Treatment Protocols

Most women with gestational trophoblastic neoplasia (GTN) receive their diagnosis during their reproductive years. An important aspect of treatment is curing GTN while attempting to preserve future fertility. Fortunately, GTN is very sensitive to chemotherapy. Chemotherapeutic treatment recommendations are based on stage, World Health Organization (WHO) prognostic score, and histology.

Treatment recommendations for low-risk GTN (prognostic score, 0-6)

Consider the following:

Methotrexate (MTX) and dactinomycin (Act-D) are the two single agents used to treat GTN; there is no standard regimen. ^{[1, 2, 33]}
Many practitioners use a 5-day MTX regimen or an alternating 8-day MTX regimen because of high response rates. ^{[3, 4, 5, 6]}
Ease of administration and cost favor regimens such as weekly MTX or biweekly (pulsed) Act-D; however, risks associated with extravasation of Act-D and adverse effects such as alopecia and neutropenia make MTX regimens more commonly used as front-line therapy (see Table 1, below). ^[7]

Table 1. Single-Agent Regimens (Open Table in a new window)

Single-agent chemotherapy regimen	Response rates (%) ^[8]
MTX regimens
5-day MTX regimen: MTX 0.4 mg/kg/day IV or IM for 5 days, not to exceed 25 mg/day Repeat cycle every 14d	87-93
8-day alternating MTX regimen: MTX 1 mg/kg IM days 1, 3, 5, and 7 plus folinic acid 15 mg PO 30h after each MTX dose on days 2, 4, 6, and 8 Repeat cycle every 14d	74-90
MTX 100 mg/m² IVP, then 200 mg/m² in 500 mL D5W infused over 12h on day 1 plus folinic acid 15 mg IM/PO q12h for 4 doses Initiate folinic acid 24h after start of MTX Repeat cycle every 18d or as needed	69-90
Weekly MTX: MTX 30-50 mg/m² IM weekly	49-74
Act-D regimens
5-day Act-D regimen: Act-D 10-13 mcg/kg or 0.5-mg flat dose IV qd for 5d Repeat cycle every 14d	77-94
Pulsed Act-D: Actinomycin 1.25 mg/m² IV every 2wk	69-90
Other
Alternating 5-day MTX/5-day Act-D regimens	100

Four randomized, controlled trials have demonstrated a superiority of pulsed Act-D over weekly MTX, and in 2011, the Gynecologic Oncology Group (GOG) reported on the superiority of pulsed Act-D over weekly MTX^{[9, 10, 11, 12, 34]}; however, the clinical relevance of these results has been questioned because many practitioners use a 5-day MTX regimen or an alternating 8-day MTX regimen, with response to these treatments being superior to those for weekly MTX regimens.^{[3, 4, 5, 6]}

If a single-agent drug regimen fails in low-risk patients, they may continue to be eligible for an alternative single-agent regimen.

Charing Cross Hospital has proposed that in patients with MTX resistance but with continued low-risk International Federation of Gynecology and Obstetrics (FIGO) scores, as well as a beta-human chorionic gonadotropin (beta-hCG) level of less than 100 IU/L, a 5-day Act-D regimen may be appropriate; however, if the beta-hCG level is greater than 100 IU/L, a multidrug regimen may be more appropriate.^[6]

Treatment recommendations for high-risk GTN (prognostic score, ≥7) and FIGO stage IV

A multidrug regimen is the initial therapy in patients with high-risk GTN; while no randomized trials have compared regimens, the multidrug regimen of etoposide, MTX, Act-D, cyclophosphamide, and vincristine (EMA-CO) is the one most commonly used (see Table 2, below) and is considered to be the standard of care.^{[13, 14, 15, 36]}

Bower et al reported on a series using EMA-CO; the 5-year survival rate was 86.2%; in this series, patients with brain metastases received an increased dose of MTX to 1 g/m² IV infused over 24 hours, followed by folinic acid.^[13]

In patients in whom hCG levels plateau or increase during or after EMA-CO, a drug regimen of etoposide, MTX, folinic acid, and cisplatin (EMA-EP) is used.

Table 2. EMA-CO Regimen (Open Table in a new window)

EMA-CO regimen	Chemotherapeutic agent	Dosage and administration
Day 1
EMA	Act-D Etoposide MTX	0.5 mg IVP 100 mg/m² IVPB 300 mg/m² IV continuous infusion over 12h
Day 2
EMA	Act-D Etoposide Leucovorin	0.5 mg IVP 100 mg/m² IVPB 15 mg PO/IM q12h x 48h; initiate 24h after start of MTX
Day 8
CO	Vincristine Cyclophosphamide	0.8 mg/m² IVP 600 mg/m² IVPB

Other multiagent drug regimens include the following^{[16, 17]}:

MAC: MTX, folinic acid, Act-D, and cyclophosphamide/chlorambucil
EMA: Etoposide, MTX, folinic acid, and Act-D (EMA/CO without the CO)
CHAMOCA: MTX, Act-D, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine
CHAMOMA - MTX, folinic acid, hydroxyurea, Act-D, vincristine, melphalan, and doxorubicin

Management of brain metastases

Of patients with brain metastasis, 50-80% may achieve long-term remission.^{[13, 14, 18, 19]}

Craniotomy is often avoided in the treatment of brain metastasis. Most brain lesions that are not actively hemorrhaging or causing significant neurologic findings can be managed with chemotherapy with or without radiation, relying on higher doses of MTX to achieve therapeutic central nervous system levels.^[20]Some centers use brain irradiation with or without intrathecal MTX.^[18]

Management of liver metastases

Treatment of liver metastases requires multiagent drug regimens; if liver lesions are actively bleeding, arterioembolization or wedge resection may be required; drug-resistant lesions can also be surgically managed with wedge resection^[20]

Treatment of placental site trophoblastic tumor

Placental site trophoblastic tumor (PSTT) is not as responsive to chemotherapy as other types of GTN; therefore, hysterectomy and surgical removal of stage 1 disease are the standard of care.^[35]Data regarding the need for oophorectomy or lymphadenectomy are scarce.

In a large retrospective study, patients with stage 1 disease were treated with hysterectomy with or without chemotherapy. The 10-year survival rate was 90%, with no statistical survival advantage for the group that received adjuvant therapy.^{[21, 22, 23]}

In patients with disease outside the uterus, resection followed by adjuvant therapy is recommended. The most common drug regimen is EMA-EP; resistant disease may be controlled with surgical resection.

Treatment of epithelioid trophoblastic tumor

Epithelioid trophoblastic tumors (ETTs) arise from the intermediate trophoblast cells and appear to behave like PSTTs; therefore, this tumor is managed in a fashion similar to that for PSTT. There are no data to guide therapy.^[24]

Salvage therapies

If up-front therapy fails, approximately 50% of patients can achieve disease-free survival with combination drug regimens after relapse.^[25]

Various regimens have been reported, with combinations that include cisplatin, etoposide, bleomycin, ifosfamide, 5-fluorouracil, paclitaxel, and floxuridine.^{[26, 27, 28, 29, 30, 31]}

Surgical resection is an option for patients with recurrent or refractory disease.^[32]

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