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SGO, FWC, and GOG-F* Communique: Considerations When Treating Gestational Trophoblastic Neoplasia in the Setting of a Methotrexate Shortage

News Article
May 11, 2023

Several chemotherapy drugs utilized to treat gynecologic cancers are currently in short supply in the U.S., including cisplatin, carboplatin, and methotrexate. Please refer to the SGO Rapid Communique dated 4/21/23 for details and guidance regarding platinum-based chemotherapy drug shortages[1]. The nationwide methotrexate drug shortage was first reported to the FDA on March 14th, 2023[2]. Methotrexate is utilized commonly in treatment regimens for gestational trophoblastic neoplasia[3]; in high risk or refractory cases, cisplatin may be used[4]. The communication presented here provides guidance for treating patients with gestational trophoblastic neoplasia in the context of limited drug availability.
Hospital systems or similar organizations are encouraged to facilitate open and frequent communication among multi-specialty teams, including gynecologic, medical, surgical, and radiation oncologists, pharmacists, infusion managers, advanced practitioners, and patient advocates. In doing so, the goal is to create institution- and population-specific strategies to overcome anticipated treatment challenges.
Importantly, cancer care disparities may emerge or worsen in times of resource scarcity. As treatment recommendations are adjusted during this shortage, identifying patients at risk for experiencing structural barriers to care – and having a plan to mitigate those barriers – must be considered as part of each institution’s strategic plan. Therefore, the allocation of limited-supply drugs must be prioritized in a transparent and data-driven fashion to ensure thoughtful and equitable distribution.

General Principles
  1. Gestational trophoblastic neoplasia (GTN) comprises the following subtypes: invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT)[1].

  2. GTN is staged according to International Federation of Gynecology and Obstetrics (FIGO)[2,3]. Additionally, GTN is stratified as low-risk or high-risk disease by the World Health Organization (WHO) scoring system[4] based on the risk of disease progression and resistance to single-agent chemotherapy.

  3. Patients with low-risk disease who desire to preserve fertility may be cured with single-agent chemotherapy, using either methotrexate or dactinomycin[3-4]. Cure may also be possible in select cases with dilation and curettage (D&C) procedures[5].

  4. When methotrexate is in short supply, it should be preserved for curative intent treatment in patients with high-risk GTN (e.g. WHO score ≥7 or WHO score of >5-6 with additional high-risk features)[6] or for the treatment of patients with low-risk GTN who did not respond to, relapsed from, or had an allergic reaction to single-agent treatment with dactinomycin[4,6].

  5. When cisplatin is in short supply, it should be reserved for curative intent treatment in patients with GTN who have not responded to, or relapsed, after multi-agent chemotherapy regimens (e.g., EMA-CO: etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine). Platinum-based chemotherapy is critical in this disease setting[7].

  6. Duration of therapy: Despite drug shortages patients should not be undertreated. All patients require three additional courses of chemotherapy after hCG normalization.

  7. Consider referral of patients with high-risk GTN to centers with trophoblastic disease expertise for care and potential enrollment in clinical trials.

  8. In the setting of drug shortage, consider the following treatment alternatives:

    1. Low-risk GTN – for patients not desiring future fertility:
      1. Patients with apparent FIGO stage I GTN who do not wish to preserve fertility may be treated with primary hysterectomy +/- one cycle of dactinomycin chemotherapy (see dosing guidelines below)[4,8] (Level of Evidence III). Note, there is a risk of micrometastases in the setting of apparent early-stage disease, hence the rationale for a dose of chemotherapy.

    2. Low risk GTN – for patients desiring future fertility:
      1. A D&C is often performed initially to establish a GTN diagnosis. Consider a second D&C procedure when transvaginal ultrasound demonstrates residual molar tissue and/or a patient has persistent uterine bleeding[5]. A Phase II Gynecologic Oncology Group study demonstrated that 43% of the study population were successfully treated with D&C alone and were cured without subsequent chemotherapy. The risk of uterine perforation and grade 3 hemorrhage were low[5] (Level of Evidence II).
      2. Dactinomycin 1.25 mg/m2 IV “pulsed dosing” every 14 days is the preferred regimen based on a Phase III Gynecologic Oncology Group trial demonstrating significantly improved complete response rate compared to weekly IM methotrexate (Level of Evidence I) in patients with low-risk GTN[9,11]. Note that both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 42% dactinomycin and 9% methotrexate, respectively). Patients should be counseled that this drug is associated with increased toxicity compared to methotrexate, e.g., hyperemesis, alopecia, and extravasation tissue injuries[3-4,9,10,12].
      3. Methotrexate 1 mg/kg as an IM or IV injection and administered on days 1, 3, 5, and 7, with folic acid administered on days 2, 4, 5, 8 every 1. There is no preferred dose established and a fixed dose 50 mg/m2 eight-day regimen every 14 days or weekly IM administration of 0.5 mg/kg, IM or IV, for five consecutive days every 14 days are also reasonable[4,9] (Level of Evidence I). Note: Utilize only in setting of resistance, relapse, or allergic reaction to dactinomycin treatment.
      4. Etoposide 100 mg/m2 IV daily for 5 days every 10-14. This drug is an option for primary therapy for low-risk disease in the setting of dactinomycin or methotrexate resistance[11]. The risk of secondary malignancy is a noted concern in select studies, although the largest study on long-term outcomes reports a low relative risk of 0.9 (Level of Evidence III).
      5. Fluorouracil 30 mg/kg daily for 10 days every 28 days is among the preferred single-agent regimens for low-risk GTN in China, with complete remission rates of 93 and 86% of patients with stage I or II disease, respectively[13] (Level of Evidence III). Note, however, that on 4/26/23, the American Society of Hospital Pharmacists reported a fluorouracil shortage[14].

    3. High-risk GTN:
      Patients with high-risk GTN are likely to develop drug resistance if single-agent therapy is administered[3,11,15]. Therefore, patients are treated with multi-agent regimens.
      1. EMA-CO (Etoposide 100 mg/m2 IV over 30 minutes on days 1 and 2; Methotrexate 100 mg/m2 IV bolus followed by 200 mg/m2 IV over 12 hours on day 1; Dactinomycin 0.5 mg IV bolus on days 1 and 2; Leucovorin calcium 15 mg orally every 12 hours for four doses, starting 24 hours after start of MTX; Cyclophosphamide 600 mg/m2 IV on day 8; Vincristine1.0 mg/m2 IV on day 8): EMA-CO is the most utilized and preferred first-line regimen in the US for high-risk GTN, though this has not been tested in randomized studies[15]. Cure is possible with this regimen; therefore, methotrexate should be preserved for curative intent treatment in patients with high-risk GTN (Level of Evidence III).
      2. FAEV (Vincristine 2 mg IV bolus day 1 3 hours before Dactinomycin, on days 1-5 Dactinomycin 0.2 mg/m2/day IV infusion over 30 minutes, Etoposide 100 mg/m2/day IV infusion over 30 minutes, and floxuridine 800-900 mg/m2/day IV infusion for 8 hours): A randomized trial comparing FAEV to EMA-CO showed statistically similar complete remission rates and relapse rates[15]. There was no difference in toxicities between the two regimens if GCSF was used (Level of Evidence I).
      3. Surgery: Nearly 50% of patients with high-risk, metastatic GTN will require adjuvant surgery to achieve cure, even in the presence of multi-organ involvement. This should be considered in the setting of chemoresistant residual disease or significant uterine bleeding[16].
    4. Resistant or Recurrent GTN:
      There are no universally accepted guidelines on second-line treatment in this setting. Performance of prospective or randomized studies in this extremely rare tumor population is challenging. Several regimens used to treat GYN refractory to front-line chemotherapy contain platinum drugs, which at the present time, are also in shortage
      1. CarboplatinAUC 6and paclitaxel 175 mg/m2 IV every 21 days: This regimen produced durable complete remission and manageable side effect profiles in a prospective trial of patients with refractory GTN previously treated extensively with frontline chemotherapies[17] (Level of Evidence II).
      2. TP-TEPaclitaxel 135 mg/m2 and cisplatin 60 mg/2 on day 1 and paclitaxel 135 mg/m2 and etoposide 150 mg/2 on day 15: This regimen has demonstrated encouraging results in pretreated patients[18]. It appears to be well tolerated as well, though the experience remains quite limited. Care should be taken with etoposide given the risk of secondary malignancy, though the overall risk is quite low (Level of Evidence III).
      3. Pembrolizumab 200 mg IV every 21 days: PD-L1 expression in pre-malignant and malignant GTD is ubiquitous[19]. Case series in chemotherapy-resistant choriocarcinoma demonstrate excellent and durable response rates[20-22]. This promising data is congruent with response rates to pembrolizumab in other PDL1 or TIL-positive tumors[20-22] (Level of Evidence III).
      4. Avelumab 10 mg/kg IV every 14 days: In a small multi-center study in women with disease progression after single agent chemotherapy, 53% experienced normalization of hCG with minimal toxicity. Conversely, this was not effective for patients for resistance to multi-agent chemotherapy[24-25] (Level of Evidence II).

    5. Non-metastatic PSTT or ETT:
      PSTT and ETT are relatively chemoresistant
      [3,26,27]. The preferred treatment modality for most patients diagnosed with these GTN subtypes is hysterectomy (Level of Evidence III). Select patients with high-risk tumors diagnosed >48 months after the antecedent pregnancy may benefit from the addition of chemotherapy after hysterectomy. The EMA/EP regimen may be the preferred treatment in this setting[26,27] (Level of Evidence IV).
      1. EMA/EP (Etoposide 100 mg/m2 IV on day 1; Methotrexate 100 mg/m2 IV bolus followed by 200 mg/m2 IV over 12 hours on day 1; Dactinomycin 0.5 mg IV bolus on days 1; Leucovorin calcium 15 mg orally on Days 2-3; Etoposide 150 mg/m2 IV on Day 8 and Cisplatin 50 mg/m2 IV on Day 8.)

    6. Metastatic PSTT or ETT:
      Limited data is available on a first-line management approach to patients with metastatic PSTT or ETT
      [3,26,27]. Consideration of combination modality treatment with surgery and chemotherapy has been recommended in retrospective studies. Multi-agent regimens are usually administered, with EMA-EP being the preferred regimen (see dosing above) (Level of Evidence III-IV).


*Organizations involved in production of this communique include the Society of Gynecologic Oncology, the Foundation for Women’s Cancer, and The GOG Foundation, Inc.

For questions or further guidance, please email

These recommendations are not meant to be a substitute for clinical judgment at the individual patient level, nor should they supersede other policies at the institutional level. All decisions should be made in the context of the unique circumstances where members practice, including other local resource considerations. We encourage members to work closely with their institutions to ensure that patients’ needs are being met.


The SGO, FWC, and GOG-F wish to acknowledge the following members and professionals for their contributions to this communique: Amanda Fader, MD; Neil Horowitz, MD; Brian Slomovitz, MD; Wendy Brewster, MD, PhD; Thomas Herzog, MD; Peter Rose, MD; Angeles Alvarez Secord, MD; Renata Urban, MD; Ms. Elizabeth Kix; Ms. Katie Martino; Ms. Erika Miller; Ms. Kayla Nixon; Ms. Jessica Oldham; and Ms. Traci Schwendner.



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  2. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Methotrexate%20Injection&st=c Accessed on 4/29/23
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