Dataset Information

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

ABSTRACT:

Background

In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments.

Methods

A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii rcts in advanced hcc following sorafenib failure. Baseline characteristics and outcomes of placebo were examined for heterogeneity. Primary outcomes of interest were extracted for results, including overall survival (os), progression-free survival (pfs), objective response rate (orr), grade 3/4 toxicities, and subgroups. An nma was conducted to compare both drugs through the intermediate placebo. Comparisons were expressed as hazard ratios (hrs) for os and pfs, and as risk difference (rd) for orr and toxicities. Subgroup analyses for os and pfs were also performed.

Results

Two rcts were identified (1280 patients) and compared through an indirect network; celestial (cabozantinib vs. placebo) and resorce (regorafenib vs. placebo). Baseline characteristics of patients in both trials were similar. Both trials also had similar placebo outcomes. Cabozantinib, compared with regorafenib, showed similar os [hazard ratio (hr): 1.21; 95% confidence interval (ci): 0.90 to 1.62], pfs (hr: 1.02; 95% ci: 0.78 to 1.34) and orr (-3.0%; 95% ci: -7.6% to 1.7%). Both treatments showed similar toxicities, but there were marginally higher risks of grade 3/4 hand-foot syndrome (5%; 95% ci: 0.1% to 9.8%), diarrhea (4.8%; 95% ci: 1.1% to 8.5%), and anorexia (4.4%; 95% ci: 0.8% to 8.0%) for cabozantinib. Subgroup results for os and pfs were consistent with overall results.

Conclusions

Overall, this nma determined that cabozantinib and regorafenib have similar clinical benefits and toxicities for second-line hcc.

SUBMITTER: Delos Santos S

PROVIDER: S-EPMC7755448 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

Delos Santos S S Udayakumar S S Nguyen A A Ko Y J YJ Berry S S Doherty M M Chan K K W KKW

Current oncology (Toronto, Ont.) 20201201 6

<h4>Background</h4>In patients with advanced hepatocellular carcinoma (hcc) following sorafenib failure, it is unclear which treatment is most efficacious, as treatments in the second-line setting have not been directly compared and no standard therapy exists. This systematic review and network meta-analysis (nma) aimed to compare the clinical benefits and toxicities of these treatments.<h4>Methods</h4>A systematic review of randomized controlled trials (rcts) was conducted to identify phase iii ...[more]

PMID: 33380861

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Project description:ImportanceThe treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials.ObjectiveTo evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy.Data sourcesWe searched various databases for abstracts and full-text articles published from database inception through March 2020.Study selectionWe included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting.Data extraction and synthesisThe reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model.Main outcomes and measuresOutcomes of interest included overall (OS) and progression-free survival (PFS).FindingsFourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others.Conclusions and relevanceThis systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Project description:BackgroundHepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality. Sorafenib used to be the main treatment for unresectable HCC patients. However, regimens based on immune checkpoint inhibitors (ICIs) have attracted attention in recent years because of their reported benefits. This study aimed to evaluate the efficacy and safety of monotherapy and combination therapy of ICIs as first-line treatment for unresectable HCC patients by conducting a systematic review, meta-analysis, and network meta-analysis.MethodsStudies published up to 11st August 2022 were searched from 4 commonly used databases, including PubMed, Web of Science, Embase, and Clinical trials.gov. All eligible clinical trials were included. Data about reported objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were extracted.ResultsOf the 8579 studies retrieved, 24 met the inclusion criteria. In patients with unresectable HCC taking ICIs-based therapy as first-line treatment, the pooled result of median PFS and median OS was 5.76 months (95% CI 4.82-6.69) and 16.35 months (95% CI 15.19-17.51) The ORR and DCR were 25.1% (95% CI 20.8-29.5%) and 75.2% (95% CI 70.3-80.2%) measured by RECIST v1.1 or 40.2% (95% CI 31.7-48.6%) with 75.2% (95% CI 68.3-82.1%) measured by mRECIST v1.1. Compared to sorafenib, ICIs-based therapy significantly prolonged OS. The combination treatment of sintilimab plus IBI305 had the highest ORR, while atezolizumab plus bevacizumab had the highest DCR. The pooled incidence of any grade TRAEs was 82.3% (95% CI 73.9-90.7%), with highest incidence appeared in dysphonia.ConclusionsThis study demonstrated that first-line ICIs-based therapies could provide survival benefits for patients with unresectable HCC, with manageable TRAEs. The potential of combination treatment to become the new treatment trend in clinical practice is promising.

Project description:ObjectiveSeveral new first-line treatments were recently approved for unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compare the efficacy and safety of first-line systemic treatments to provide information for clinical decision making in unresectable HCC.MethodsPubmed, Science Direct, Web of Science, Scopus, Ovid MEDLINE, Embase, Google Scholar, the Cochrane Library, EMbase, CNKI, CBM, VIP, and the Wanfang databases, as well as the Cochrane Central Register of Controlled Trails were searched for randomized clinical trials evaluating the efficacy of first-line chemotherapy, molecular targeted therapy, or immunotherapy for unresectable HCC. Hazard ratios with 95% confidence intervals (CIs) were calculated to explore the effects of various treatment options on overall survival (OS) and progression-free survival (PFS), whereas odd ratios with 95% CIs were used for adverse events (AEs) and serious adverse events (SAEs). A network meta-analysis was performed to synthesize data and for direct and indirect comparisons between treatments. The cumulative ranking curve (SUCRA) and P score were used to rank treatments. The risk of bias across studies was assessed graphically and numerically using the funnel plot and Egger's regression test.ResultsFifteen studies including 9005 patients were analyzed. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, and donafenib had better OS outcomes than sorafenib. Sintilimab plus bevacizumab, atezolizumab plus bevacizumab, lenvatinib, and linifanib had better PFS outcomes than sorafenib. The results of network meta-analysis showed that sintilimab plus bevacizumab was associated with the best OS and PFS. Egger's tests indicated that none of the included studies had obvious publication deviation.ConclusionSintilimab plus bevacizumab showed the best OS and PFS outcomes with no additional AEs or SAEs. Thus, sintilimab plus bevacizumab may be a better first line choice for the treatment of patients with unresectable HCC.Systematic review registrationPROSPEROI [https://www.crd.york.ac.uk/PROSPERO/index.php], identifier CRD42021269734.

Project description:BackgroundIn recent years, there has been rapid development in systemic therapeutic agents for advanced hepatocellular carcinoma. However, most treatment modalities lack head-to-head comparisons, and the distinctions in their efficacy and safety have yet to be elucidated. Consequently, the accurate selection of a treatment regimen poses a significant challenge for clinicians.MethodsThis study incorporated twenty-three randomized controlled trials, encompassing fifteen first-line and eight second-line treatments, and involving a total of 14,703 patients with advanced hepatocellular carcinoma. Results: In the context of first-line treatment, it was observed that the combination of a PD-1 inhibitor with bevacizumab (1/15) significantly extended overall survival in patients with advanced HCC. Furthermore, PD-1 inhibitors combined with TKIs (1/15) and PD-1 inhibitors combined with bevacizumab (2/15) exhibited enhanced efficacy in reducing the risk of progression-free survival events. In second-line therapy, the network meta-analysis revealed that all investigational agents prolonged progression-free survival in patients with advanced hepatocellular carcinoma when compared to placebo. Cabozantinib ranked first (1/7) in this regard. However, this translated into an overall survival benefit only for cabozantinib, regorafenib, ramucirumab, and pembrolizumab, with regorafenib achieving the highest ranking (1/7).ConclusionIn the treatment of advanced HCC, the immune checkpoint inhibitor combined with bevacizumab regimen and the immune checkpoint inhibitor combined with TKI regimen stand out as the two most effective first-line treatment options. It is noteworthy that, for patients with absolute contraindications to VEGF inhibitors, dual immunotherapy is the preferred choice. For second-line treatment, regorafenib and cabozantinib are identified as the two most effective options.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42023440173.

Project description:BackgroundHepatocellular carcinoma (HCC) is an intractable public health threat worldwide, representing the second leading cause of cancer-related mortality, with limited early detection and therapeutic options. Recent findings have revealed that the susceptibility of HCC is closely related to microRNA (miRNA). We performed this systematic review with a network meta-analysis to investigated four single nucleotide polymorphisms (SNPs) that most regularly reported in miRNAs, exploring their involvement in HCC susceptibility and interaction with hepatitis B virus (HBV).MethodsDatabases were reviewed for related studies published up to May 2019 to identify all studies that compared genotypes of miR-146a rs2910164, miR-149 rs2292832, miR-196a2 rs11614913, and miR-499 rs3746444 with no language and date restrictions. A pairwise meta-analysis was performed to estimate pooled odds ratios and 95% confidence intervals incorporating heterogeneity to assess the relationship between four miRNA polymorphisms and HCC. To further clarify the effect of polymorphisms on HCC, a Bayesian network meta-analysis was conducted to combine the effective sizes of direct and indirect comparisons. Calculations were performed by R version 3.6.1 and STATA 14.0. All steps were performed according to PRISMA guidelines.ResultsA total of 20 studies were enrolled in this network meta-analysis, providing 5,337 hepatocellular carcinoma cases and 6,585 controls. All included studies had an acceptable quality. Pairwise meta-analysis demonstrated that miR-196a2 rs11614913 was significantly associated with the susceptibility of HCC, while the other three SNPs were not found to have a significant association. In the analysis of HCC patients under different HBV infection status, only miR-196a2 revealed correlation of threefold risk. The network results showed no significant difference in the distribution of genotype frequencies except for miR-196a2, which appeared to have the highest superiority index when comparing and ranking four SNPs.ConclusionMiR-196a2 rs11614913 was significantly associated with the susceptibility of HCC, especially for HBV- related HCC, and that individuals with TC/CC were more susceptible. No significant association was found in the other three miRNA genes. MiR-196a2 could serve as the best predictor of susceptibility in HCC.

Dataset Information

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

Background

Methods

Results

Conclusions

Publications

A systematic review and network meta-analysis of second-line therapy in hepatocellular carcinoma.

Similar Datasets

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