichment of CD133+/EpCAM+ cells and sphere formation. Yet, Rapamycin, LY294002 and DAPT significantly reduced CD133/EpCAM positivity and dramatically decreased the number of LCSC spheres. Combination studies revealed that sequential treatment strategy decreased the ratio of LCSCs as opposed to Sorafenib treatment alone (Table). Additionally, a large panel of genes involved in cancer pathways were analyzed using Nanostring® nCounter® Technology to identify the differentially expressed genes in Rapamycin, Sorafenib, their combination or DAPT treated cells. Genes involved in stemness were down-regulated in cells treated with Rapamycin or DAPT, whereas JAG1 gene was found to be up-regulated in Sorafenib treated cells. Interleukin 8 (IL-8) was down-regulated upon treatment with DAPT, yet up-regulated upon Sorafenib treatment (Table). Following IL-8 inhibition with Reparixin, the ratio of CD133+/EpCAM+ cells and the LCSC sphere size and count decreased significantly, indicating that IL-8 signaling is crucial for the conservation of stemness features of liver cancer cells. In this study we demonstrated that PI3K/Akt/mTOR pathway inhibitors alter hepatic CSC composition and gene expression in favor or to the detriment of cancer stem cell survival. IL-8 signaling can be promising therapeutic target for LCSC. Normalized IL-8 expression in correlation with LCSC ratioLCSC ratio (%)IL-8 expression (nCounter)IL-8 expression (qRT-PCR)Sorafenib25.14.96.6Rapamycin18.50.2-2.4Sorafenib+Rapamycin353.64.4Sorafenib then Rapamycin374.56.4Rapamycin then Sorafenib12.11.91.4DAPT18.3-2.5-4.7DMSO27.5NANA Citation Format: Deniz Cansen Kahraman, Rengul Cetin Atalay. Differential alteration of IL-8 in response to Sorafenib and PI3K/Akt/mTOR inhibitors in liver cancer cells and in liver cancer stem cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A08.

Absence of antitumor effects of metformin in sorafenib-treated patients with hepatocellular carcinoma recurrence after hepatic resection and liver transplantation.

Backgrounds/AimsHepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) and liver transplantation (LT) remains a great concern. We assessed the antitumor effects of metformin in patients treated with sorafenib for HCC recurrence after HR or LT.MethodsThe two clinical retrospective studies involved metformin therapy of 304 HR patients and 74 LT recipients who were treated with sorafenib.ResultsIn the study involving patients who had undergone HR, death occurred in 245 of the 304 patients (80.6%) during a median follow-up of 10.2 months after sorafenib administration. The metformin HR group (group 1; n=40) showed no prognostic difference in progression-free and overall survival rates compared with the all-HR control group (group 3; n=241) and propensity score-matched HR control group (group 4; n=80). In the clinical study of recipients exposed to LT, death occurred in 62 of the 74 patients (83.8%) during a median follow-up of 13.6 months (range: 3–76 months) after sorafenib administration. The metformin LT group (group 5; n=14) showed no prognostic difference in progression-free and overall survival rates compared with the all-LT control group (group 7; n=43) and propensity score-matched LT control group (group 8; n=28).ConclusionsOur clinical studies demonstrated absence of synergistic antitumor effects of metformin. Further high-volume studies are necessary to assess the role of metformin in patients treated with sorafenib for advanced HCC.

132P - Biomarker analysis using circulating tumor DNA in patients treated with sorafenib for advanced hepatocellular carcinoma

132P - Biomarker analysis using circulating tumor DNA in patients treated with sorafenib for advanced hepatocellular carcinoma

Treatment by Transarterial Chemoembolization and Sorafenib for Hepatocellular Carcinoma vs Advanced Hepatocellular Carcinoma in Bangladesh: A Real-life Situation.

ABSTRACTBackgroundAlthough there are thousands of patients with hepatocellular carcinoma (HCC) in Bangladesh, almost there is no nationwide recommendations for therapeutic maneuver for HCC patients. As most of the HCC patients of Bangladesh are diagnosed late, patients with advanced HCC with large and multiple HCC nodules represent the usual presentation of HCC. The study is presented here to assess the effects of a combined therapy of transarterial chemoembolization (TACE) and sorafenib in advanced HCC patients.Materials and methodsA total of 77 patients with advanced HCC were enrolled in this study. All of them had advanced HCC with variable etiologies and clinical conditions. All patients were treated by TACE and also given systemic sorafenib at the same time. The patients were checked 1 and 3 months after therapy commencement.ResultsOut of 77 patients, 18 patients died within 1 month and additional 15 patients died within 3 months after therapy commencement. Thus, there remains 44 surviving patients after 3 months. When different parameters of dead patients and survived patients were compared, no specific parameters dictated the factors about overall survival of more than 3 months.DiscussionThis is the first approach to initiate an invasive and a systemic therapy for treatment of advanced HCC in Bangladesh. Further follow-up of patients and their long-term overall survival may cast some lights about the role of these therapies in Bangladeshi HCC patients.How to cite this articleAl Mahtab, M, Rahim MA, Noor-E-Alam SM, et al. Treatment by Transarterial Chemoembolization and Sorafenib for Hepatocellular Carcinoma vs Advanced Hepatocellular Carcinoma in Bangladesh: A Real-life Situation. Euroasian J Hepato-Gastroenterol 2019;9(2):63–66.