Chemotherapy resistance and risk stratification in gestational trophoblastic neoplasia: A systematic review and network meta‐analysis

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is highly chemosensitive, but resistance to initial chemotherapy remains clinically important despite International Federation of Gynecology and Obstetrics (FIGO) score-guided management. Evidence on pretreatment predictors of chemoresistance and comparative chemoresistance across chemotherapy regimens remains limited. This study aimed to estimate the burden of chemoresistance, identify pretreatment risk factors, and compare chemotherapy regimens using pairwise and network meta-analysis to inform risk stratification and future treatment optimization. MATERIAL AND METHODS: Eight databases (PubMed, Embase, Cochrane Library, Web of Science, CBM, CNKI, VIP, and Wanfang) were searched from inception to August 26, 2025. Two reviewers independently screened records, extracted data, and assessed risk of bias using the RTI Item Bank. Pairwise meta-analyses were used to pool the chemoresistance rate and evaluate associations between pretreatment factors and chemoresistance. A frequentist random-effects network meta-analysis was performed to compare chemoresistance risks across chemotherapy regimens, with ranking probabilities summarized using the surface under the cumulative ranking curve (SUCRA). RESULTS: IU/L, longer intervals from antecedent pregnancy (7-12 and > 12 months), greater tumor burden (tumor diameter ≥5 cm, presence of metastasis, and ≥ 5 metastatic lesions), FIGO stage II or IV disease, and first-line single-agent chemotherapy. In exploratory ranking analyses, methotrexate (MTX) and fluorouracil (FU) tended to rank higher for predicted chemoresistance, whereas etoposide (ETP) and FU + actinomycin D + etoposide + vincristine (FAEV) tended to rank lower. CONCLUSIONS: Approximately one quarter of patients with GTN develop chemoresistance. Pretreatment factors, including clinicopathologic type when available, tumor burden, FIGO score and stage, antecedent pregnancy characteristics, and pretreatment β-hCG level, may help identify patients at higher risk of chemoresistance. Exploratory regimen-ranking analyses suggested lower predicted chemoresistance for etoposide-containing regimens, particularly FAEV; however, these findings require prospective validation before they can inform treatment selection.