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. 2024 May 27:15:1423891.
doi: 10.3389/fphar.2024.1423891. eCollection 2024.

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

Yao Xie  1 , Fei Zhou  1
Affiliations

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

Yao Xie et al. Front Pharmacol. .

Abstract

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.

Keywords: VEGF; anti-angiogenic drugs; bevacizumab; combination therapy; meta-analysis; monotherapy; ovarian cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow 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 4
Trial 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 5
Trial 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.
See this image and copyright information in PMC

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