Efficacy and Safety of Biweekly Single-Dose Actinomycin D vs Multiday Methotrexate in Low-Risk Gestational Trophoblastic Neoplasia: A Prospective Multicenter Randomized Trial

F Jiang; C L Guan; L Z Jiao; T Xu; X R Wan; S S Shi; B B Wu; X Zhang; L Zhen; J W Miao; M Tian; M Du; C Li; F Z Feng; J J Yang; T Ren; J Zhao; Y Li; X Q Zhang; X Lu; Y Xiang

doi:10.1016/j.annonc.2025.06.006

Efficacy and Safety of Biweekly Single-Dose Actinomycin D vs Multiday Methotrexate in Low-Risk Gestational Trophoblastic Neoplasia: A Prospective Multicenter Randomized Trial

Ann Oncol. 2025 Jun 19:S0923-7534(25)00811-7. doi: 10.1016/j.annonc.2025.06.006. Online ahead of print.

Authors

F Jiang¹, C L Guan², L Z Jiao³, T Xu⁴, X R Wan¹, S S Shi², B B Wu⁵, X Zhang⁶, L Zhen⁷, J W Miao⁸, M Tian⁸, M Du¹, C Li¹, F Z Feng¹, J J Yang¹, T Ren¹, J Zhao¹, Y Li¹, X Q Zhang⁹, X Lu¹⁰, Y Xiang¹¹

Affiliations

¹ Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Beijing, China.
² Department of Obstetrics & Gynecology, Gansu Provincial Maternity and Child-care Hospital, Lanzhou City, Gansu Province, China.
³ Department of Gynecology Oncology, Dalian Women and Children's Medical Center (Group), Dalian, China.
⁴ Department of Epidemiology and Statistics Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
⁵ Department of Gynecologic Oncology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
⁶ Department of Gynecology Oncology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province, China.
⁷ Department of Gynecology, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, China.
⁸ Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
⁹ Department of Obstetrics & Gynecology,Taiyuan Maternal and Child Health Hospital,Shanxi Province, China.
¹⁰ Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China. Electronic address: luxin@fudan.edu.cn.
¹¹ Department of Obstetrics & Gynecology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, National Clinical Research Centre for Obstetric & Gynecologic Diseases, Beijing, China. Electronic address: xiangy@pumch.cn.

PMID: 40543844
DOI: 10.1016/j.annonc.2025.06.006

Abstract

Background: Cure rates for low-risk gestational trophoblastic neoplasia (GTN) are high, but there is no consensus on optimal first-line chemotherapy. Here we evaluated the efficacy and safety of biweekly single-dose actinomycin D (Act-D) versus an 8-day methotrexate-folinic acid (MTX-FA) regimen as first-line single-agent chemotherapy for low-risk GTN.

Patients and methods: This multicenter, randomized controlled trial enrolled patients with FIGO stage I-III, low-risk GTN (FIGO 2000 prognostic scores 0-4) across eight centers in China (ClinicalTrials.gov identifier: NCT04562558). Patients were randomized (1:1) to Act-D (1.25 mg/m², maximum 2 mg, every 14 days) or MTX-FA (50 mg intramuscularly, days 1, 3, 5, and 7; leucovorin rescue, days 2, 4, 6, and 8). Treatment continued until β-hCG normalization, followed by 2-3 consolidation cycles. Primary outcomes were complete remission (CR) rates for single-agent chemotherapy and overall CR rates. Secondary outcomes were time to CR, chemotherapy cycles, toxicity, and anti-Müllerian hormone (AMH) changes.

Results: Between September 27, 2020, and June 18, 2024, 228 patients were randomized to MTX or Act-D. Act-D achieved significantly higher single-agent CR rates than MTX (72.8% vs. 54.4%, p=0.0038) with shorter median remission time (7.86 vs. 9.43 weeks, p=0.0296). Overall CR rates were 100% in both groups following combination chemotherapy for resistant cases. Most adverse events were grade 1-2, but grade ≥2 nausea and vomiting and hair loss were more frequent with Act-D, and ALT was more frequently elevated in the MTX group. AMH reductions were transient in both groups. After a 28.5-month median follow-up, recurrence rates remained low and comparable (MTX: 0.88% vs. Act-D: 0.88%; p>0.05). Fertility outcomes were favorable in both groups.

Conclusion: Biweekly Act-D demonstrated superior efficacy and faster remission than the 8-day MTX regimen as first-line single-agent chemotherapy for low-risk GTN, offering a well-tolerated option despite a higher incidence of nausea, vomiting, and hair loss.

Keywords: Actinomycin D; Gestational trophoblastic neoplasia; Low-risk GTN; Methotrexate; Randomized controlled trial.

Associated data

ClinicalTrials.gov/NCT04562558