Safety and effcacy of remimazolam tosilate for sedation during combined spinal-epidural anesthesia for orthopedic procedures: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the efficacy and safety of Remimazolam in the context of combined spinal-epidural anesthesia for sedation during orthopedic surgery. METHODS: This randomized controlled trial enrolled patients scheduled for orthopedic surgery under combined spinal-epidural anesthesia (N = 80), who were randomly allocated to receive either dexmedetomidine (Group-D) or remimazolam (Group-R). The target sedation range aimed for a Ramsay score of 2-5 or a BIS value of 60-80 to evaluate the effectiveness and safety of remimazolam during sedation. RESULTS: The time taken to achieve the desired level of sedation was significantly shorter in the remimazolam group compared to the dexmedetomidine group (3.69 ± 0.75 vs. 9.59 ± 1.03; P < 0.0001). Patients in the remimazolam group exhibited quicker recovery, fewer intraoperative adverse events, more consistent vital signs, and greater satisfaction at various time points throughout the surgery. CONCLUSION: This preliminary study demonstrates that remimazolam tosilate serves as a safe and effective sedative for orthopedic surgery performed under combined spinal-epidural anesthesia, in comparison with dexmedetomidine.

Comparison of trypan blue and Brilliant Blue G for staining of the anterior lens capsule during cataract surgery: short-term results.

PURPOSE: The present study aimed to evaluate the potential corneal endothelial cell toxicity of trypan blue (TB) and Brilliant Blue G (BBG), two dyes used to stain the anterior capsule in cataract surgery. METHODS: We conducted a single-center, prospective, randomized study in which 150 eyes of 117 patients were randomly divided into control (CT), TB, and BBG groups. Preoperative and postoperative (1, 3, and 6 months) values for corrected distance visual acuity (CDVA), corneal endothelial cell count, and central corneal thickness were compared among the three groups. RESULTS: A total of 111 eyes from 88 patients were completely analyzed. The CDVA (logarithm of the minimal angle of resolution) values in the CT, TB, and BBG groups 1 month after surgery were 0.001, 0.023, and 0.019, respectively. The corneal endothelial cell counts 6 months after surgery were 2711 ± 225, 2748 ± 251, and 2680 ± 284 cells/mm2, respectively. The central corneal thicknesses 6 months after surgery were 524.3 ± 35.5, 532.2 ± 36.1, and 531.4 ± 33.0 µm, respectively. There were no significant differences in CDVA, endothelial cell count, or central corneal thickness among the three groups during the follow-up period. CONCLUSIONS: Our findings indicate that neither TB nor BBG was associated with detectable toxicity to corneal endothelial cells during cataract surgery, even when injected directly into the anterior chamber. Additionally, BBG exhibited equivalent staining efficiency to TB.

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition.

Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.

[Efficacy and Safety of A0001 (Brilliant Blue G250) for Internal Limiting Membrane Staining and Peeling: Phase III Investigator-initiated Multicenter Clinical Trial].

PURPOSE: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy. METHODS: Patients (n = 31) requiring ILM peeling during vitrectomy were enrolled in this clinical trial. After injection of A0001 (range: 0.0625 to 0. 125 mg), the staining grade and the peeling ease of the ILM were evaluated in five steps (levels 0 to 4). The safety of A0001 was investigated for 7 days after surgery. RESULTS: From the evaluation of a primary endpoint by the Independent Data Monitoring Committee (IDMC) and a secondary endpoint by each surgeon, A0001 was effective in all cases at three or more levels ( ≥ level 2 was defined as effective) for evaluation of the grade of visualization and operating ease. Adverse events occurring in two or more cases included elevated intraocular pressure, eye pain, eye discharges, and retinal bleeding. One serious adverse event was a case of unclosed macular hole after vitrectomy, but the patient recovered after reoperation. CONCLUSIONS: A0001 was effective and safe for visualization of the ILM during vitrectomy, and there was an improvement in ease of operation.

Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system.

BACKGROUND & AIMS: In the intestines, Toll-like receptor 2 (TLR2) mediates immune responses to pathogens and regulates epithelial barrier function; polymorphisms in TLR2 have been associated with inflammatory bowel disease phenotype. We assessed the effects of TLR2 signaling on the enteric nervous system (ENS) in mice. METHODS: TLR2 distribution and function in the ileal neuromuscular layer of mice were determined by immunofluorescence, cytofluorimetric analysis, immunoprecipitation, and immunoblot analyses. We assessed morphology and function of the ENS in Tlr2(-/-) mice and in mice with wild-type Tlr2 (wild-type mice) depleted of intestinal microbiota, using immunofluorescence, immunoblot, and gastrointestinal motility assays. Levels and signaling of glial cell line-derived neurotrophic factor (GDNF) were determined using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and immunoprecipitation analyses. Colitis was induced by administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid to Tlr2(-/-) mice after termination of GDNF administration. RESULTS: TLR2 was expressed in enteric neurons, glia, and smooth muscle cells of the intestinal wall. Tlr2(-/-) mice had alterations in ENS architecture and neurochemical profile, intestinal dysmotility, abnormal mucosal secretion, reduced levels of GDNF in smooth muscle cells, and impaired signaling via Ret-GFRα1. ENS structural and functional anomalies were completely corrected by administration of GDNF to Tlr2(-/-) mice. Wild-type mice depleted of intestinal microbiota had ENS defects and GDNF deficiency, similar to Tlr2(-/-) mice; these defects were partially restored by administration of a TLR2 agonist. Tlr2(-/-) mice developed more severe colitis than wild-type mice after administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid; colitis was not more severe if Tlr2(-/-) mice were given GDNF before dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid. CONCLUSIONS: In mice, TLR2 signaling regulates intestinal inflammation by controlling ENS structure and neurochemical coding, along with intestinal neuromuscular function. These findings provide information as to how defective TLR2 signaling in the ENS affects inflammatory bowel disease phenotype in humans.

Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation.

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

Chromovitrectomy and the vitreoretinal interface.

It still remains unclear to which extent the presence and the amount of retinal debris seen in internal limiting membrane (ILM) specimens harvested during macular surgery for macular holes or epiretinal membranes are related to the procedure of ILM peeling itself or to modifications of the surgical technique, such as application of vital dyes for visualization of the ILM, or to pathological conditions with epiretinal membrane formation at the vitreoretinal interface. The presence of cellular fragments on the retinal side of the removed ILM appears to be of multifactorial origin, and additional causes besides dye application need to be considered. However, morphological studies with evaluation of vital dyes are still of relevance and provide additional insights into the ultrastructure of the vitreoretinal interface and its interaction with adjuvants used during macular surgery. Chromovitrectomy is an emerging field in vitreoretinal surgery. It is of importance to better understand the tissue-dye interactions, which not only alter the mechanical properties of the tissue being stained, but may also have an impact on the functional result postoperatively.

Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

BACKGROUND: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients. PATIENTS AND METHODS: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid). In the absence of limiting toxicity, dose escalation of 200 mg bid levels was done every 2 weeks. Plasma sorafenib measurement was performed at each visit, allowing a retrospective pharmacodynamic/pharmacokinetic analysis for safety and efficacy. RESULTS: In all, 19 of 30 patients underwent dose escalation over 400 mg bid, and 28 were evaluable for response. The overall disease control rate was 61% (95% confidence interval (CI): 42.6-78.8), including three confirmed responses (12%). Disease control rate and progression-free survival (PFS) were improved in patients with high vs low exposure (80% vs 32%, P=0.02, and 5.25 vs 2.5 months, P=0.005, hazard ratio (HR)=0.28 (95% CI: 0.11-0.73)). In contrast, drug dosing had no effect on PFS. In multivariate analysis, drug exposure was the only factor associated with PFS (HR=0.36 (95% CI: 0.13-0.99)). Diarrhoea and anorexia were correlated with drug dosing, while hypertension and hand-foot skin reaction were correlated with drug exposure. CONCLUSIONS: Although sorafenib had modest efficacy in melanoma, these results suggest a correlation between exposure and efficacy of sorafenib. Therefore, dose optimisation in patients with low exposure at standard doses should be evaluated in validated indications.

Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is an important palliative treatment for unresectable hepatocellular carcinoma (HCC), but TACE-induced ischemic injury can upregulate angiogenic factors and is associated with poor prognosis. The aim of this study was to evaluate the safety and efficacy of concurrent conventional TACE and sorafenib in patients with unresectable HCC. METHODS: The primary objectives of this prospective, single-arm, phase II study were to evaluate safety and time to progression (TTP). Sorafenib was given 3 days after TACE and was administered for up to 24 weeks. Repeated TACE was performed on demand. Tumor response was assessed every 8 weeks. RESULTS: Fifty patients were treated and followed from July 2009 to May 2011. All patients were in Barcelona Clinic Liver Cancer (BCLC) stage B (82%) or C (18%). The median time of follow-up was 14.9 months and a median of 1 TACE session was given (range, 1-4). The median dose intensity of sorafenib was 68.7% (range, 37.3-100) of 800 mg daily. The most common reasons for dose reduction were hand-foot syndrome and thrombocytopenia. Thirty patients completed the study and 17 patients discontinued sorafenib due to disease progression. The overall median TTP was 7.1 months (95% confidence interval (CI), 4.8-7.5 months): 7.3 months in BCLC stage B; 5.0 months in BCLC stage C. The 6-month progression-free survival rate was 52% (95% CI, 37.3-66.1). CONCLUSIONS: Concurrent treatment of unresectable HCC with conventional TACE and sorafenib demonstrates a manageable safety profile and a possibility of promising efficacy.

Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses.

BACKGROUND & AIMS: Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS: Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS: Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS: These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.

Phase II study of sorafenib in patients with relapsed or refractory lymphoma.

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate (ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission (CR), and two achieved partial remission (PR) for an ORR of 13%. Stable disease (SD) and progressive disease (PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival (OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens.

Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.

BACKGROUND: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. FUNDING: Pfizer Inc.

Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO).

BACKGROUND: Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced phase remains poor with current cytotoxic agents (progression-free survival [PFS] time of ∼4 months and overall survival [OS] time of ∼8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial. METHODS: We conducted a stratified phase II trial. The primary endpoint was the progression-free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two-stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874). FINDINGS: Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31-82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy-naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected. INTERPRETATION: Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.

Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis.

BACKGROUND: Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity. METHODS: We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography. RESULTS: For 83 patients (median age, 62 years; range, 21-84 years), median sorafenib 12-hour area under the curve (AUC(0-12)) was 52.8 mg · h/L (range: 11.8-199.6). A total of 51 patients (61%) experienced grade 3-4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC(0-12) preceding grade 3-4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC(0-12) on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time. CONCLUSION: Sorafenib AUC(0-12) decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.

Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical or ablative treatments. The aim of this prospective, single-center, placebo-controlled, randomized, double-blind clinical study was to evaluate the effectiveness of transarterial chemoembolization (TACE) combined with sorafenib as a sequential treatment regimen in delaying time to progression (TTP) of intermediate-stage HCC in patients with chronic hepatitis C virus (HCV) infection. MATERIAL AND METHODS: Between October, 2007 and January, 2011, 80 HCV-infected patients with Barcelona Clinic Liver Cancer stage B HCC underwent the TACE procedure. All had Child-Pugh class A disease. They were randomized 1:1 to receive sorafenib at a dose of 400 mg twice daily or placebo. Endpoints were the TTP and the rates of adverse events and toxicity. RESULTS: Sixty-two of 80 patients (77%), 31 in the sorafenib group and 31 in the control group, completed the study. The median TTP was 9.2 months in the sorafenib group and 4.9 months in the placebo group (hazard ratio, 2.5; 95% confidence interval, 1.66-7.56; p < .001). Metachronous, multicentric HCC progression occurred less frequently in sorafenib-treated patients (p < .05). Adverse reactions to sorafenib caused withdrawal from the study of 9 (22%) patients. CONCLUSION: A conventional TACE procedure followed by sorafenib treatment resulted in a significantly longer TTP in patients with intermediate-stage HCV-related HCC, with no unexpected side effects.

Development and validation of a prediction index for hand-foot skin reaction in cancer patients receiving sorafenib.

BACKGROUND: This study describes a repeated measures prediction index to identify patients at high risk of ≥grade 2 hand-foot skin reaction (HFSR) before each week of sorafenib therapy. METHODS: Data from 451 patients who received a sorafenib (400 mg bid) as part of a clinical trial were reviewed (Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125-134). Generalized estimating equations were used to develop the final risk model. A risk-scoring algorithm (range 0-58) was then derived from the final model coefficients. External validation was then carried out on a new sample of 1145 patients who received sorafenib under an expanded access program. RESULTS: Pretreatment white blood cell count, female gender, good performance status, presence of lung and liver metastases and number of affected organs were predictors for ≥grade 2 HFSR. A nonlinear association between HFSR risk and treatment duration was also identified where risk was maximized at week 5 followed by a gradual decline. Before each week of therapy, patients with risk scores>40 would be considered at high risk for developing ≥grade 2 HFSR. CONCLUSIONS: The application and planned continued refinement of this prediction tool will be an important source of patient-specific risk information for the development of moderate to severe HFSR.

Advanced-stage hepatocellular carcinoma: transarterial chemoembolization versus sorafenib.

PURPOSE: To compare the efficacies of transarterial chemoembolization (TACE) and sorafenib in patients with advanced-stage hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The retrospective analysis of the data was approved by the institutional review board; the requirement to obtain informed consent was waived. Three hundred seventy-two patients with HCC were treated between January 1999 and December 2009. Patients with advanced HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging classification (Child-Pugh class A or B, Eastern Cooperative Oncology Group performance status of 1-2, and/or macrovascular invasion or extrahepatic metastasis) were included in the study (n = 97). Thirty-four patients underwent conventional TACE with doxorubicin plus lipiodol or TACE with drug-eluting beads; 63 patients were treated with sorafenib. RESULTS: The median duration of sorafenib treatment was 4.6 months (95% confidence interval [CI]: 3.2, 6.0 months). The median number of TACE sessions per patient was 3 ± 2. Side effects of TACE and sorafenib were comparable to those reported in the literature. The median time to progression was similar between the two treatment groups (P = .737). The median overall survival was 9.2 months (95% CI: 6.1, 12.3 months) for patients treated with TACE and 7.4 months (95% CI: 5.6, 9.2 months) for those treated with sorafenib (P = .377). Only Child-Pugh class was associated with a better overall survival at uni- and multivariate analysis. CONCLUSION: TACE achieved a promising outcome in select patients with advanced HCC (BCLC stage C).

Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.

Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.

UNLABELLED: A multicenter randomized controlled trial established sorafenib as a standard of care for patients with advanced hepatocellular carcinoma (HCC). Because the study was prematurely interrupted due to survival benefits in the sorafenib arm, we conducted an observational study to adequately assess risks and benefits of this regimen in field practice. Starting in 2008, all clinically compensated patients with advanced HCC and those with an intermediate HCC who were unfit or failed to respond to ablative therapies were consecutively evaluated in six liver centers in Italy, for tolerability as well as radiologic and survival response to 800-mg/d sorafenib therapy. Treatment was down-dosed or interrupted according to drug label. Two hundred ninety-six patients (88% Child-Pugh A, 75% Barcelona Clinic Liver Cancer [BCLC]-C, and 25% BCLC-B) received sorafenib for 3.8 months (95% CI 3.3-4.4). Two hundred sixty-nine (91%) patients experienced at least one adverse event (AE), whereas 161 (54%) had to reduce dosing. Treatment was interrupted in 103 (44%) for disease progression, in 95 (40%) for an AE, and in 38 (16%) for liver deterioration. The median survival was 10.5 months in the overall cohort, 8.4 months in BCLC-C versus 20.6 months in BCLC-B patients (P < 0.0001), and 21.6 months in the 77 patients treated for >70% of the time with a half dose versus 9.6 months in the 219 patients treated for >70% of the time with a full dose. At month 2 of treatment, the overall radiologic response was 8%. Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic spread of the tumor, radiologic response at month 2, and sorafenib dosing were independent predictors of shortened survival. CONCLUSION: Overall, safety, effectiveness, and generalizability of sorafenib therapy in HCC was validated in field practice. The effectiveness of half-dosed sorafenib may have implications for tailored therapy.