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Hepatocellular carcinoma tumour volume doubling time: a systematic review and meta-analysis.
Nathani, P, Gopal, P, Rich, N, Yopp, A, Yokoo, T, John, B, Marrero, J, Parikh, N, Singal, AG
Gut. 2021;(2):401-407
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Abstract
BACKGROUND Tumour growth patterns have important implications for surveillance intervals, prognostication and treatment decisions but have not been well described for hepatocellular carcinoma (HCC). The aim of our study was to characterise HCC doubling time and identify correlates for indolent and rapid growth patterns. METHODS We performed a systematic literature review of Medline and EMBASE databases from inception to December 2019 and national meeting abstracts from 2010 to 2018. We identified studies reporting HCC tumour growth or tumour volume doubling time (TVDT), without intervening treatment, and abstracted data to calculate TVDT and correlates of growth patterns (rapid defined as TVDT <3 months and indolent as TVDT >9 months). Pooled TVDT was calculated using a random-effects model. RESULTS We identified 20 studies, including 1374 HCC lesions in 1334 patients. The pooled TVDT was 4.6 months (95% CI 3.9 to 5.3 months I2=94%), with 35% classified as rapid, 27.4% intermediate and 37.6% indolent growth. In subgroup analysis, studies from Asia reported shorter TVDT than studies elsewhere (4.1 vs 5.8 months). The most consistent correlates of rapid tumour growth included hepatitis B aetiology, smaller tumour size (continuous), alpha fetoprotein doubling time and poor tumour differentiation. Studies were limited by small sample sizes, measurement bias and selection bias. CONCLUSION TVDT of HCC is approximately 4-5 months; however, there is heterogeneity in tumour growth patterns, including more aggressive patterns in Asian hepatitis B-predominant populations. Identifying correlates of tumour growth patterns is important to better individualise HCC prognostication and treatment decisions.
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The diagnostic performance of gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced ultrasound in detecting hepatocellular carcinoma: A meta-analysis.
Wang, J, Ye, X, Li, J, He, S
Medicine. 2021;(6):e24602
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Abstract
The purpose of this study was to identify and compare the diagnostic performance of gadolinium-ethoxybenzyl-diethyltriethylenetriacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) in hepatocellular carcinoma (HCC).Two researchers searched PubMed, EMBASE, and Cochrane Library databases from the inception of each database to 10 February 2020, to find comparative studies of Gd-EOB-DTPA-MRI and CEUS in detection of HCC.The study included eight studies (374 patients). MRI is superior to CEUS in diagnostic sensitivity of HCC, P = .03. The diagnostic sensitivity of MRI in lesions with a diameter of less than 30 mm was significantly higher than that of CEUS, P = .04. MRI and CEUS had no significant difference in diagnostic specificity of HCC, P = .95. Summary Receiver Operating Characteristics (SROC) of MRI showed a larger than that of CEUS, but with P > .05.Gd-EOB-DTPA-MRI showed higher sensitivity than CEUS for hepatocellular carcinoma lesions, especially for lesions of less than 30 mm across.
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Sorafenib versus hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a systematic review and meta-analysis.
Zhuang, BW, Li, W, Xie, XH, Hu, HT, Lu, MD, Xie, XY
Japanese journal of clinical oncology. 2019;(9):845-855
Abstract
BACKGROUND The clinical benefits and safety of Sorafenib versus hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) are inconsistent in some studies. This meta-analysis aims to evaluate the effectiveness and safety of Sorafenib versus HAIC for patients with advanced HCC. METHODS An electronic search was performed from PubMed, Embase, the Cochrane Library and Web of Science to identify comparative studies evaluating Sorafenib versus HAIC for HCC. Objective response rate, disease control rate, overall survival, progression-free survival and adverse events were evaluated using meta-analytical techniques. RESULTS Fourteen retrospective studies with 1779 patients (Sorafenib = 773, HAIC = 1006) were included in the meta-analysis. HAIC delivered favorable outcomes in objective response rate (odds ratio 0.13; 95%CI, 0.07-0.24) and disease control rate (odds ratio 0.48; 95%CI 0.26-0.87) assessed by the Response Evaluation Criteria in Solid Tumors. The pooled hazard ratio for overall survival at 0.60 (95% CI 0.39-0.91) and the pooled hazard ratio for progression-free survival at 0.69(95% CI 0.51-0.95), further indicates that HAIC was superior to Sorafenib. There was a higher incidence of adverse events, including hypertension (odds ratio 13.07; 95% CI 2.37-71.67), fatigue (odds ratio 6.72; 95% CI 2.14-21.13), dermatological disorders (odds ratio 15.87; 95% CI 5.58-45.16) and gastrointestinal disorders (odds ratio 3.20; 95% CI 2.02-5.07) in patients receiving Sorafenib than in those receiving HAIC. CONCLUSION HAIC offers a safe and effective alternative to Sorafenib with better tumor response and longer overall survival and progression-free survival, hence HAIC should be recommended for the patients with advanced HCC.
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Which is the best combination of TACE and Sorafenib for advanced hepatocellular carcinoma treatment? A systematic review and network meta-analysis.
Feng, F, Jiang, Q, Jia, H, Sun, H, Chai, Y, Li, X, Rong, G, Zhang, Y, Li, Z
Pharmacological research. 2018;:89-101
Abstract
The aim of this study was to assess the comparative efficacy and safety of combination therapy with transarterial chemoembolization (TACE) and Sorafenib for patients with advanced hepatocellular carcinoma (HCC) through a systematic review and network meta-analysis and identify the best combination of TACE and Sorafenib. We searched databases for publications prior to May 2018. The prespecified efficacy outcomes were the objective response rate, overall survival rate, and time to progression. adverse effects included dermatologic, gastrointestinal, and general disorders. Subgroup analyses, meta-regression, and a network meta-analysis regarding two types of outcomes by different chemotherapy agents in TACE (5-fluorouracil, Adriamycin, Platinum, mitomycin C, hydroxycamptothecin) were included. The study is registered with PROSPERO (CRD42018098541). For efficacy outcomes, subgroups which included 5-fluorouracil and hydroxycamptothecin ranked higher than other chemotherapy agents, while mitomycin C ranked the lowest. For advanced effects, the use of mitomycin C or 5-fluorouracil as the chemotherapy agent ranked higher, while hydroxycamptothecin ranked the lowest. Therefore, we excluded 5-Fu and Mitomycin C in subsequent studies. Additionally, in the evaluation of primary adverse effects by the network meta-analysis, Platinum ranked the highest while hydroxycamptothecin ranked the lowest. Therefore, we excluded Platinum this time. Furthermore, all types of Adriamycin are not same, and some studies included two types of Adriamycin. The network meta-analysis results showed that the TACE (hydroxycamptothecin + pirarubicin) +Sorafenib arm and TACE (hydroxycamptothecin + epirubicin) +Sorafenib arm had significant efficacy differences. In conclusion, for patients with advanced HCC, combination therapy with HCPT plus THP/EPI in TACE and Sorfenib may be used as a first-line treatment.
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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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Fatal adverse events with molecular targeted agents in the treatment of advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials.
Li, X, Wan, J, Wu, Z, Tu, J, Hu, Y, Wu, S, Lou, L
Drug design, development and therapy. 2018;:3043-3049
Abstract
AIMS: Concerns have increased about the risk of fatal adverse events (FAEs) associated with molecular targeted agents (MTAs) in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study is to investigate the overall incidence and risk of FAEs in advanced HCC with administration of MTAs by using a meta-analysis of available clinical trials. MATERIALS AND METHODS Electronic databases were searched for relevant articles before March 2017. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Pooled incidence, Peto ORs and 95% CIs were calculated according to the heterogeneity of selected studies. RESULTS A total of 4,716 HCC participants from 10 randomized controlled trials (RCTs) were finally considered for this meta-analysis. The pooled incidence of death due to MTAs was 2.1% (95% CI 1.6%-2.8%) with a Peto OR of 1.79 (95% CI 1.07-3.01; p=0.027) in comparison with controlled groups. Subgroup analysis according to biological agents showed that brivanib treatment in HCC patients significantly increased the risk of developing FAEs (Peto OR 3.97; 95% CI 1.17-13.51; p=0.028) but not for sorafenib (Peto OR 1.78; 95% CI 0.54-5.89; p=0.34) and other MTAs (Peto OR 1.43; 95% CI 0.75-2.76; p=0.28). Sensitive analysis showed that the pooled results were influenced by removing each single trial. The most common causes of FAEs were hepatic failure (22.2%) and hemorrhage (13.3%), respectively. CONCLUSION Clinicians should be aware of the risks of FAEs during the administration of MTAs in advanced HCC patients, especially for patients with abnormal liver function. However, the use of sorafenib remains justified in its approved indications due to their potential survival benefits and limited toxicities.
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Transcatheter arterial chemoembolization plus sorafenib versus transcatheter arterial chemoembolization alone to treat advanced hepatocellular carcinoma: a meta-analysis.
Cai, R, Song, R, Pang, P, Yan, Y, Liao, Y, Zhou, C, Wang, S, Zhou, X, Wang, H, Zhang, H, et al
BMC cancer. 2017;(1):714
Abstract
BACKGROUND Many studies have combined sorafenib with transcatheter arterial chemoembolization (TACE) to treat patients with advanced hepatocellular carcinoma (HCC), but the results are disputable. Thus, we conducted this meta-analysis to assess the efficacy and safety of the combination treatment in patients with advanced HCC. METHODS Clinical data were collected from a computer search of literature published from January 2009 to June 2016 in PubMed, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang and the China Science and Technology Journal Database (CSTJ). The final analysis included 14 studies and 1670 patients. The primary endpoints were overall survival (OS), the objective response rate (ORR) and the disease control rate (DCR). RESULTS The combination group exhibited significantly more improvement than the group treated with TACE alone in ORR (RR =1.62, 95% confidence interval (CI) = 1.34-1.94, p < 0.00001), DCR (RR = 1.43, 95% CI = 1.26-1.62, p < 0.00001), 0.5-year OS (OR = 2.60, 95% CI = 1.57-4.29, p = 0.0002) and 1-year OS (OR = 1.88, 95% CI =1.39-2.53, p < 0.0001). The incidence of adverse events from combination therapy was increased compared to that from treatment with TACE alone, and the most commonly reported adverse events were fatigue, hand-foot skin reaction and diarrhoea, which were bearable. CONCLUSIONS The meta-analysis indicated that combination therapy is safe and efficient for clinical application.
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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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Incidence and Determinants of Hepatocellular Carcinoma in Autoimmune Hepatitis: A Systematic Review and Meta-analysis.
Tansel, A, Katz, LH, El-Serag, HB, Thrift, AP, Parepally, M, Shakhatreh, MH, Kanwal, F
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017;(8):1207-1217.e4
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BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH. METHODS We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I2 statistic. RESULTS A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I2 = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I2 = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis. CONCLUSIONS Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.
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Arsenic trioxide combined with transarterial chemoembolization for primary liver cancer: A meta-analysis.
Lv, XH, Wang, CH, Xie, Y
Journal of gastroenterology and hepatology. 2017;(9):1540-1547
Abstract
BACKGROUND AND AIM The benefit of combination therapy of arsenic trioxide (As2 O3 ) and transarterial chemoembolization (TACE) is debated. This meta-analysis was conducted to determine whether As2 O3 &TACE therapy achieves better therapeutic effects compared with TACE alone for primary liver cancer. METHODS A systematic search of both English and Chinese databases was conducted for randomized controlled trials. The main outcomes were therapeutic responses, survival rates, improvement in quality of life, and adverse events. All data analyses in this study were carried out using Review Manager software and STATA software. RESULTS Eighteen randomized controlled trials involving 1412 participants were included. The pooled objective response rate was significantly higher in the As2 O3 &TACE group compared with the TACE group (relative risk [RR] 1.36, 95% confidence interval [CI] 1.16-1.58, P < 0.0001), and the pooled clinical benefit rate was also significantly higher (RR 1.18, 95% CI 1.08-1.29, P = 0.0002). A higher pooled result was obtained from the combination group for 1-year survival rate (RR 1.37, 95% CI 1.23-1.53, P < 0.00001). As2 O3 &TACE therapy was not superior to TACE alone for improvement in quality of life (RR 1.15, 95% CI 0.98-1.36, P = 0.09). There was no significant difference in the risk of adverse effects. When a subgroup analysis was performed, both administration methods of As2 O3 (intravenous or arterial) were effective for all evaluating indicators except the improvement in quality of life. CONCLUSIONS Adjuvant As2 O3 therapy combined with TACE achieves better therapeutic effects compared with TACE alone. Both the intravenous administration of As2 O3 and the arterial administration of As2 O3 were good options for clinical practice.