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Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis.
Wang, P, Tan, G, Zhu, M, Li, W, Zhai, B, Sun, X
Expert review of gastroenterology & hepatology. 2018;(1):1-8
Abstract
BACKGROUND Sorafenib remains the only standard first-line drug for advanced hepatocellular carcinoma (HCC). Hand-foot skin reaction (HFSR) is a very common side-effect in patients treated with sorafenib, and also affects the treatment schedule and quality of life. However, the association of HFSR and response of HCC to sorafenib remain unclear. METHODS Databases including PubMed, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials were searched up to May 7th, 2017. Review Manager 5.3 software was adopted for performing meta-analyses, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofler software for further assessing outcomes obtained from meta-analyses. RESULTS 1478 articles were reviewed, and 12 cohort studies with 1017 participants were included in the analyses. The pooled hazard ratio (HR) of overall survival is 0.45 (95% confidence interval (CI) 0.36, 0.55; P < 0.00001; I2 = 35%). The pooled HR of time to progression is 0.41 (95% CI 0.28, 0.60; P < 0.00001; I2 = 0%). Patients suffering HFSR had significantly better outcomes from sorafenib therapy than those without HFSR. CONCLUSIONS The results indicate that HFSR is a beneficial indicator for HCC patients receiving sorafenib therapy. However, molecular mechanisms accounting for sorafenib-induced HFSR in HCC patients remain.
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Impact of Viral Status on Survival in Patients Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized Phase III Trials.
Jackson, R, Psarelli, EE, Berhane, S, Khan, H, Johnson, P
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;(6):622-628
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Purpose Following the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib has become the standard of care for patients with advanced unresectable hepatocellular carcinoma, but the relation between survival advantage and disease etiology remains unclear. To address this, we undertook an individual patient data meta-analysis of three large prospective randomized trials in which sorafenib was the control arm. Methods Of a total of 3,256 patients, 1,643 (50%) who received sorafenib were available. The primary end point was overall survival (OS). A Bayesian hierarchical approach for individual patient data meta-analyses was applied using a piecewise exponential model. Results are presented in terms of hazard ratios comparing sorafenib with alternative therapies according to hepatitis C virus (HCV) or hepatitis B virus (HBV) status. Results Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], -0.27; 95% CI, -0.46 to -0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for "other" treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran's Q statistic. Conclusion There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status. There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib. There was no evidence of any improvement in OS attributable to sorafenib for patients positive for HBV and negative for HCV.
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Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials†.
Gyawali, B, Shimokata, T, Ando, M, Honda, K, Ando, Y
Annals of oncology : official journal of the European Society for Medical Oncology. 2017;(2):246-253
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BACKGROUND Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. PATIENTS AND METHODS We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). RESULTS Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0-36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs. CONCLUSIONS This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making.
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Efficacy of sequential therapies with sorafenib-sunitinib versus sunitinib-sorafenib in metastatic renal cell carcinoma: A systematic review and meta-analysis.
Wen, T, Xiao, H, Luo, C, Huang, L, Xiong, M
Oncotarget. 2017;(12):20441-20451
Abstract
The most efficient sequence of targeted agents for metastatic renal cell carcinoma patients has yet to be identified. Whether the sequence of sorafenib and sunitinib really matters is controversial and not answered clearly until now. This meta-analysis aims to estimate the efficacy of receptor tyrosine kinase inhibitors sorafenib-sunitinib and sunitinib-sorafenib for metastatic renal cell carcinoma, on the outcome of first-line progression-free survival, second-line progression-free survival, total progression-free survival and overall survival.We searched PubMed, Embase, Cochrane Library and ClinicalTrails.gov for eligible studies. Data were analyzed using random or fixed effects model depending on the heterogeneity of the eligible studies. Heterogeneity across studies were analyzed using Q and I2 statistics.Of 902 identified studies, ten were qualified in our analysis (N = 1732 patients). Sorafenib-sunitinib yielded no statistically significant benefit in first-line progression-free survival (fixed effects; HR = 0.95; 95%CI 0.75-1.21; p = 0.702), total progression-free survival (random effects; HR = 0.92; 95%CI 0.71-1.19; p = 0.531) and overall survival (fixed effects; HR = 0.89; 95%CI 0.72-1.09; p = 0.257), compared with sunitinib-sorafenib. Second-line progression-free survival was longer for sorafenib-sunitinib than sunitinib-sorafenib (fixed effects; HR = 0.55; 95%CI 0.44-0.68; p = 0.000).Sequential therapies with sorafenib and sunitinib is well tolerated and efficient in mRCC. However, there are no evidence supported that sorafenib-sunitinib has the superiority to sunitinib-sorafenib in sequence. The ideal sequence of targeted agents requires further elucidation.
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Development of sorafenib-related side effects in patients diagnosed with advanced hepatocellular carcinoma treated with sorafenib: a systematic-review and meta-analysis of the impact on survival.
Abdel-Rahman, O, Lamarca, A
Expert review of gastroenterology & hepatology. 2017;(1):75-83
Abstract
Introduction: Clinical markers to predict the benefit from sorafenib in patients diagnosed with hepatocellular carcinoma (HCC) are lacking. A meta-analysis exploring the impact of development of sorafenib-related side effects on survival was conducted. Areas covered: Eligible studies included all clinical studies reporting on the survival/toxicity relationship in sorafenib-treated HCC patients. Data sources included Pub-Med, the Cochrane Controlled Trials Register, and Google scholar. After exclusion of ineligible studies, 16 studies were included in the analysis. Pooled hazard ratio (HR) for overall survival (OS) for patients developing diarrhoea vs. patients who did not was 0.42 (95% confidence interval (CI): 0.30-0.60; p < 0.00001); pooled HR for patients developing hypertension vs. those who did not was 0.46 (95% CI: 0.30-0.70; p = 0.0003); pooled HR for patients developing hand foot skin reaction vs. those who did not was 0.47 (95% CI: 0.35-0.62; p < 0.00001); pooled HR for OS for all types of skin toxicities was 0.51 (95% CI: 0.36-0.72; p = 0.0002); while pooled HR for OS for a combination of selected side effects (hypertension, HFS and diarrhoea) was 0.38 (95% CI: 0.30-0.48; p < 0.00001). No information was available regarding the impact of thyroid dysfunction or proteinuria. Expert commentary: This analysis of data demonstrated that the occurrence of sorafenib-related side effects (such as diarrhoea, hypertension and skin toxicities) is associated with a better OS in sorafenib-treated HCC patients.
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Management of people with intermediate-stage hepatocellular carcinoma: an attempted network meta-analysis.
Roccarina, D, Majumdar, A, Thorburn, D, Davidson, BR, Tsochatzis, E, Gurusamy, KS
The Cochrane database of systematic reviews. 2017;(3):CD011649
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BACKGROUND There is significant uncertainty in the treatment of intermediate-stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi-nodular, Child-Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease. OBJECTIVES To assess the comparative benefits and harms of different interventions used in the treatment of intermediate-stage hepatocellular carcinoma (BCLC stage B) through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma. SELECTION CRITERIA We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate-stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE. MAIN RESULTS Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I2 = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials. AUTHORS' CONCLUSIONS Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).
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Risk of Hypertension With Sorafenib Use in Patients With Cancer: A Meta-Analysis From 20,494 Patients.
Yang, X, Pan, X, Cheng, X, Kuang, Y, Cheng, Y
American journal of therapeutics. 2017;(1):e81-e101
Abstract
Sorafenib is a new multikinase inhibitor; the incidence of hypertension (HTN) with sorafenib has been reported to vary substantially among clinical trials. We searched multiple databases to investigate the risk of sorafenib-induced HTN in patients with cancer. A total of 93 trials involving 20,494 patients were selected for this meta-analysis. The relative risks (RRs) of all-grade and high-grade HTN associated with sorafenib were 3.06 (P < 0.001) and 3.33 (P < 0.001). There are no significantly RRs of all-grade, 0.81 (P = 0.047), and high-grade HTN, 0.64 (P = 0.075), in sorafenib monotherapy versus other multitargeted antiangiogenic tyrosine kinase inhibitors. The incidence of sorafenib-associated all-grade and high-grade HTN was 21.3% (P < 0.001) and 5.9% (P < 0.001), respectively. The patients with renal cell carcinoma (RCC) and thyroid cancer have high incidence (≥20%) of sorafenib-associated all-grade HTN and high incidence (≥5%) of sorafenib-associated high-grade HTN. The trials with median treatment duration ≥ 4, 5, and 7 months were 21.0% (P < 0.001), 25.4% (P < 0.001), and 27.6% (P < 0.001); progression-free survival ≥ 6, 9, and 12 months were 24.5% (P < 0.001), 26.8% (P < 0.001), and 32.8% (P < 0.001); and overall survival ≥ 12, 18, and 24 months were 18.5% (P < 0.001), 22.5% (P < 0.001), and 25.9% (P < 0.001), respectively. There is a significantly high risk of sorafenib-induced HTN. In comparison between sorafenib and other multitargeted antiangiogenic tyrosine kinase inhibitors, RRs had no significance. The patients with RCC and thyroid cancer have significantly higher incidence of HTN. With prolonged treatment duration, progression-free survival, and overall survival, the incidence of all-grade HTN may increase.
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Sorafenib in combination with transarterial chemoembolization for hepatocellular carcinoma: a meta-analysis.
Hu, MD, Jia, LH, Liu, HB, Zhang, KH, Guo, GH
European review for medical and pharmacological sciences. 2016;(1):64-74
Abstract
OBJECTIVE This meta-analysis aimed to analyze the efficacy of sorafenib in combination with transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS Electronic data bases were searched for studies (1) enrolled HCC patients undergoing TACE; (2) with sorafenib therapy and control arm of no sorafenib therapy were included for meta-analysis and meta-regression; (3) studies without control arm were included for data review and (4) had time to progression (TTP) and overall survival (OS) or relative outcome of HCC as the endpoint. Meta-analysis and meta-regression were performed according to Cochrane guidelines. RESULTS Five studies (3 randomized trials, 1 cohort study and 1 prospective non- randomized controlled trial, totally 899 patients) were eligible for meta-analysis. The hazard ratio (HR) for TTP was 0.75 (95% CI: 0.48-1.03, p = 0.003) with significant heterogeneity (I2 = 82.7%) and for OS was 0.76 (95% CI: 0.47-1.05, p = 0.147) with slight heterogeneity (I2 = 47.9%). However, no covariate was found as independent predictor for better treatment efficacy. Hand-foot skin reaction, alopecia, rash/desquamation, diarrhea, hypertension, fatigue, anorexia, nausea and vomiting were common adverse events. CONCLUSIONS TACE combined with sorafenib has potential efficacy for HCC.
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Efficacy and safety of transarterial chemoembolization plus sorafenib for early or intermediate stage hepatocellular carcinoma: A systematic review and meta-analysis of randomized controlled trials.
Zeng, J, Lv, L, Mei, ZC
Clinics and research in hepatology and gastroenterology. 2016;(6):688-697
Abstract
BACKGROUND AND AIM The efficacy and safety of transarterial chemoembolization (TACE) plus sorafenib for patients with hepatocellular carcinoma (HCC) have been explored by many studies, but the results were controversial. Therefore, we performed this meta-analysis of high-quality randomized controlled trials to evaluate the efficacy and safety of TACE plus sorafenib versus TACE monotherapy in the early or intermediate stage HCC. METHODS Multi-databases were systematically searched to identify all eligible literatures. The hazard ratio (HR) or risk ratio (RR) with 95% confidence intervals (95%CIs) for time to progression (TTP), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and the incidence of treatment-related adverse events (AEs) were pooled using a fixed or random effect model in STATA 12.0. RESULTS Four randomized controlled trials, including a total of 887 patients with early or intermediate stage HCC, were included in this meta-analysis. The pooled results showed that TACE plus sorafenib significantly improved TTP (HR=0.77, 95% CI: 0.64-0.92; P=0.005). Nevertheless, the OS (HR=0.97, 95% CI: 0.72-1.29; P=0.828), ORR (RR=1.20, 95% CI: 0.88-1.64; P=0.257) and DCR (RR=1.04, 95% CI: 0.90-1.02; P=0.568) were not improved. The incidence of treatment-related AEs was higher in the TACE plus sorafenib. CONCLUSIONS Evidences from the meta-analysis of high-quality randomized controlled trials indicate that TACE plus sorafenib can significantly improve TTP but not OS, ORR and DCR in early or intermediate stage HCC. In addition, the combination therapy increases the adverse events which usually disturb the treatment progress and should be increased attention.
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Short-term and long-term efficacy of 7 targeted therapies for the treatment of advanced hepatocellular carcinoma: a network meta-analysis: Efficacy of 7 targeted therapies for AHCC.
Niu, M, Hong, D, Ma, TC, Chen, XW, Han, JH, Sun, J, Xu, K
Medicine. 2016;(49):e5591
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BACKGROUND A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare the short-term and long-term efficacies of different targeted drugs in advanced hepatocellular carcinoma (AHCC) treatment using a network meta-analysis approach. METHODS PubMed, Embase, Ovid, EBSCO, and Cochrane central register of controlled trials were searched for randomized controlled trials (RCTs) of different targeted therapies implemented to patients with AHCC. And the retrieval resulted in 7 targeted drugs, namely, sorafenib, ramucirumab, everolimus, brivanib, tivantinib, sunitinib, and sorafenib+erlotinib. Direct and indirect evidence were combined to evaluate stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR), overall response ratio (ORR), overall survival (OS), and surface under the cumulative ranking curve (SUCRA) of patients with AHCC. RESULTS A total of 11 RCTs were incorporated into our analysis, including 6594 patients with AHCC, among which 1619 patients received placebo treatment and 4975 cases had targeted therapies. The results revealed that in comparison with placebo, sorafenib, and ramucirumab displayed better short-term efficacy in terms of PR and ORR, and brivanib was better in ORR. Regarding long-term efficacy, sorafenib and sorafenib+erlotinib treatments exhibited longer OS. The data of cluster analysis showed that ramucirumab or sorafenib+erlotinib presented relatively better short-term efficacy for the treatment of AHCC. CONCLUSION This network meta-analysis shows that ramucirumab and sorafenib+erlotinib may be the better targeted drugs for AHCC patients, and sorafenib+erlotinib achieved a better long-term efficacy.