Changing the Course for First-Line, Low-Risk Gestational Trophoblastic Neoplasia
Study marks first substantial cohort enrollment and analysis of this nature.
A first-line treatment for low-risk gestational trophoblastic neoplasia (LW-GTN) is rising to the top in clinical decision-making. In a new study, a biweekly, single-dose of the chemotherapy drug, actinomycin D (Act-D) has proven to yield a higher complete remission (CR) rate and shorter treatment duration than that of an eight-day methotrexate-folinic acid (MTX-FA) regimen.
Beyond the promising results, the multicenter, randomized trial makes history for another reason as well. It marks the first time a study of this nature has enrolled and analyzed a substantial cohort. Previous studies have attempted similar comparisons. However, challenges in patient recruitment have limited their completion, according to principal investigator Yang Xiang, MD, PhD, director of the department of obstetrics and gynecology at Peking Union Medical College Hospital in Beijing. Fang Jiang, MD, PhD, associate professor and lead author of the study, served as the head of the coordinating center. Earlier today, Dr. Jiang presented the full trial results of the study, “Comparing efficacy and safety of biweekly single-dose actinomycin d versus multiday methotrexate therapy in low-risk gestational trophoblastic neoplasia: a prospective multicenter randomized trial,” earlier today.
“Although both Act-D and MTX are standard options for low-risk GTN, there has been no consensus on the optimal regimen. This study provides high-level evidence that can directly inform clinical decision-making,” Dr. Jiang said. “Our findings suggest that biweekly Act-D is more effective in achieving remission while maintaining a favorable safety profile. For clinicians, this means potentially fewer treatment cycles and faster β-hCG normalization, which can reduce patient anxiety and treatment burden. This is particularly relevant in resource-limited settings, where optimizing chemotherapy efficiency is critical.”
According to Dr. Jiang, cure rates for low-risk gestational trophoblastic neoplasia (LW-GTN) are high, yet no consensus exists on the optimal first-line chemotherapy regimen. Currently, she said, multiple dosing strategies are used without robust evidence to support one over the others. International Federation of Gynecology and Obstetrics (FIGO) guidelines recommend lowering the threshold of using combination chemotherapy for scores of 5-6; however, this study focuses on a FIGO score 0-4.
This trial enrolled patients with FIGO stage 1-3, low-risk GTN across eight centers in China. Patients were randomized one-to-one to receive Act-D (1.25 mg/m2, maximum 2 mg, every 14 days) or MTX-FA (50 mg intramuscularly on days one, three, five, and seven, with leucovorin rescue on days two, four, six, and eight). Treatment continued until beta-hCG normalization, followed by two to three consolidation cycles. Primary outcomes included complete remission (CR) rates for single-agent chemotherapy and overall CR rates. Secondary outcomes included time-to-CR, chemotherapy cycles, toxicity, and changes on anti-Müllerian hormone (AMH). Adverse events were graded per Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Between Sept. 27, 2020, and June 18, 2024, 228 patients were randomized to MTX or Act-D. Act-D achieved significantly higher, single-agent complete remission rates compared to MTX (72.8% versus 54.4%, p=0.0038) with faster remission (8.75 versus 10.24 weeks, p=0.0296). Overall CR rates reached 100% in both groups following combination chemotherapy for resistant cases. Most adverse events were grades 1-2. For anything grade 2 or higher, nausea and vomiting were more frequent with Act-D (49.1% versus 18.4%, p<0.001) as was hair loss (6.1% versus 0%, p=0.0142).
Alanine Aminotransferase (ALT) elevation occurred more commonly with MTX (13.2% versus 4.4%, p=0.0192). Hematologic toxicities were mild across both regimens. Grade 3 events were rare but occurred more frequently in the Act-D group during the single-agent chemotherapy phase, with nausea and vomiting observed in 14% of patients compared to 4.4% in the MTX group (p=0.0118).
According to Dr. Jiang, both treatments caused transient AMH reductions by 0.24 for MTX versus 0.84 for Act-D, p=0.0123 and p<0.0001, respectively, which recovered within six months. By November 2024, after a median follow-up of 28.5 months, recurrence rates remained low and comparable between groups (MTX: 0.88% versus Act-D: 1.75%; p>0.05), with all recurrent cases achieving remission after salvage therapy. Fertility outcomes were favorable in both groups, with multiple patients successfully achieving pregnancies, including full-term deliveries. Longer follow-up is necessary to fully assess the regimen’s full effects, she said.
“Future research should explore predictive biomarkers to identify patients most likely to benefit from either regimen, the long-term effect on fertility and pregnancy outcomes post-chemotherapy, and real-world implementation in diverse populations beyond our study setting,” Dr. Jiang said.
Act-D may be the preferred option for those prioritizing rapid remission and fewer treatment cycles. However, Dr. Jiang noted that MTX remains a viable alternative with a more favorable toxicity profile. Primary considerations when selecting the optimal first-line regimen, she said, include the importance of balancing efficacy with side effects and patient preferences.
“Although our study demonstrates strong evidence for Act-D’s efficacy, we also acknowledge the importance of individualized treatment decisions. Most importantly, we emphasize the need for standardized, evidence-based treatment,” Dr. Jiang said. “When managed with guideline-recommended protocols, low-risk GTN has an excellent prognosis, with nearly all patients achieving remission.”
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