What is the initial treatment for gestational trophoblastic neoplasia (GTN)?

Initial Treatment for Gestational Trophoblastic Neoplasia

The initial treatment for GTN is determined by the FIGO prognostic score: patients with low-risk disease (score 0-6) should receive single-agent chemotherapy with either methotrexate or dactinomycin, while patients with high-risk disease (score ≥7) require multi-agent chemotherapy with EMA/CO. 1

Risk Stratification Using FIGO Scoring

Before initiating treatment, GTN must be staged and scored according to the FIGO staging and prognostic scoring system, which incorporates tumor volume (hCG level, size and number of metastases), site of involvement, prior chemotherapy resistance, and duration from antecedent pregnancy 1. This scoring system predicts resistance to single-agent chemotherapy and guides treatment selection 1.

Low-Risk GTN (FIGO Score 0-6)

First-Line Single-Agent Chemotherapy

For low-risk GTN, single-agent chemotherapy with either methotrexate or dactinomycin is the standard treatment, achieving cure rates approaching 100%. 1, 2

Methotrexate Regimens:

• 5-day methotrexate: 0.4 mg/kg IV or IM daily for 5 days, repeated every 2 weeks (primary remission rates 87-93%) 1
• 8-day methotrexate with folinic acid rescue: 1.0-1.5 mg/kg IM every other day for 4 days, alternating with leucovorin 15 mg PO, repeated every 2 weeks 1
• Methotrexate/folinic acid (MTX/FA) is preferred in most European centers because it is less toxic than methotrexate alone or single-agent dactinomycin, and notably does not cause alopecia 1

Dactinomycin Regimens:

• 5-day dactinomycin: 12 mcg/kg IV daily for 5 days as a single agent for nonmetastatic and low-risk metastatic disease (primary remission rates 77-94%) 1, 3
• Pulse dactinomycin: 1.25 mg/m² IV every 2 weeks (primary remission rates 69-90%) 1

Choosing Between Methotrexate and Dactinomycin:

While a 2016 Cochrane review showed dactinomycin may be more likely to achieve primary cure than methotrexate (particularly weekly IM methotrexate), a phase III trial comparing pulse dactinomycin to multiday methotrexate regimens found primary remission rates of 75% for pulse dactinomycin versus 88.5% for multiday methotrexate regimens 1. Given that overall survival is 100% even with treatment failure requiring second-line therapy, it is reasonable to start with the least toxic therapy first—typically methotrexate with folinic acid—to minimize exposure to more harmful treatments. 1

Important Caveat for Very High hCG Levels:

Patients with low-risk scores but hCG >400,000 IU/L should receive multi-agent chemotherapy from the outset, as they are unlikely to be cured by single-agent therapy. 1, 4 For patients with hCG between 100,000-400,000 IU/L, single-agent therapy can be attempted, as it will cure approximately 30% and only prolongs treatment by 2 weeks if a change to combination agents is required 4.

Maintenance Therapy:

Chemotherapy for low-risk disease should be continued for 6 weeks of maintenance treatment after hCG normalization 1.

High-Risk GTN (FIGO Score ≥7)

Patients with high-risk disease require multi-agent chemotherapy, with EMA/CO being the most commonly used regimen as it is highly effective, simple to administer, and relatively non-toxic. 1

EMA/CO Regimen:

Multi-agent chemotherapy with EMA/CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide, vincristine) achieves survival rates of 80-90% in high-risk disease 1, 2, 5.

High-Risk Metastatic Disease Dosing:

For high-risk metastatic GTN, dactinomycin 500 mcg IV on Days 1 and 2 every 2 weeks for up to 8 weeks is recommended as part of multi-agent combination chemotherapy 3.

Maintenance Therapy:

Patients with high-risk disease should have maintenance therapy for 6 weeks, extended to 8 weeks for poor prognostic features such as liver with or without brain metastasis 1.

Ultra-High-Risk Disease:

Early deaths in ultra-high-risk GTN can be reduced by induction with low-dose etoposide and cisplatin. 1 Such patients may also benefit from substitution of EMA/CO with EP/EMA 1.

Special Considerations

Placental Site Trophoblastic Tumor (PSTT) and Epithelioid Trophoblastic Tumor (ETT):

The FIGO scoring system is not valid for PSTT/ETT due to their discrete biological behavior with less hCG production, slower growth, late metastasis, and slightly less chemosensitivity 1. For stage I PSTT/ETT presenting within 4 years of the last known pregnancy, hysterectomy with pelvic lymph node sampling is recommended. 1 Multi-agent chemotherapy with EP/EMA is recommended for metastatic disease 1.

Surgical Options:

Repeat dilation and curettage can be considered for persistent postmolar GTN, with 68% of patients having no further evidence of disease or chemotherapy requirements after this procedure 1, 6. However, second D&C does not usually prevent the subsequent need for chemotherapy and should only be attempted after discussion with a GTD reference center 1.

Common Pitfalls to Avoid

• Do not biopsy visible lesions in the lower genital tract due to hemorrhage risk from fragile trophoblastic tumor vessels 1
• Consider phantom hCG if hCG is elevated with no evidence of disease on imaging 1
• Do not use weekly intramuscular methotrexate as it is less effective than 5- or 8-day methotrexate regimens 1
• Monitor for drug resistance early during initial therapy using weekly hCG measurements to detect plateau or rise requiring treatment change 1
• Centralize care at specialized GTD reference centers for optimal pathology review and hCG monitoring 1