Efficacy and safety of anti-angiogenic drug monotherapy and combination therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials

Background As the development of novel anti-angiogenic drugs and the continuous evolution of guideline recommendations, the efficacy and safety of anti-angiogenic agents in ovarian cancer (OC) remains unclear. Consequently, a meta-analysis was carried out to assess the efficacy and safety of anti-angiogenic drug monotherapy and combination therapy for OC. Methods An exhaustive literature review was performed across multiple databases, including PubMed, Embase, Web of Science, and Cochrane, encompassing all relevant randomized controlled trials (RCTs) up until 6 April 2024. The evaluation of efficacy outcomes incorporated progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Safety was assessed through the occurrence of any grade adverse events (AEs) and grade ≥3 AEs. Synthesis of the data involved the calculation of hazard ratios (HRs), relative risks (RRs), and their corresponding 95% confidence intervals (CIs) and prediction intervals (PIs). Trial sequential analysis was executed employing TSA v0.9.5.10 Beta software, STATA 12.0, and R software 4.3.1. Results In this meta-analysis, 35 RCTs were included, encompassing 16,199 subjects in total. The overall analysis indicated that anti-angiogenic drug combination therapy significantly improved PFS (HR [95% CI] = 0.678 [0.606–0.759], 95% PI: 0.415–1.108), OS (HR [95% CI] = 0.917 [0.870–0.966], 95% PI: 0.851–0.984), and ORR (RR [95% CI] = 1.441 [1.287–1.614], 95% PI: 1.032–2.014), but also increased the incidence of grade ≥3 AEs (RR [95% CI] = 1.137 [1.099–1.177], 95% PI: 1.011–1.252). The analysis did not corroborate any benefit of anti-angiogenic monotherapy over placebo concerning PFS (HR [95% CI] = 0.956 [0.709–1.288], 95% PI: 0.345–2.645) and OS (HR [95% CI] = 1.039 [0.921–1.173], 95% PI: 0.824–1.331). However, it was observed that monotherapy with anti-angiogenic drugs did increase the incidence of any grade AEs (RR [95% CI] = 1.072 [1.036–1.109], 95% PI: 0.709–1.592). Conclusion Our study confirmed the PFS, OS, and ORR benefits of anti-angiogenic drug combination therapy for OC patients. The efficacy results of anti-angiogenic monotherapy necessitates further evaluation as more RCTs become available. Clinicians should be vigilant of AEs when administering anti-angiogenic agents in a clinical setting.


Introduction
Ovarian cancer (OC) stands as the primary cause of death related to gynecologic cancer and the fifth most prevalent malignancy, thereby posing a substantial global health risk to women (Siegel et al., 2021).The difficulty in early-stage detection of OC often leads to diagnoses at advanced stages, contributing to a reduced 5-year relative survival rate (Wang et al., 2021).The current standard of care for newly diagnosed patients typically encompasses cytoreductive surgery and platinum-based systemic chemotherapy, with the optional inclusion of bevacizumab.Even with optimal treatment leading to complete remission, about 70% of patients experience a recurrence within 5 years (Hope et al., 2010;McGee et al., 2017).Notably, recurrence rates are nearly 25% for those in early stages and exceed 80% in advanced stages (Garzon et al., 2020).Despite the availability of multiple active therapies for recurrent OC, such as targeted therapy (e.g., poly ADP-ribose polymerase [PARP] inhibitors), chemotherapy, and immunotherapy, the median survival post-recurrence remains less than 3 years, underscoring the critical need to explore new therapeutic options for this patient group (Richardson et al., 2018).
New therapeutic agents, particularly those inhibiting angiogenesis, have shown considerable potential for the treatment of OC.Aberrant angiogenesis, a defining characteristic of solid tumors, is instrumental in tumor advancement (Jászai et al., 2019).By interfering with the formation of blood vessels, anti-angiogenic medications impede the nutrient supply to tumor cells, both by causing damage to the established tumor vasculature and by blocking the creation of new blood vessels (Abdalla et al., 2018).Additionally, these treatments may induce normalization of the tumor vasculature, reversing tumor microenvironment hypoxia, reducing the tumor's aggressive nature, and augmenting the effectiveness of traditional therapies (Teleanu et al., 2019).The efficacy of angiogenesis inhibitors results from intricate interactions among various pathways, including numerous angiogenic factors like angiopoietin, vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR) (Saman et al., 2020).Recently, a variety of anti-VEGF strategies, including monoclonal antibodies against VEGF (for instance, bevacizumab) and VEGFR inhibitors (such as cediranib, pazopanib, sorafenib, and apatinib), have undergone evaluation in OC patients (Monk et al., 2016a).The AURELIA trial, a phase III randomized trial, revealed that OC patients experienced a notable extension in progression-free survival (PFS) when treated with a regimen of bevacizumab in combination with chemotherapy versus chemotherapy alone.The trial also recorded an enhancement in the objective response rate (ORR) by 15.5% over chemotherapy exclusively.Nonetheless, the addition of bevacizumab to chemotherapy did not yield a statistically significant increase in overall survival (OS) (Pujade-Lauraine et al., 2014).
In the comparison of combined therapy involving angiogenesis inhibitors and standard chemotherapy versus conventional chemotherapy alone, a number of randomized controlled trials (RCTs) have illustrated an enhancement in PFS.Nevertheless, debates persist regarding the OS advantage and the safety profile of these combined treatments (Chekerov et al., 2018;Ray-Coquard et al., 2020;Pignata et al., 2021).Prior meta-analyses have explored the efficacy and toxicity of anti-angiogenic drugs in different subtypes of OC (Yi et al., 2017;Helali et al., 2022;Zhang et al., 2022).However, there is a lack of a comprehensive meta-analysis to evaluate the effects of monotherapy or combination therapy with anti-angiogenic drugs on OC.Moreover, multiple RCTs have published the latest relevant clinical results in recent years (Liu et al., 2022;Roque et al., 2022;Ferron et al., 2023;Nicum et al., 2024).Therefore, we conducted a meta-analysis to systematically assess the efficacy and safety of anti-angiogenic drug monotherapy or combined with chemotherapy or PARP inhibitors in the treatment of OC.

Study design
The methodology and reporting of our study were aligned with the guidelines delineated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Page et al., 2021).Furthermore, our study protocol was registered within the PROSPERO database (registration number: CRD42024534864).Given the nature of this research as a meta-analysis synthesizing findings from existing literature, it does not necessitate ethical approval and informed consent, as it neither engages with ethics nor patient privacy.

Study selection
Eligibility for study selection was determined by the following criteria: 1) RCTs; 2) the participants are adult women (aged 18 and above) diagnosed with OC at any stage through histological examination; 3) intervention: monotherapy with anti-angiogenic medication or its combination with chemotherapy or PARP inhibitors; 4) comparison: treatment with placebo alone or chemotherapy (alone or plus placebo) or PARP inhibitors (alone or plus placebo); 5) outcomes: PFS, OS, ORR, adverse events (AEs) of any grade, or grade ≥3 AEs.Studies were excluded based on the following: 1) retrospective studies and non-interventional, noncomparative or single-arm trials; 2) studies lacking pertinent outcomes or presenting duplicated data; 3) trial design involving both the intervention and control groups receiving anti-angiogenic drugs; 4) literature reviews, case reports, conference abstracts, commentaries, and study protocols.

Data extraction and quality assessment
Two independent reviewers conducted the study screening, selection, exclusion, and extraction of data.From each RCT, we collated details such as the name of the lead author, year of publication, trial name and phase, patient condition, variety of anti-angiogenic medication used, number of participants and their median age, the doses and cycles of drugs used in the antiangiogenic agent treatment group and the control group, duration of follow-up, and the outcomes in meta-analysis.PFS and OS were designated as the primary endpoints for this meta-analysis, with ORR, AEs of any grade, and grade ≥3 AEs serving as secondary endpoints.When encountering multiple reports from a single trial, preference was given to the most updated or complete report offering the necessary details.If PFS or OS outcomes were not available directly, the Engauge Digitizer Version 10.8 tool (available at http://markummitchell.github.io/engauge-digitizer/)and Tierney et al.'s proposed methodology (Tierney et al., 2007) were employed to derive data from Kaplan-Meier curves (Xie et al., 2022).
The quality of the RCTs was evaluated utilizing the modified Jadad scale (Jadad et al., 1996), which includes criteria such as the process of randomization, concealment of randomization, implementation of double-blinding, and the tracking of withdrawals and dropouts.Trials were categorized based on their quality with scores ranging from 0 to 3 indicating low quality, while scores from 4 to 7 signified high-quality research.

Statistical analysis
Statistical analyses were carried out using R software Version 4.3.1 and STATA Version 12.0.We calculated the combined hazard ratios (HRs) along with their 95% confidence intervals (CIs) for both PFS and OS.Dichotomous data outcomes were synthesized by computing relative risks (RRs) and delineating these with 95% CIs.We employed I 2 statistics, Cochran's Q test, and the 95% prediction interval (PI) to assess heterogeneity across studies (Bowden et al., 2011;IntHout et al., 2016).Findings with I 2 exceeding 50% or a p-value less than 0.10 were deemed to show significant heterogeneity, prompting the use of a random-effects model; if not, we used the fixed-effects model (Higgins et al., 2002).We performed subgroup analysis considering OC subtypes or the types of anti-angiogenic agents.To identify potential sources of heterogeneity, we conducted a sensitivity analysis.Furthermore, the trim-and-fill method was employed to detect and adjust for any publication bias (Duval et al., 2000).A two-sided p < 0.05 was considered statistically significant.

Trial sequential analysis
We conducted a trial sequential analysis (TSA) to determine whether the compiled data met the required information size (RIS) for a conclusive finding (Wetterslev et al., 2017).This methodological approach, applied to dichotomous outcomes, utilized TSA software v0.9.5.10 Beta (accessible at www.ctu.dk/tsa).The RIS was calculated, and O'Brien-Fleming α-spending boundaries were established, based on a 5% type I error and a 20% type II error, both set for two-side tests.We engaged STATA Version 12.0, employing the metacumbounds and rsource function, and R software Version 4.3.1, using the foreign and ldbounds packages, to execute TSA on the PFS and OS data, adopting the a priori information size (APIS) approach.The crossing of the cumulative Z-curve over the trial sequential monitoring boundary or the RIS (or APIS) threshold was interpreted as an indication that no additional trials are necessary, and the evidence could be considered conclusive.

Study characteristics and quality assessment
Table 1 provided a detailed overview of the characteristics of the RCTs and the participants that were incorporated into the study.This research encompassed a total of 35 RCTs, which included 15 phase 2 trials and 20 phase 3 trials, all of which were published in English between the years 2011 and 2024.The study population consisted of 8,839 OC patients who were assigned to the antiangiogenic agent treatment group, while 7,360 patients were administered either a placebo alone or underwent drug therapy that did not involve anti-angiogenic agents.The anti-angiogenic drugs utilized were categorized into VEGF inhibitors (specifically bevacizumab), VEGFR inhibitors (which included pazopanib, cediranib, apatinib, sorafenib, and nintedanib), and angiopoietin inhibitors (solely trebananib).The design of anti-angiogenic therapy was bifurcated into monotherapy with anti-angiogenic drugs and combination therapy with chemotherapy or PARP inhibitors.The corresponding control design was either placebo alone, chemotherapy (alone or plus placebo), or PARP inhibitors only.Notably, the only PARP inhibitor used in the trials was olaparib.Out of the 35 RCTs, 31 were assessed as high quality, whereas 4 were deemed low quality.A notable methodological limitation observed was the lack of double-blinding in the trial design among multiple RCTs (Supplementary Files S2).

Trial sequential analysis results
In the execution of TSA for both PFS and OS, the analysis necessitated an APIS of 1,990.It was noted that in the monotherapy analysis with anti-angiogenic drugs, only the cumulative Z-curve for OS and any grade AEs breached the RIS threshold, albeit without breaching the trial sequential monitoring boundary.Theses results indicated the possibility of deriving a relatively solid conclusion.However, the cumulative Z-curve for PFS and grade ≥3 AEs in the same monotherapy analysis neither crossed the trial sequential monitoring boundary nor the RIS threshold, implying that the results are inconclusive and may include false positives (Figure 4).In the scenario of combination therapy with antiangiogenic drugs, every cumulative Z-curve successfully crossed either the trial sequential monitoring boundary or the RIS threshold, suggesting that additional research is not necessary for a conclusive result (Figure 5).

Sensitivity analysis and publication bias
We performed sensitivity analyses and publication bias tests on the combined results that included more than 10 studies.The sensitivity analysis entailed the computation of pooled HRs or RRs along with their respective 95% CIs, excluding individual studies to ascertain if a single study significantly influenced the combined results.The sensitivity analysis demonstrated that the exclusion of any single study did not significantly impact the quantitative findings, which implies that the combined results from the anti-angiogenic drug combination therapy are both robust and dependable (Supplementary Figure S15).We also conducted a trim-and-fill analysis, yielding funnel plots with imputed studies for the outcomes of ORR, any grade AEs, and grade ≥3 AEs, indicating the potential for publication bias (Supplementary Figure S16).However, the trim-and-fill analysis correction for possible publication bias did not change the results for ORR, AEs of any grade, and grade ≥3 AEs, suggesting that the presence of publication bias did not significantly affect the final results.

Discussion
The progression of OC and the standard physiological processes of the ovary are both substantially reliant on angiogenesis.The growth and advancement of malignancies necessitate angiogenesis, as tumors cannot exceed 1-2 mm in size without adequate neovascularization.Consequently, anti-angiogenic drugs have been incorporated into OC treatment regimens.The VEGF pathway is the most extensively studied in the process of neovascularization.VEGF initiates the formation of new blood vessels, which is then sustained by platelet-derived growth factor, fibroblast growth factor, and angiopoietin- 1 and -2 (Fernando et al., 2008;Timke et al., 2008;Ionescu et al., 2011).Overexpression of VEGF is associated with the tumor's prognosis and stage (Nusrat et al., 2016).A number of angiogenesis inhibitors targeting this pathway, including bevacizumab, cediranib, sorafenib, pazopanib, aflibercept, nintedanib, trebananib, and sunitinib, are currently under investigation (Singh et al., 2020).This study conducted a metaanalysis of previous RCTs and concluded that compared to drug therapy without anti-angiogenic agents, combination therapy with anti-angiogenic drugs significantly improved PFS and OS, while also elevating the ORR.Further subgroup analysis revealed that combination therapy with VEGF or VEGFR inhibitors can bring benefits in terms of PFS and OS, as well as an improvement in ORR.Bevacizumab is the main VEGF inhibitor of interest in the trials included in this study.This agent, a humanized monoclonal antibody targeting VEGF, received approval in 2014 as the treatment for platinum-resistant OC, to be used in conjunction with chemotherapy (Monk et al., 2016a).Our findings revealed that bevacizumab in combination with chemotherapy not only significantly improved PFS and OS but also increased ORR compared with chemotherapy alone or plus placebo in patients with OC.Bevacizumab achieves its therapeutic effect by preventing VEGF-A from engaging with VEGFR, resulting in the destruction of established vessels, interference with new vessel formation, and the reduction of intratumoral pressure (Reinthaller, 2016).Research indicated that inhibiting VEGF signaling not only diminishes tumor vascularization but also aids in the morphological and functional normalization of the remaining vessels (Mei et al., 2023).In addition, trebananib stands out as the sole angiopoietin inhibitor in our comprehensive analysis.This peptide, which obstructs the action of angiopoietin-1 and angiopoietin-2-key players in angiogenesis-acts by preventing ANGPT from interacting with its receptor, Tie2 (Mullen et al., 2019).Utilizing photoacoustic tomography, one study observed notable changes in tumor vascularization following trebananib treatment, including significant vessel regression and a decrease in vessel density.Notably, while trebananib therapy did not halt angiogenesis entirely, it encouraged the formation of more stable and less permeable residual vessels (Bohndiek et al., 2015).The TRINOVA-1 trial, assessing patients with recurrent OC less than 12 months after previous platinum-based therapy, allocated participants to either a combination of weekly paclitaxel and trebananib or weekly paclitaxel with placebo.The trebananib cohort experienced prolonged PFS (HR = 0.66, p < 0.001) (Monk et al., 2016b).Our analysis confirmed the benefit of trebananib combined with chemotherapy in improving PFS.Regrettably, this study did not demonstrate any significant improvement in OS and ORR when comparing trebananib plus chemotherapy to placebo plus chemotherapy.
Currently, VEGFR inhibitors attracting substantial clinical attention include cediranib, nintedanib, and pazopanib.Cediranib, an orally administered tyrosine kinase inhibitor (TKI), acts on VEGFR-1, -2, and -3, and c-kit.Preclinical OC models have demonstrated that cediranib therapy leads to a significant reduction in tumor vascular density and vessel regression (Ruscito et al., 2016).When combined with standard chemotherapy as a maintenance therapy, cediranib has demonstrated an extension in PFS and OS compared to chemotherapy alone (Mahner et al., 2015).When paired with the PARP inhibitor olaparib in patients with platinum-sensitive relapse OC, cediranib has exhibited a remarkable 80% response rate and an increase in PFS from 9 to 17.7 months (Liu et al., 2014).However, our combined analysis did not corroborate that cediranib combination therapy could enhance OS compared to treatments devoid of cediranib.Our research did affirm the benefit of cediranib combination therapy in extending PFS.Notably, the cediranib and olaparib combination therapy demonstrated a higher ORR compared to olaparib monotherapy in our study.Additional RCTs are needed to further probe the effectiveness of pairing anti-angiogenic drugs with PARP inhibitors in OC treatment.Nintedanib, a multi-targeted antiangiogenic agent available orally, has been shown through dynamic magnetic resonance imaging assessments to significantly reduce blood flow in approximately 55% of OC patients.It also fosters vascular normalization and tumor regression in pre-clinical models (Khalique et al., 2017).Nintedanib, when combined with carboplatin and paclitaxel, has been proven to improve PFS, although it has no effect on OS (Ray-Coquard et al., 2020).Pazopanib, an oral multi-target TKI, inhibits platelet-derived growth factor receptors (PDGFR) alpha/beta, VEGFR, c-Kit, and fibroblast growth factor receptor (FGFR)-1 and −3.In mouse orthotopic OC models, pazopanib treatment significantly curtailed tumor microvessel density and pericyte coverage (Merritt et al., 2010).
While not yet approved for OC, numerous phase 2 and 3 clinical trials have explored the potential role of pazopanib in OC therapy (Davidson et al., 2014;du Bois et al., 2012;Plummer et al., 2013).Our research indicated that the combination of nintedanib and chemotherapy can improve PFS compared with chemotherapy alone or plus placebo.The combination of pazopanib and chemotherapy has been shown to provide higher ORR, which aligns with a previous meta-analysis (Zhang et al., 2023).
In addition to examining the impacts of various VEGF, VEGFR, and angiopoietin inhibitors on OC by classifying specific antiangiogenic medications, our analytical approach distinguished itself from prior meta-analyses by performing subgroup analyses based on multiple OC subtypes (Wang et al., 2018;Guo et al., 2021).The results from our subgroup analysis suggested that compared to drug therapy without anti-angiogenic agents, combination therapy with anti-angiogenic drugs notably improved PFS, OS, and ORR in platinum-sensitive and recurrent OC patients.Traditionally, OC has been classified as "platinum sensitive" if relapse occurs 6 months or more after the final dose of platinum-based chemotherapy, and "platinum resistant" if relapse happens earlier (Ledermann et al., 2013).For platinum-resistant OC, our research also concluded that anti-angiogenic drug combination therapy yielded benefits in terms of PFS and OS, along with a higher ORR.Bevacizumab is the sole anti-VEGF treatment for platinum-sensitive and recurrent OC approved by the US Food and Drug Administration (FDA).Its FDA approved indication is for combination with carboplatin/ gemcitabine or carboplatin/paclitaxel, followed by single-agent maintenance (Arend et al., 2020).Bevacizumab is also available in the United States as a second-line and third-line treatment for platinum-resistant OC and frontline therapy for stage III/IV disease (Arend et al., 2020).The majority of the participants in the RCTs included in our study were OC patients of various subtypes.Grouping the subdivided subtypes of OC into a single category in a general manner could lead to some degree of bias and confusion.Furthermore, the fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup recommended that tumors should be defined by a multitude of factors, including surgical outcomes, mutation status, platinum sensitivity, histology, and response to non-platinum treatments.Consequently, more RCTs need to be incorporated to bolster future meta-analysis targeting a specific and clearly defined subtype of OC.
The results of our monotherapy analysis indicated that antiangiogenic monotherapy did not provide substantial improvements in PFS and OS compared with placebo.This monotherapy, however, was associated with an elevated risk of any grade AEs.Despite the pooled analysis revealing a greater ORR with the use of antiangiogenic monotherapy (Ferron et al., 2023), the inference made from a single trial could not be broadly applied.From a therapeutic efficacy standpoint, the combination of anti-angiogenic drugs with chemotherapy or PARP inhibitors seems to be a more effective alternative to monotherapy with anti-angiogenic drugs, as combination therapy brings benefits in terms of PFS, OS, and ORR.RCTs needs to be designed to directly compare the effectiveness of anti-angiogenic drug monotherapy and combination therapy to verify this hypothesis.Moreover, the increased incidence of AEs caused by combination therapy warrants attention.Our combined and subgroup analyses revealed that anti-angiogenic drug combination resulted in a higher incidence of grade ≥3 AEs.Additionally, the combination of VEGFR or angiopoietin inhibitor was linked to an increased risk of any grade AEs.These findings underscore the importance for vigilant monitoring and management of AEs during anti-angiogenic therapy to mitigate potential risks.
There are several limitations in our meta-analysis.First, the heterogeneity in PFS results could be attributed to the variations in the trial design, patient baseline characteristics, anti-angiogenic therapies utilized, chemotherapy protocols, OC stages, and duration of follow-up across the RCTs.The existence of considerable heterogeneity may compromise the dependability of pooled estimates.Second, it is noteworthy that despite the majority of the incorporated studies being featured in high-impact journals, certain inherent aspects like pharmaceutical industry sponsorship and an open-label design could potentially introduce elements of bias, such as publication bias, which might have an impact on the overall findings.Third, despite the participation of independent assessors and meticulous data extraction and quality assessment using the modified Jadad scale, subjective biases may still be present in the process of evaluating study quality and extracting data.Fourth, diversity in OC types across the original RCTs could make the subgroup analyses based on OC subtypes potentially biased and confusing.These subgroup analyses could potentially introduce the possibility of false positives and inflated type I error.Finally, TSA findings point out the need for future meta-analysis with larger sample sizes and more RCTs to validate the results related to PFS and grade ≥3 AEs in the context of anti-angiogenic drug monotherapy.

Conclusion
In summary, our meta-analysis of RCTs demonstrated that the combination of anti-angiogenic drugs with chemotherapy or PARP inhibitors significantly improved PFS, OS, and ORR in OC patients compared with chemotherapy or PARP inhibitors alone.Although the efficacy superiority of anti-angiogenic drug monotherapy over placebo has not been observed, the increased risk of AEs associated with anti-angiogenic drug monotherapy and combination therapy warrants attention.Clinicians should meticulously detect and manage AEs to mitigate the potential treatment-related risks while employing anti-angiogenic therapies.

FIGURE 1 Flow
FIGURE 1Flow diagram of the process of study selection.

FIGURE 2
FIGURE 2 Forest plot of the efficacy and safety outcomes after anti-angiogenic agent monotherapy for ovarian cancer.(A) Progression-free survival; (B) Overall survival; (C) Objective response rate; (D) Adverse events of any grade; (E) Grade ≥3 adverse events.

FIGURE 3
FIGURE 3 Forest plot of the efficacy and safety outcomes after anti-angiogenic drug combination therapy for ovarian cancer.(A) Progression-free survival; (B) Overall survival; (C) Objective response rate; (D) Adverse events of any grade; (E) Grade ≥3 adverse events.

FIGURE 4
FIGURE 4Trial sequential analysis of anti-angiogenic agent monotherapy for ovarian cancer.(A) Progression-free survival; (B) Overall survival; (C) Adverse events of any grade; (D) Grade ≥3 adverse events.Uppermost and lowermost red curves represent trial sequential monitoring boundary lines for benefit and harm, respectively.Inner red lines represent the futility boundary.Blue line represents evolution of cumulative Z-score.Horizontal green lines represent the conventional boundaries for statistical significance.Cumulative Z-curve crossing the trial sequential monitoring boundary or the RIS boundary provides firm evidence of effect.

FIGURE 5
FIGURE 5Trial sequential analysis of anti-angiogenic drug combination therapy for ovarian cancer.(A) Progression-free survival; (B) Overall survival; (C) Objective response rate; (D) Adverse events of any grade; (E) Grade ≥3 adverse events.Uppermost and lowermost red curves represent trial sequential monitoring boundary lines for benefit and harm, respectively.Inner red lines represent the futility boundary.Blue line represents evolution of cumulative Z-score.Horizontal green lines represent the conventional boundaries for statistical significance.Cumulative Z-curve crossing the trial sequential monitoring boundary or the RIS boundary provides firm evidence of effect.

TABLE 1
The basic characteristics of the included RCTs.

TABLE 1 (
Continued) The basic characteristics of the included RCTs.

TABLE 1 (
Continued) The basic characteristics of the included RCTs.

TABLE 1 (
Continued) The basic characteristics of the included RCTs.

TABLE 1 (
Continued) The basic characteristics of the included RCTs.

TABLE 1 (
Continued) The basic characteristics of the included RCTs.

TABLE 2
Pooled effect of the efficacy and safety of monotherapy or combination therapy with anti-angiogenic drugs in the treatment of ovarian cancer.

TABLE 3
Subgroup analysis of the efficacy and safety of anti-angiogenic agent monotherapy for ovarian cancer.

TABLE 4
Subgroup analysis of the efficacy and safety of anti-angiogenic agent combination therapy for ovarian cancer.

TABLE 4 (
Continued) Subgroup analysis of the efficacy and safety of anti-angiogenic agent combination therapy for ovarian cancer.