Direct comparisons of efficacy and safety between actinomycin-D and methotrexate in women with low-risk gestational trophoblastic neoplasia: a meta-analysis of randomized and high-quality non-randomized studies

Abstract

Background Actinomycin-D (Act-D) and Methotrexate (MTX) are both effective first-line agents for low-risk gestational trophoblastic neoplasia (LRGTN) with no consensus regarding which is more effective or less toxic. The primary objective of this meta-analysis is to compare Act-D with MTX in the treatment of LRGTN. Methods We systematically searched electronic databases, conferences abstracts and trial registries for randomized controlled trials (RCTs) and high-quality non-randamized controlled trials (non-RCTs), comparing Act-D with MTX for patients with LRGTN. Studies were full-text screened for quality assessment and data extraction. Eligible studies must have reported complete remission rate. A fixed-effects meta-analysis was conducted to quantify the efficacy and safety of Act-D and MTX on odds ratios (ORs) and 95% confidence intervals (95%CIs), respectively. Results A total of 8 RCTs and 9 non-RCTs (1674 patients) were included. In terms of efficacy, Act-D is superior to MTX in complete remission (80.2% [551/687] vs 65.1% [643/987]; OR 2.15, 95%CI 1.70 to 2.73). In the stratified analysis, patients from RCTs and non-RCTs both had a better complete remission from Act-D-based regimen (RCTs: 81.2% [259/319] vs 66.1% [199/301], OR 2.17, 95%CI 1.49 to 3.16; non-RCTs: 79.3% [292/368] vs 65.0% [444/686], OR 2.14, 95%CI 1.57 to 2.92). In terms of safety, patients receiving Act-D had higher risks of suffering nausea (OR 2.35, 95%CI 1.68 to 3.27), vomiting (OR 2.40, 95%CI 1.63 to 3.54), and alopecia (OR 2.76, 95%CI 1.60 to 4.75). Notably, liver toxicity (OR 0.38, 95%CI 0.19 to 0.76) was the only one that was conformed to have a higher risk for patients receiving MTX. In addition, the pooled results showed no significant difference of anaemia, leucocytopenia, neutropenia, thrombocytopnia, constipation, diarrhea, anorexia, and fatigue between Act-D and MTX. Conclusions Our meta-analysis suggests that Act-D had better efficacy profile in general, and MTX had less toxicities in LRGTN. Future clinical trials should be better orchestrated to provide more valid data on efficacy and toxicity.

Flat-dose versus weight or body surface area-based methotrexate dosing in low-risk gestational trophoblastic neoplasia

“…Incomplete and missing data affected a higher proportion of CR compared to TR patients, leading to inclusion bias. This also explained the lower-thanexpected CR rates (49%) amongst the included cohort (n = 364), whilst the CR rate for all identified patients (64%, n = 935) was in keeping with previous literature [11,21,[29][30][31][32][33]. Reassuringly, the FIGO scores of the included (median = 3, IQR 2-4) and excluded patients (median = 3, IQR 2-4) were comparable.…”

“…Much of the high quality evidence for treatment of LR-GTN, including a Cochrane review of randomised control trials [29] and another meta-analysis of both randomised and non-randomised studies [30], have focused upon comparing various MTX-FA regimens to actinomycin-D. Limitations of the studies included underpowered studies, heterogeneity between included studies such as the different dosage regimens, definitions of persistence, different FIGO risk score thresholds, inclusion of patients with or without metastatic disease and choriocarcinoma, differing outcome measures and follow-up times.…”

Low‐risk gestational trophoblastic neoplasia – 20 years experience of a state registry

“…This is significantly higher than reported by Hao et al in their meta-analysis, who reported a primary remission rate of only 65.1% with methotrexate, compared to 80.2% with actinomycin D for low-risk GTN. 9 This may be due to the wide variation in methotrexate regimens used globally and included in the study, the majority of which were less intensive than the regimen used in our centre -which may underestimate the effectiveness of the drug.…”