What is the role of Methotrexate (MTX) therapy in the management of molar pregnancy with persistent Gestational Trophoblastic Disease (GTD) or Gestational Trophoblastic Neoplasia (GTN)?

Methotrexate Therapy in Molar Pregnancy with Persistent GTD/GTN

Methotrexate is the first-line chemotherapy agent for low-risk gestational trophoblastic neoplasia (GTN) following molar pregnancy, with cure rates approaching 90% when using the recommended 5-day or 8-day regimens. 1

Diagnosis of Post-Molar GTN

GTN requiring chemotherapy is diagnosed when any of the following FIGO criteria are met:

• hCG levels plateau for 4 consecutive values over 3 weeks 1, 2
• hCG levels rise >10% for 3 values over 2 weeks 1, 2
• hCG persistence 6 months or more after molar evacuation 1
• Histological evidence of choriocarcinoma 2
• Evidence of metastases 2

Risk Stratification

Before initiating methotrexate therapy, proper risk assessment is essential:

• Low-risk GTN (FIGO score 0-6): Single-agent chemotherapy is appropriate 1
• High-risk GTN (FIGO score ≥7): Multi-agent chemotherapy is required 1

The FIGO scoring system evaluates:

• Age, antecedent pregnancy type, interval from pregnancy
• hCG level, number and site of metastases
• Largest tumor size, prior chemotherapy 1

Methotrexate Regimens for Low-Risk GTN

For low-risk post-molar GTN, the following methotrexate regimens are recommended:

1. 5-day methotrexate regimen: 0.4 mg/kg IV or IM daily for 5 days, repeated every 2 weeks (primary remission rates 87-93%) 1

2. 8-day methotrexate with leucovorin rescue: 1.0-1.5 mg/kg IM every other day for 4 doses, alternating with leucovorin 15 mg orally, repeated every 2 weeks (primary remission rates 74-93%) 1, 3

3. Methotrexate and folinic acid regimen: 50 mg IM methotrexate repeated every 48 hours for 4 doses with 15 mg oral folinic acid 30 hours after each methotrexate dose, repeated every 2 weeks 1

Monitoring Response to Treatment

• Monitor hCG levels every 1-2 weeks during treatment 1
• Continue therapy for 2-3 additional cycles after hCG normalization to minimize recurrence risk 1
• Treatment resistance is indicated by hCG plateau over 3 consecutive cycles or rise over 2 consecutive cycles 1
• After normalization, monthly hCG monitoring for 1 year is recommended 1

Second-Line Therapy

If methotrexate resistance develops:

• Switch to dactinomycin as second-line single-agent therapy (75% complete response rate) 1
• Consider multi-agent chemotherapy (EMA/CO) if there is poor response to dactinomycin 1
• EMA/CO (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine) is the preferred multi-agent regimen 1

Special Considerations

• Prophylactic methotrexate at the time of molar evacuation is controversial but may be considered for high-risk patients 1, 2
• Risk factors for post-molar GTN include age >40 years, hCG >100,000 mIU/mL, excessive uterine enlargement, and theca lutein cysts >6 cm 1, 2
• Adjuvant surgery (hysterectomy) can be considered for patients with localized disease who do not desire fertility preservation 1
• Weekly methotrexate regimens are no longer recommended due to lower efficacy compared to 5-day or 8-day protocols 1, 4

Potential Toxicities

• Common toxicities with methotrexate include gastrointestinal disorders (24-48%), abnormal laboratory findings (28-48%), and eye disorders (19-37%) 3
• The 8-day methotrexate/folinic acid regimen has higher toxicity rates but also higher effectiveness compared to single-day regimens 3
• Granulocytopenia, thrombocytopenia, and hepatotoxicity occur in approximately 6.6%, 2.8%, and 9.4% of patients, respectively 5

In rare cases where surgical evacuation of molar pregnancy is not possible due to uterine abnormalities, primary treatment with methotrexate followed by EMA/CO has been reported as successful 6.