Dose Of Sorafenib Research Articles

Detection of circulating tumor cells (CTC) using a non-EpCAM-based, high-definition, single-cell assay in advanced hepatocellular carcinoma (HCC) for patients enrolled on phase I and II trials of sorafenib plus temsirolimus.

311 Background: Noninvasive biomarkers are needed for diagnosis, prognosis, and molecular profiling of HCC due to scarcity of tumor tissue and heterogeneous tumor biology. CTC are detectable in metastatic HCC using methods which enrich for expression of the cell adhesion molecule, EpCAM. Because a subset of HCC does not express EpCAM, however, non-EpCAM enrichment methods are needed for CTC studies in HCC. Methods: This CTC cohort was derived from patients enrolled on multicenter phase 1 and 2 trials of the combination of sorafenib plus temsirolimus in advanced HCC (NCT01008917, NCT01687673) with approval and funding from the National Comprehensive Cancer Network (NCCN) Oncology Research Program. Eligibility required histologic diagnosis of incurable HCC with no prior systemic therapy. All patients in the cohort were treated at the recommended phase 2 dose of sorafenib 200 mg PO BID and temsirolimus 10 mg IV weekly. Whole blood samples were collected at baseline and on treatment. CTC were enumerated and analyzed cytomorphologically using a high-definition, single cell assay without EpCAM enrichment and blinded to clinical outcomes. Results: The CTC cohort was comprised of 36 patients (phase 1 n = 9, phase 2 n = 27). Characteristics: male 89%; white 64%, Asian/PI 28%, black 6%; HBsAg+ 31%, HCV+ 44%; Child Pugh A 92%, B7 8%; BCLC C 83%; tumor vascular invasion 47%; median AFP 74 ng/mL. Median OS from start of treatment was 392 days (95% CI: 214, 569). CTC ≥ 1/mL were detectable at baseline in 23/36 (64%) overall (95% CI: 47%, 80%), with similar findings in the phase 1 (56%) and phase 2 (67%) subsets. There was no significant relationship between baseline CTC values ≥ 1, 2, or 5/mL and overall survival (OS) on univariate analysis. Analyses of CTC relationship to clinical characteristics and time to progression, changes on treatment, and multivariable analysis for relationship to OS will be presented. Conclusions: CTC were detected in over 60% of patients in this advanced HCC clinical trial cohort using a non-EpCAM, high-definition single cell assay, suggesting future potential for noninvasive molecular profiling of HCC.

Sorafenib treatment in recurrent hepatocellular carcinoma post liver transplantation.

479 Background: Liver transplantation (LT) is a potentially curative treatment for patients (pts) with selective hepatocellular carcinoma (HCC). HCC recurrence post LT is estimated to be 15-20%. Data on systemic therapy post-recurrence is scarce and limited case series suggest that sorafenib (SOR) may have benefit in this population. We reviewed a single center experience with SOR in recurrent HCC post LT. Methods: A retrospective review was conducted on patients with recurrent HCC post LT at University Health Network (UHN) who were treated with SOR. Pt characteristics were collected including age, gender, comorbidities, background liver disease, type of LT, and time to recurrence after LT. Treatment information collected included: initial SOR dose and subsequent adjustments, adverse events (AEs), duration of treatment and survival. Results: Between 2006 and 2016, 24 patients were identified. The average age was 60 years (range: 18-72), most patients were male (20/4), living/cadaveric transplant: 11/13. HCC etiology included hepatitis B (10), alcohol (4), NASH (3), hepatitis C (2), hemochromatosis (2), Budd-Chiari (2) and unknown (1). The average time to recurrence of HCC was 16.08 (range: 1.5-60) months post LT. There was a bimodal time to recurrence with a median of 6 months. SOR starting doses were 200 mg BID in 18 pts, 300 mg BID in 1 and 400 mg BID in 4. 14 pts required dose adjustment due to AEs, mainly relating to fatigue and palmar-plantar syndrome. The median time on treatment was 2.5 (range: 0.25-37) months, 4/24 patients were on treatment > 6 months. The average time to progression on SOR and/or discontinuation due to AEs was 4.30 (+/- 7.2) months. Conclusions: SOR is reasonably tolerated in patients with recurrent HCC post LT, with expected AE profiles. In this small case series, the median time on sorafenib was short and estimated time to progression was shorter than that in non-transplant HCC population. Overall, sorafenib has limited activity in this population, but selected patients may derive extended benefit. Better understanding of responders and investigations of other therapies are needed for this population.

PREDICTORS OF AGGRESSIVE DIFFERENTIATED THYROID CANCER. A REPORT OF A CASE OF PAPILLARY THYROID CANCER

Background. Differentiated thyroid cancer has a favorable prognosis in terms of relapse-free and overall survival. However, some cases of differentiated thyroid cancer (TC) are characterized by aggressive course with distant metastases and/or radioiodine refractoriness. Identification of histological subtypes of papillary thyroid cancer (PTC) and detection of specific mutations may have some prognostic value in the prediction of the disease course and clinical response to treatment. The severity of the disease depends on multiple clinical characteristics, morphological and molecular features of the tumor. Several histological variants of PTC with varying degrees of malignancy have been described so far: from well-differentiated PTC to radioiodine refractory undifferentiated anaplastic carcinoma with a high mitotic index and high probability of relapses. In this article, we present a case of PTC in a 76-year-old patient. The patient found a formation on the neck and complained of memory impairment. Upon examination, the patient was found to have a thyroid tumor with metastases in lungs, brain, and bones. The patient underwent thyroidectomy and started to receive suppressive doses of thyroxine. Stereotactic radiotherapy was performed to treat brain metastases. We observed a regression of small formations and partial response of larger metastatic foci. The patient received no radioiodine therapy due to his poor somatic status and extensive tumor spread. The patient received target therapy with sorafenib (800 mg/day) and bisphosphonates (BFT) for treatment of bone metastases. After the second cycle of target therapy, the dose of sorafenib was reduced by 50 % due to adverse events; during the next 10 month the patient received sorafenib at a dose of 400 mg/day. After the third cycle of target therapy we observed a stabilization of metastatic foci in the lungs and bones. However, during the treatment, the patient developed visceral metastases to the liver and the adrenal gland, a lytic metastasis in the right side of the mandible, and pain syndrome. A course of radiotherapy to the mandible was conducted along with BFT treatment. The patient received adequate analgesia and symptomatic therapy. The survival from the moment of diagnosis was 2 years. Results. We found that in some cases of differentiated TC, the disease has quite aggressive course with a rapid growth of the primary tumor and metastases into the brain and bones. Patients usually seek medical assistance at the advanced stages of the disease, when it is problematic to provide adequate therapy. The use of target therapy should be considered in such cases. There is a need to find new targets for the development of novel drugs for these patients. Conclusion . The most aggressive forms of PTC include diffuse sclerosing, tall cell, and insular variants of PTC. Various genetic abnormalities, such as BRAF mutation, can be detected in this case. The following clinical prognostic factors are used to determine metastatic potential, probability of relapse, and mortality: age under 15 years or over 45 years, male gender, family history of TC, and exposure to ionizing radiation. Thus, in some cases these markers can help to predict the course of TC and to provide adequate and timely treatment.

The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism

Context: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb–drug interaction remains unknown.Objective: This study investigates the herb–drug interaction between triptolide and sorafenib.Materials and methods: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems.Results: The results showed that the Cmax (low dose: 72.38 ± 8.76 versus 49.15 ± 5.46 ng/mL; medium dose: 178.65 ± 21.05 versus 109.31 ± 14.17 ng/mL; high dose: 332.81 ± 29.38 versus 230.86 ± 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 ± 1.16 to 12.17 ± 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 ± 6.37 to 32.4 ± 4.43 μL/min/mg protein in rat liver microsomes.Discussion and conclusions: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver.

ソラフェニブ増量により著明な腫瘍縮小効果を認めた肝細胞癌の一例

症例は81歳男性．肝細胞癌に対して，2007年に肝S7亜区域切除，肝S5の再発に対して2013年4月，12月にRFAを施行．その後肝内再発は認めなかったが，椎骨と肺に多発転移を認めたため，2014年1月よりソラフェニブを800 mg/日で開始した．手足症候群の出現により400 mg/日まで減量したところ，AFPの上昇（59716 ng/ml），肝内再発，転移巣の増大を認めた．その後，ソラフェニブの副作用は軽快傾向にあったため，2015年7月より600 mg/日に増量したところ，転移巣は著明に縮小し，2016年6月にはAFP 16 ng/mlと正常化を認めた．ソラフェニブは副作用を懸念し400 mg/日で開始する場合も多い．しかしながら，本症例のように増量で著明な抗腫瘍効果が得られる症例も存在するため，たとえ減量後であっても忍容性をみながら増量することを考慮すべきである．

The analysis of the long-term outcomes of sorafenib therapy in routine practice in imatinib and sunitinib resistant gastrointestinal stromal tumors (GIST).

Aim of the studywas to analyze the outcome of treatment and factors predicting results of sorafenib therapy in inoperable/metastatic CD117-positive GIST patients after failure on imatinib and sunitinib.Material and methodsWe identified 60 consecutive patients (40 men, 20 women) with advanced inoperable/metastatic GIST after failure on at least imatinib and sunitinib treated in one sarcoma center with sorafenib at initial dose 2 × 400 mg daily in 2007–2015 (in 56 cases it was 3rd line therapy). Median follow-up time was 39 months.ResultsOne year progression-free survival (PFS; calculated from the date of the start of sorafenib to disease progression) rate was 23% and median PFS = 7.7 months. The median overall survival (OS) was 13.5 months calculated from sorafenib start (1-year OS rate = 57%) and 7 years from imatinib start. Three patients (5%) had objective partial responses to therapy, 31 patients (52%) had stabilization of disease > 4 months. Primary tumor mutational status was known in 43 cases (73%), but we have not identified the differences in PFS between tumors carrying different KIT/PDGFRA mutations. The most common adverse events were: diarrhoea, hand and foot syndrome, fatigue, loss of weight and skin reactions; grade 3–5 toxicity occurred in 35% of patients. 23 patients required sorafenib dose reductions due to AEs.ConclusionsWe confirmed that many advanced GIST patients benefit from sorafenib therapy after imatinib/sunitinib failure with OS > 1 year.

Advanced hepatocellular carcinoma: A regional cancer center experience of 48 cases.

Hepatocellular carcinoma (HCC) is a major health burden and the seventh most common cause of cancer-related death in India. Patients with advanced unresectable HCC have a poor prognosis with a reported median survival of only 2-3 months with the best supportive care (BSC). Sorafenib is the only drug that has demonstrated a survival benefit over BSC in advanced HCC. Unfortunately, even though it has been used for a long time, there are very few published data regarding the experience of sorafenib therapy in advanced HCC from India. Patients diagnosed with advanced HCC from January 2012 to July 2017 at our center were reviewed retrospectively. Patients' profile, time to progression, survival, and toxicity of sorafenib therapy were evaluated. Of the 48 advanced patients with HCC, 35 (72.9%) were male. The median age at diagnosis was 52 years. The most common presenting symptom was abdominal pain (77%, n = 37), followed by abdominal distension (37.5%, n = 18), loss of appetite and/or weight (33.3%, n = 16), and jaundice (16.7%, n = 8). Hepatitis B virus infection was documented in 37 patients (77%), whereas 4 patients had hepatitis C virus infection. Patients were treated with standard dose sorafenib (n = 30), BSC alone (n = 14), or transarterial chemoembolization followed by sorafenib (n = 4). Sorafenib therapy was well-tolerated in most cases. The median progression-free survival with upfront sorafenib was 4.3 months. The median overall survival (OS) of the patients who received upfront sorafenib was significantly better than those treated with BSC alone (5.9 vs 3.0 months; log-rank P= 0.00). Sorafenib therapy was well-tolerated and provided about 3 months longer median OS in our patients with advanced HCC than those treated with BSC alone.

Intravoxel incoherent motion MRI for monitoring the therapeutic response of hepatocellular carcinoma to sorafenib treatment in mouse xenograft tumor models.

Background With the introduction of targeted therapies, there has been a growing need for non-invasive imaging methods which accurately evaluate therapeutic effects and overcome the limitations of tumor size-based therapeutic response assessments. Purpose To assess diagnostic values of intra-voxel incoherent motion (IVIM) imaging in evaluating therapeutic effects of sorafenib on hepatocellular carcinoma (HCC) using mouse xenograft model. Material and Methods Twenty-four mice bearing Huh-7 were divided into a control group and two treatment groups received sorafenib doses of 5 mg/kg (5 mg-Tx) or 30 mg/kg (30 mg-Tx). IVIM imaging was performed using 10 b-values (0-900 s/mm2). The apparent diffusion coefficient (ADC), diffusion coefficient ( D), and perfusion fraction ( f) were measured for whole tumors and tumor periphery. Changes between baseline and post-treatment parameters ( Δ ADC, Δ D, and Δ f) were calculated, and these parameters were compared with microvessel density (MVD) and area of tumor cell death. Results The post-treatment f and Δ f for tumor periphery were significantly higher in control group, followed by 5 mg-Tx and 30 mg-Tx ( P < 0.001). MVD showed significant positive correlation with post-treatment f ( r = 0.584, P = 0.003) and negative correlation with D ( r = -0.495, P = 0.014) for tumor periphery, while no parameter showed significant correlation with area of tumor cell death. Conclusion The f is significantly correlated with MVD of HCC, and could potentially be used to evaluate the anti-angiogenic effects of sorafenib.

Pilot Study of Combined Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib with Sorafenib in Pediatric Patients with Relapsed/Refractory FLT3+Ve AML

Background: Crenolanib is a novel type I pan-FLT3 inhibitor, which inhibits both FLT3-ITD, as well as FLT3 tyrosine kinase domain (TKD) activating mutations. Combination of crenolanib (Type I) and sorafenib (Type II) has been shown to have synergistic apoptotic effects in FLT3+ve AML blasts derived from patients (pts) who have relapsed after prior sorafenib treatment. We hypothesized that the combination of crenolanib and sorafenib may provide enhanced FLT3 inhibition by targeting both inactive as well as active FLT3 kinase conformations. We here report the results of a dose finding study of sorafenib given with fixed doses of crenolanib in pediatric pts with FLT3+ve AML.Design: This pilot study was designed to assess the tolerability of escalating doses of sorafenib with full doses of crenolanib (66.7 mg/m2 TID) in pediatric pts with relapsed or refractory FLT3+ve AML. Crenolanib was administered continuously at 66.7 mg/m2 TID starting on d1. Sorafenib was administered continuously starting from d8 at 150 mg/m2/d (dose level 1). The rolling-6 design was used and if no DLTs were seen, sorafenib was escalated to 200 mg/m2/d (dose level 2). Additionally, triple intrathecal therapy with methotrexate, hydrocortisone, and cytarabine was given on d8 and continued weekly in pts with CNS leukemia until CSF was free of blasts.Results: From April 2015 to March 2016, 7 children (median age, 9yrs; range, 5-14yrs) have been enrolled. All pts had progressed after a median of 3 prior AML therapies (range, 1-7). Four pts had progressed after frontline treatment, which included sorafenib maintenance; the other 3 pts had progressed after standard chemotherapy. Two pts had undergone prior allo SCT. Median WBC count prior to therapy was 1.7 x 109/L (range 0.7-7.5 x 109/L) with median blast percentage of 15% (range 0-60%). All 7 pts had a FLT3-ITD (mutant to wild-type FLT3 ratio ranged from 0.048 to 22, with one pt not having any wild type FLT3 allele). At the time of study entry, 2 pts had active CNS leukemia and required additional intrathecal therapy.Crenolanib 66.7 mg/m2 TID was well tolerated with no pt requiring crenolanib dose reduction. Sorafenib was administered to the first 3 pts at 150 mg/m2 QD from d8 onward. As no DLTs were observed at 150 mg/m2 QD dose, sorafenib was dose escalated to 200 mg/m2 QD for the next 4 pts. No DLTs were observed at either of the sorafenib doses. The combination of crenolanib/sorafenib was well tolerated with most AEs being grade 1 and 2 in severity. Rash was frequently seen in pts following the addition of sorafenib and one pt developed grade 2 hand-foot syndrome which resolved within 5d on the same dosing regimen. No grade 4 LFT elevations were seen in any pt.During cycle 1 of therapy, crenolanib/sorafenib combination resulted in clearance of peripheral blood blasts in 5/6 pts and 1 pt without blasts at baseline had resolution of extramedullary neck mass. Reduction of bone marrow blasts was seen in 4/7 pts. By Cheson criteria, one patient achieved a CR (with FLT3 negativity), two had a PR, and one had a marrow response of CRi but with persistent CNS disease. Three pts had NR although 2 had transient benefit from crenolanib on day 8 as determined by BM blast percentage. Peripheral blood and bone marrow blast percentages are summarized in Figure 1 and Table 1, respectively. Median overall survival was 221d (Figure 2) with 2 pts currently still alive.Conclusions: Crenolanib 66.7 mg/m2 TID can be safely combined with sorafenib at 200 mg/m2 QD. Even in pts with prior exposure to sorafenib, this combination showed clinical benefits, represented by rapid reduction of bone marrow or peripheral blasts, and was able to have improved quality of life. Although dual TKI combinations targeting the same receptor have not been tried in AML, such strategies have been shown to have efficacy in other diseases like HER2+ve breast cancer. Pharmacokinetics of crenolanib and sorafenib and FLT3-TKD mutation analysis will be presented. Accrual to this trial continues. [Display omitted] [Display omitted] [Display omitted] DisclosuresInaba:Arog: Research Funding. Eckardt:Arog: Employment, Equity Ownership.

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma

BackgroundSorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child–Pugh A status.MethodsAll patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child–Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients.ResultsThe 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child–Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child–Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively.ConclusionsThere was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia–Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

Resveratrol enhances the efficacy of sorafenib mediated apoptosis in human breast cancer MCF7 cells through ROS, cell cycle inhibition, caspase 3 and PARP cleavage.

Despite advances in diagnosis and treatment options, breast cancer is one of the main causes of cancer related death among women worldwide. Present study is aimed to preliminarily evaluate our hypothesis that the combination of resveratrol (RSV), a natural antioxidant, and lower dose of sorafenib (SF), a multi-kinase inhibitor and a component of ERK1/2 (extracellular signal-regulated kinase 1/2) pathway, would augment apoptosis in human breast cancer MCF7 cells. MCF7 cellexpressions s were treated with RSV, SF and their combination. MTT (3-[4,5-dimethylthiazol-2-yl] -2, 5-diphenyl-tetrazolium bromide) assay, DNA fragmentation assay, Hoechst33342, H2DCFDA (2', 7'-Dichlorodihydrofluorescein diacetate), Rhodamine123 staining, and Western Blot to detect different signaling protein expressions, were conducted to test the hypothesis. Combination of RSV and SF showed higher cytotoxicity on MCF7 cells than their individual treatment. Results from morphology change, Hoechst33342 staining, and DNA fragmentation suggested higher apoptosis data in the combinational treatment. Intracellular ROS (reactive oxygen species) levels, p53 and Bax/Bcl2 expressions, and decrease in mitochondrial membrane potential were also higher in the combinational treatment. Up-regulation of apaf-1, cl. caspase 9, cl. caspase 3 and cl. PARP (poly (ADP-Ribose) polymerase) were also noticed, while the expressions of cyclinD1 and cyclinB1 were decreased in the combinational group. The increase in apoptosis and signaling protein expressions with RSV and SF combinational treatment were increased over time. The combination of RSV and lower dose of SF at 6μM showed enhanced apoptotic activity than SF alone. Therefore, RSV can be considered as a neo-adjuvant to improve SF efficacy in breast cancer treatment.

Paraneoplastic Hypoglycemia in Hepatocellular Carcinoma: A Paucity of Treatments

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer worldwide. Up to one third of patients with HCC can develop paraneoplastic hypoglycemia. Two distinct types have been described: Type A occurs with rapidly growing tumors while Type B results from non-islet cell tumors by overstimulation of insulin receptors via IGF2. The management of paraneoplastic hypoglycemia remains challenging due to variable responses among patients. A 35-year-old Haitian male with a six-month history of advanced HCC-post one dose of sorafenib, presented with intractable nausea/vomiting and severe hypoglycemia despite aggressive supportive management with intravenous glucose infusion. Physical examination revealed a large protruding mass in the epigastrium, cachexia, lower extremity edema and an ECOG performance status of 4. He had no history of alcohol abuse or toxin exposure. Ancillary testing was negative for Hepatitis B, C or other active liver disease. His alpha-fetoprotein was >300,000 ng/mL, while C-peptide, insulin and IGF-I levels were suppressed. An abdominal CT scan revealed a predominant hepatic mass occupying the entire left lobe and caudate lobe of the liver complicated by portal vein thrombosis. The mass measured 21x21 cm in transverse and craniocaudal dimensions and had increased in size as compared to a prior imaging. Our patient's hypoglycemia was refractory to various inpatient therapeutic strategies including administration of glucocorticoids, counter regulatory hormones, and diazoxide. In an attempt to further palliate symptoms, two bland embolizations as well as one chemoembolization of the left hepatic artery were performed without success. Hospice care was recommended based on the patient's advanced stage, however he declined. Multiple palliative approaches were attempted to reduce overall tumor burden that most likely led to his severe hypoglycemia however were not fruitful in decreasing hypoglycemic events. His tumor burden was observed to correlate to the high degree of resistance to available treatment options. Ultimately, the patient succumbed to a cardiac arrhythmia and expired. This case describes a rare paraneoplastic syndrome, which can be seen in HCC, and the challenges associated with its treatment. This unusual cause of HCC associated mortality establishes that effective treatment modalities should be further investigated for paraneoplastic hypoglycemia in HCC.Figure 1Figure 2

Combined sorafenib and yttrium-90 radioembolization for the treatment of advanced hepatocellular carcinoma.

In this pilot study, we assessed the safety and tolerability of combining sorafenib with 90Y radioembolization for the treatment of unresectable hepatocellular carcinoma (hcc). The study, conducted prospectively during 2009-2012, included eligible patients with unresectable hcc and a life expectancy of at least 12 weeks. Each patient received sorafenib (400 mg twice daily) for 6-8 weeks before 90Y treatment. Safety and tolerability were assessed. Of the 40 patients enrolled, 29 completed treatment (combined therapy). In the initial cohort, the most common cause of hcc was hepatitis C (32.5%), and most patients were staged Child A (82.5%). The 29 patients who completed the study had similar baseline characteristics. Grades 1 and 2 toxicities accounted for 77.8% of all adverse events reported. The most common toxicities reported were fatigue (19.0%), alteration in liver function (7.9%), and diarrhea (6.3%). There were 12 grade 3 and 2 grade 4 toxicity events reported. One patient died of liver failure within 30 days after treatment. During the study, the sorafenib dose was reduced in 6 patients (20.7%), and sorafenib had to be interrupted in 4 patients (13.8%) and discontinued in 4 patients (13.8%). The disease control rate was 72.4% per the modified Response Evaluation Criteria in Solid Tumors, and tumour necrosis was observed in 82.8% of patients. Overall survival in patients undergoing combined therapy was 12.4 months. Preliminary results demonstrate the safety and tolerability of combining 90Y radioembolization and sorafenib for advanced hcc. A larger prospective study is needed to determine the extent of the survival benefit.

ALBI Grade Determines Post-progression Survivals after Sorafenib Treatment Failure in Advanced HCC Patients: A Model for Second-Line Trial Selection

Introduction: Sorafenib can improve the overall survival (OS) and progression-free survival (PFS) of advanced hepatocellular carcinoma (HCC). Appropriate criteria for selection patients who can be enrolled in second-line trials are in unmet need. In this study, we aimed to evaluate the post-progression survival (PPS) in patients undergoing sorafenib for advanced HCC based on Albumin-Bilirubin (ALBI) grade, a new model with good performance in predicting OS of HCC. Methods: Consecutive 276 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh A status and BCLC stage C with either portal vein invasion or extrahepatic metastasis. Radiologic evaluation was based on mRECIST criteria, clinical and compliance assessments were performed every two months, and two to four weeks, respectively. Results: During the median follow-up period of 5.6 months (interquartile range [IQR], 3.0-13.5), 220 (79.7%) patients developed progressive disease (PD) and 245 (88.8%) deaths occurred. The mean sorafenib dosage was 613.3mg (standard deviation, 189.7mg) per day; and the medium treatment duration was 64 days (IQR, 50-125). The median PFS, OS, and PPS were 2.1 (IQR, 1.4-5.9), 5.7 (IQR, 3.1-13.6), and 4.0 (IQR, 1.9-9.1) months, respectively. The ALBI grade could independently predict the OS (hazard ratio [HR], 1.505 for grade 2 vs 1; and 4.354 for grade 3 vs 1) but did not have a role in predicting PFS. Independent predictors of PPS included ALBI grade at progression (HR, 1.654 for grade 2 vs 1; and 2.655 for grade 3 vs 1), new extrahepatic lesions (NEH) (HR, 2.026), high alpha-fetoprotein level (HR, 1.801), and early progression within 4 months (HR, 1.591). In the subgroup analysis according to the alpha-fetoprotein level at PD and time to progression interval, better PPS was only presented while NEH(-), ALBI grade 1 in early PD, high AFP group as well as NEH(-), ALBI grade 1-2 in late PD, low AFP group. Conclusion: Liver function and progression pattern are important determinants of survival after sorafenib failure. The presence of NEH is contraindicated for second-line trials as a poor PPS can be expected. Patients with early PD and high AFP level, ALBI grade 1; or patients without early PD or high AFP level, ALBI grade 1 & 2 can be a new inclusion criteria of second-line trials for advanced HCC.

Efficacy of low dose capecitabine and sorafenib in patients with advanced alfa-fetoprotein secreting hepatocellular carcinoma: a 1year experience.

BackgroundThere is no global consensus for the optimal management of HCC. Most of patients at the time of diagnosis are not candidate for potentially curative therapy. The study aimed to evaluate the efficacy of low dose capecitabine combined with sorafenib in subset of Egyptian HCV patients presented with advanced HCC unfit for surgical or locoregional therapies.Methods15 patients with advanced HCC, unfit for surgical or locoregional intervention, with PS <2 recieved Capecitabine 500 mg/day with sorafeneb 200 mg twice daily till normalization of AFP then the treatment was modified to capecitabine 250 mg every other day and sorafenib 400 mg once daily. They were followed every 3 months for size, number of focal masses and AFP. 30 patients were selected as a control group, they received supportive therapy (n = 15) or sorafenib only (n = 15).ResultsAfter 10 months of therapy, 6 patients showed complete response (40 %) with complete recanalization of portal vein (n = 2) and treatment was stopped and the others (n = 4) showed partial portal vein recanalization so, treatment is continued till now. 1 patient (6.7 %) showed recurrence of the disease and died after 1 month, 8 patients showed partial response (53.3 %) and still on treatment. The control groups showed a highly significant reduction in survival when compared to patients who received capecitabine and sorafenib (12.9 ± 2.1, 7.9 ± 0.9, 4.5 ± 1.3 months, p = 0.000).ConclusionsCombined low dose capecitabine and sorafenib proved to be safe with low toxicity profile and deserves further attention as a convenient, outpatient-based chemotherapy in patients with advanced HCC.

Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy.

Effects of sorafenib in hepatocellular carcinoma (HCC) are frequently transient due to tumor-acquired resistance, a phenotype that could be targeted by other molecules to reduce this adaptive response. Because melatonin is known to exert antitumor effects in HCC cells, this study investigated whether and how melatonin reduces resistance to sorafenib. Susceptibility to sorafenib (10nmol/L to 50μmol/L) in the presence of melatonin (1 and 2mmol/L) was assessed in HCC cell lines HepG2, HuH7, and Hep3B. Cell viability was reduced by sorafenib from 1μmol/L in HepG2 or HuH7 cells, and 2.5μmol/L in Hep3B cells. Co-administration of melatonin and sorafenib exhibited a synergistic cytotoxic effect on HepG2 and HuH7 cells, while Hep3B cells displayed susceptibility to doses of sorafenib that had no effect when administrated alone. Co-administration of 2.5μmol/L sorafenib and 1mmol/L melatonin induced apoptosis in Hep3B cells, increasing PARP hydrolysis and BAX expression. We also observed an early colocalization of mitochondria with lysosomes, correlating with the expression of mitophagy markers PINK1 and Parkin and a reduction of mitofusin-2 and mtDNA compared with sorafenib administration alone. Moreover, increased reactive oxygen species production and mitochondrial membrane depolarization were elicited by drug combination, suggesting their contribution to mitophagy induction. Interestingly, Parkin silencing by siRNA to impair mitophagy significantly reduced cell killing, PARP cleavage, and BAX expression. These results demonstrate that the pro-oxidant capacity of melatonin and its impact on mitochondria stability and turnover via mitophagy increase sensitivity to the cytotoxic effect of sorafenib.

Krüppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/β-catenin signaling.

Krüppel-like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell-like features through activation of the Wnt/β-catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell-like features through activation of the Wnt/β-catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC. © 2016 Wiley Periodicals, Inc.

Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study

GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment.

Small-molecule inhibitor sorafenib regulates immunoreactions by inducing survival and differentiation of bone marrow cells.

Sorafenib has been used for the treatment of liver cancer. However, its clinical impact on human immunity system remains poorly known. Our previous study has shown that sorafenib modulates immunosuppressive cell populations in murine liver cancer models. Here, we continue to report that low doses of sorafenib promotes the survival of murine bone marrow cells (BMCs) in a dose-dependent manner by up-regulating the anti-apoptotic protein survivin. Sorafenib induces differentiation of BMCs into suppressive dendritic cells that inhibit autologous T-cell proliferation and stimulate CD4(+) T cells to express increased IL-1β, IL-2, IL-4, IL-10, IFN-γ and TNF-α, and reduced levels of IL-6 and CD25, which indicates that sorafenib-induced dendritic cells represent a distinct cellular subset with unique properties. Taken together, our findings suggest that in addition to its anticancer effects, sorafenib has an immunoregulatory property that is apparent at low doses.

Abstract 409: Immunofluorescent digital slide technology to evaluate correlation between Glypican-3 expression and response to codrituzumab

Abstract Background: Codrituzumab/GC33/RO5137382 is a recombinant humanized monoclonal antibody against Glypican-3 (GPC3) which is highly expressed in HCC cells. As part of phase I clinical trial, GC-002US study, evaluating escalating doses of codrituzumab plus sorafenib in HCC, immunofluorescent staining of GPC3 were applied in addition to GPC3 immunohistochemistry (IHC) with conventional DAB staining. The objectives of this work were to compare GPC3 expression levels by different staining methods and evaluate the correlation between these GPC3 scores and codrituzumab activities. Methods: Biopsies specimens (n = 34) collected at baseline in the phase I trial were evaluated by GPC3-IHC and immunofluorescent quantification digital slide (IQD) methods. GPC3-IHC were conducted using mouse anti-human GPC3 antibody, mouse GC33 (Ventana Medical Systems) as reported previously (Ikeda M. et al., Cancer Sci. 2014: 105; 455-462) and H scores were derived by two pathologists. For IQD, biopsy specimens were stained with same primary antibody, and were incubated with Qdot 655-conjugated secondary antibody. Fluorescent images of whole slides were obtained with the Nano-Zoomer (Hamamatsu Photonics K. K.). The IQD intensity score (immunofluorescent intensity per pixel) and cell score (immunofluorescent intensity per cell) were calculated respectively using MatLab (MathWorks Inc.). Results: There was a statistically significant correlation between GPC3 H scores and IQD scores. Among GPC3 scores, only the IQD cell score was correlated with serum GPC3 C-terminus increase by treatment (p = 0.032), whereas in the patients treated with higher dose of GC33 (≥ 10 mg/kg/week) the cytoplasmic H and the IQD intensity score were also correlated with serum GPC3 C-terminus increase by treatment. Interestingly, increasing cut-off values of IQD cell score levels led to lower HR and longer PFS. Best HR with lowest p value was observed at a cut-off value of 66,183 (HR = 0.24, p = 0.038). Conclusion: This study suggested that higher GPC3 expression on HCC cells quantified by IQD method was superior to other scores to predict codrituzumab activity, though this analysis was conducted only with limited number of subjects assessed. Further assessment and validation in clinical study of codrituzumab would be necessary to make a final conclusion on the clinical application of GPC3 IQD. Citation Format: Takayoshi Tanaka, Yasuo Sugitani, Tokiya Abe, Miho Kawaida, Ken Yamazaki, Akinori Hashiguchi, Michiie Sakamoto, Toshihiko Ohtomo. Immunofluorescent digital slide technology to evaluate correlation between Glypican-3 expression and response to codrituzumab. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 409.