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NCI/PDQ^® Health professionals: Gestational Trophoblastic Tumors and Neoplasia Treatment (PDQ®)

National Cancer Institute
Last Modified: June 22, 2012

TABLE OF CONTENTS

• General Information About Gestational Trophoblastic Tumors and Neoplasia

• Cellular Classification of Gestational Trophoblastic Tumors and Neoplasia
  • HM
    • Complete HM
    • Partial HM
  • Invasive Mole
  • Gestational Trophoblastic Neoplasias
    • Choriocarcinoma
    • PSTT
    • ETT

• Stage Information for Gestational Trophoblastic Tumors and Neoplasia
  • Hydatidiform Mole (HM)
  • Invasive Mole (Chorioadenoma Destruens)
  • Gestational Trophoblastic Neoplasia
    • Definitions: FIGO
      • FIGO staging system (and modified World Health Organization [WHO] prognostic scoring system)

• Treatment Option Overview
  • Low Levels of hCG
    • False-positive hCG
    • Pituitary hCG

• Hydatidiform Mole (HM) Management
  • Current Clinical Trials

• Low-Risk Gestational Trophoblastic Neoplasia (FIGO Score 06) Treatment
  • Current Clinical Trials

• High-Risk Gestational Trophoblastic Neoplasia (FIGO Score 7) Treatment
  • Current Clinical Trials

• Placental-Site Gestational Trophoblastic Tumor Treatment
  • Current Clinical Trials

• Epithelioid Trophoblastic Tumor Treatment
  • Current Clinical Trials

• Recurrent or Chemoresistant Gestational Trophoblastic Tumor Treatment
  • Current Clinical Trials

• Changes to This Summary (06/22/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Gestational Trophoblastic Tumors and Neoplasia

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Gestational trophoblastic tumors (GTTs) and neoplasias (GTNs) are rare but highly curable tumors arising from the products of conception in the uterus.

GTTs include:

• Choriocarcinoma.
• Placental-site trophoblastic tumor (very rare).
• Epithelioid trophoblastic tumor (even more rare).

GTNs include:

• GTTs.
• Persistence of complete or partial gestational hydatidiform moles.
• Invasive moles.

All of these entities are grouped under the term gestational trophoblastic disease (GTD). The reported incidence of GTD varies widely worldwide, from a low of 23 per 100,000 pregnancies (Paraguay) to a high of 1,299 per 100,000 pregnancies (Indonesia). 1 However, at least part of this variability is caused by differences in diagnostic criteria and reporting. The reported incidence in the United States is about 110 to 120 per 100,000 pregnancies. The reported incidence of choriocarcinoma, the most aggressive form of GTT, in the U.S. is about 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is about 0.18 per 100,000 women between the ages of 15 years and 49 years. 1

Two factors have consistently been associated with an increased risk of GTD: 1

• Maternal age.
• Prior history of hydatidiform mole (HM).

If a woman has been previously diagnosed with an HM, she carries a 1% risk of HM in subsequent pregnancies. This increases to approximately 25% with more than one prior HM. The risk associated with maternal age is bimodal, with increased risk both for mothers younger than 20 years and older than 35 years (and particularly for mothers >45 years). Relative risks are in the range of 1.1 to 11 for both the younger and older age ranges compared to ages 20 to 35 years. However, a population-based HM registry study suggests that the age-related patterns of the two major types of HMcomplete and partial HM (see Cellular Classification section below)are distinct. 2 In that study, the rate of complete HM was highest in women younger than 20 years, then decreasing monotonically with age. However, the rates of partial HM increased for the entire age spectrum, suggesting possible differences in etiology. The association with paternal age is inconsistent. 1 A variety of exposures have been examined, with no clear associations found with tobacco smoking, alcohol consumption, diet, and oral contraceptive use. 1

GTDs contain paternal chromosomes and are placental, rather than maternal, in origin. The most common presenting symptoms are vaginal bleeding and a rapidly enlarging uterus, and GTD should be considered whenever a premenopausal woman presents with these findings. Since the vast majority of GTD types are associated with elevated human chorionic gonadotropin (hCG) levels, an hCG blood level and pelvic ultrasound are the initial steps in the diagnostic evaluation. In addition to vaginal bleeding and uterine enlargement, other presenting symptoms or signs may include the following:

• Pelvic pain or sensation of pressure.
• Anemia.
• Hyperemesis gravidarum.
• Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity).
• Preeclampsia early in pregnancy.

The most common antecedent pregnancy in GTN is that of an HM.

Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and it should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other possible signs include neurologic symptoms (resulting from brain metastases) in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.

The prognosis for cure of patients with GTTs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value. 3 The probability of cure depends on the following:

• Histologic type (mole, invasive mole, or choriocarcinoma).
• Extent of spread of the disease/largest tumor size.
• Level of serum beta-hCG.
• Duration of disease from the initial pregnancy event to start of treatment.
• Number and specific sites of metastases.
• Nature of antecedent pregnancy.
• Extent of prior treatment.

Selection of treatment depends on these factors plus the patient's desire for future pregnancies. The beta-hCG is a sensitive marker to indicate the presence or absence of disease before, during, and after treatment. Given the extremely good therapeutic outcomes of most of these tumors, an important goal is to distinguish patients who need less-intensive therapies from those who require more-intensive regimens to achieve a cure.

References:

1. Altieri A, Franceschi S, Ferlay J, et al.: Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4 (11): 670-8, 2003. [PUBMED Abstract]
2. Altman AD, Bentley B, Murray S, et al.: Maternal age-related rates of gestational trophoblastic disease. Obstet Gynecol 112 (2 Pt 1): 244-50, 2008. [PUBMED Abstract]
3. Gestational trophoblastic tumors. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p 439. [PUBMED Abstract]

Cellular Classification of Gestational Trophoblastic Tumors and Neoplasia

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Gestational trophoblastic tumors (GTTs) and neoplasias (GTNs) may be classified as follows: 1

• Hydatidiform mole (HM).
  • Complete HM.
  • Partial HM.

• Invasive mole (chorioadenoma destruens).
• GTN.
  • Choriocarcinoma.
  • Placental-site trophoblastic tumor (PSTT; very rare).
  • Epithelioid trophoblastic tumor (ETT; even more rare).

HM

HM is defined as products of conception that show gross cyst-like swellings of the chorionic villi that are caused by an accumulation of fluid. There is disintegration and loss of blood vessels in the villous core.

Complete HM

A complete mole occurs when an ovum that has extruded its maternal nucleus is fertilized by either a single sperm, with subsequent chromosome duplication, or two sperm, resulting in either case in a diploid karyotype. The former case always yields a mole with a karyotype of 46 XX, since at least one X chromosome is required for viability and a karyotype of 46 YY is rapidly lethal to the ovum. The latter case may yield a karyotype of 46 XX or 46 XY. About 90% of complete HMs are 46 XX. On ultrasound examination, complete moles rarely reveal a fetus or amniotic fluid.

Partial HM

A partial mole occurs when the ovum retains its nucleus but is fertilized by a single sperm, with subsequent chromosome duplication, or is fertilized by two sperm; the possible resulting triploid karyotypes are 69 XXY, 69 XXX, or 69 XYY. Therefore, in contrast to a complete mole, the partial mole chromosomes of a partial mole are only two-thirds paternal in origin. In contrast to complete moles, partial moles usually show a fetus, which may even be viable, and amniotic fluid is visible.

Complete HMs have a 15% to 25% risk of developing into GTNs, but transformation to malignancy is much more rare (<5%) in the case of partial moles.

Invasive Mole

Invasive moles (chorioadenoma destruens) are locally invasive, rarely metastatic lesions characterized microscopically by trophoblastic invasion of the myometrium with identifiable villous structures. They are usually diploid in karyotype, but may be aneuploid. Microscopically, these lesions are characterized by hyperplasia of cytotrophoblastic and syncytial elements and persistence of villous structures. They may resemble choriocarcinoma in histologic appearance. Invasive moles have more aggressive behavior than either complete or partial HMs, and they are treated similarly to choriocarcinoma (i.e., with chemotherapy). However, unlike choriocarcinoma, they may regress spontaneously.

Gestational Trophoblastic Neoplasias

Choriocarcinoma

Choriocarcinoma is a malignant tumor of the trophoblastic epithelium. Uterine muscle and blood vessels are invaded with areas of hemorrhage and necrosis. Columns and sheets of trophoblastic tissue invade normal tissues and spread to distant sites, the most common of which are lungs, brain, liver, pelvis, vagina, spleen, intestines, and kidney. Most choriocarcinomas have an aneuploid karyotype, and about three-quarters contain a Y chromosome. Most follow an HM pregnancy, spontaneous abortion, or ectopic pregnancy; but about one-quarter are preceded by a full-term pregnancy. Nearly all GTNs that are preceded by nonmolar pregnancies are choriocarcinomas; the rare exceptions generally are (PSTTs).

PSTT

PSTT disease is the result of a very rare tumor arising from the placental implantation site and resembles an exaggerated form of syncytial endometritis. Trophoblastic cells infiltrate the myometrium, and there is vascular invasion. Human placental lactogen is present in the tumor cells, whereas immunoperoxidase staining for human chorionic gonadotropin (hCG) is positive in only scattered cells, and elevations in serum hCG are relatively low compared with the marked elevations seen in choriocarcinoma. hCG is not a reliable marker of tumor volume. 1 2 PSTTs have much lower growth rates than choriocarcinoma, and presentation after a full-term pregnancy is often delayed by months or years. They are generally resistant to chemotherapy. Therefore, hysterectomy is the standard primary treatment if the tumor is confined to the uterus. However, about 35% of PSTTs have distant metastases at diagnosis. 2 3 Common sites of metastasis include the lungs, pelvis, and lymph nodes. Central nervous system, renal, and liver metastases have also been observed.

ETT

ETT is an extremely rare gestational trophoblastic tumor. 4 5 Although originally termed atypical choriocarcinoma, it appears to be less aggressive than choriocarcinoma and is now regarded as a distinct entity. Pathologically, it has a monomorphic cellular pattern of epithelioid cells and may resemble squamous cell cancer of the cervix when arising in the cervical canal. Its clinical behavior appears to be closer to that of PSTT than to choriocarcinoma. It has a spectrum of clinical behavior from benign to malignant. About one-third of patients present with metastases, usually in the lungs.

References:

1. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990. [PUBMED Abstract]
2. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002. [PUBMED Abstract]
3. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009. [PUBMED Abstract]
4. Shih IM, Kurman RJ: Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 22 (11): 1393-403, 1998. [PUBMED Abstract]
5. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008. [PUBMED Abstract]

Stage Information for Gestational Trophoblastic Tumors and Neoplasia

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Hydatidiform Mole (HM)

HM (molar pregnancy) is disease limited to the uterine cavity.

Invasive Mole (Chorioadenoma Destruens)

Invasive mole (chorioadenoma destruens) is a locally invasive, rarely metastatic lesion.

Gestational Trophoblastic Neoplasia

Definitions: FIGO

The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define gestational trophoblastic neoplasia; the FIGO system is most commonly used. 1 2 Some tumor registrars encourage the recording of staging in both systems.

FIGO staging system (and modified World Health Organization [WHO] prognostic scoring system)

The FIGO staging system is as follows: 1

Table 1. Gestational Trophoblastic Neoplasia (GTN)^a,b

^aAdapted from FIGO Committee on Gynecologic Oncology.^bTo stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e., stage II:4, stage IV:9. This stage and score will be allotted for each patient.

FIGO Anatomical Staging
Stage
I	Disease confined to the uterus.
II	GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament).
III	GTN extends to the lungs, with or without known genital tract involvement.
IV	All other metastatic sites.
Modified WHO Prognostic Scoring System as Adapted by FIGOb
Scores	0	1	2	4
Age	<40	40
Antecedent pregnancy	mole	abortion	term
Interval months from index pregnancy	<4	46	712	>12
Pretreatment serum hCG (iu/1)	<103	103104	104105	>105
Largest tumor size (including uterus)	<3	34 cm	5 cm
Site of metastases	lung	spleen, kidney	gastrointestinal	liver, brain
Number of metastases		14	58	>8
Previous failed chemotherapy			single drug	2 drugs
FIGO = Féderation Internationale de Gynécologie et d'Obstétrique; hCG = human chorionic gonadotropin; iu = international unit; WHO = World Health Organization.
1

In addition, the FIGO staging system incorporates a modified WHO prognostic scoring system. The scores from the eight risk factors are summed and incorporated into the FIGO stage, separated by a colon (e.g., Stage II:4, Stage IV:9, etc.). Unfortunately, a variety of risk scoring systems have been published, making comparisons of results difficult.

References:

1. FIGO Committee on Gynecologic Oncology.: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 105 (1): 3-4, 2009. [PUBMED Abstract]
2. Gestational trophoblastic tumors. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p 439. [PUBMED Abstract]

Treatment Option Overview

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Most hydatidiform moles (HMs) are benign and are treated conservatively by dilation, suction evacuation, and curettage. However, since they carry a risk of persistence or progression to malignant gestational trophoblastic neoplasms (GTNs), they must be followed carefully with weekly serum human chorionic gonadotropin (hCG) levels to normalization. Monthly follow-up for 6 months is generally recommended, although the duration of this phase of follow-up is not based on empiric study.

Prompt institution of therapy for GTN and continuing follow-up at very close intervals until normal beta-hCG titers are obtained is the cornerstone of management. When chemotherapy is instituted, the interval between courses should rarely exceed 14 to 21 days, depending on the regimen used. It is recommended that patients receive one to three courses of chemotherapy after the first normal beta-hCG titer, depending on the extent of disease. The modified World Health Organization (WHO) Prognostic Scoring System (see Table 1) should be utilized, and combination chemotherapy should be initiated when warranted by the patient's score. If a diagnosis of GTN is made, routine work-up includes the following:

• Serum beta-hCG.
• Blood work of liver, renal, and marrow function.
• Chest x-ray.
• Pelvic ultrasound.
• Head computed tomography or magnetic resonance imaging (in the case of choriocarcinoma or central nervous system signs).

Treatment of GTN depends on the risk category determined by the Modified WHO Prognostic Scoring System as adapted by the International Federation of Gynecology and Obstetrics (see Table 1). Since the very rare placental-site trophoblastic tumors (PSTTs) and the even more rare epithelioid trophoblastic tumors (ETTs) are biologically distinct entities, their management is discussed separately.

Low Levels of hCG

Accurate monitoring of hCG is critical to successfully diagnose and monitor the treatment course of gestational trophoblastic disease. False-positive results may lead to inappropriate diagnoses and treatment, and therefore must be minimized. The following are a list of possible alternate diagnoses to be considered in cases of low-level hCG.

False-positive hCG

Serum hCG testing relies on detecting two antibodies on the hCG molecule. The antibodies are polyclonal or monoclonal antibodies derived from various animals: mouse, rabbit, goat or sheep. Humans with heterophilic (or cross-species) antibodies bind the antibodies in the assay, leading to a false-positive result. This was a common problem with one of the commercially available assays until it was re-engineered in 2003. Heterophilic antibodies cannot cross the glomerular filtration barrier, so the performance of a urinary hCG can eliminate this source for a positive test result. The urine sample should be run using the same system generally reserved for serum, as opposed to over-the-counter urine-pregnancy tests, to avoid decreased sensitivity in the latter.

Pituitary hCG

The anterior stalk of the pituitary secretes luteinizing hormone (LH), which shares an alpha subunit with hCG. In normal menstrual cycles, pituitary generated hCG may be detectable at the time of the LH surge. Estrogen provides negative feedback for this LH secretion and acts as a suppressing agent. In patients in low-estrogen states (perimenopause, menopause, and status postoophorectomy), pituitary hCG may be secreted in increasing amounts, although only levels between 1 to 32 mIU/mL have been recorded. 1 To confirm a pituitary source for the hCG, patients are started on high-dose oral contraceptive pills to produce an exogenous source of estrogen. In general, patients with pituitary hCG will have their hCG levels suppressed after 3 weeks on this regimen. 1

References:

1. Muller CY, Cole LA: The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol 112 (3): 663-72, 2009. [PUBMED Abstract]

Hydatidiform Mole (HM) Management

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Treatment of HM is within the purview of the obstetrician/gynecologist and will not be discussed separately here. However, following the diagnosis and treatment of HM, patients should be monitored to rule out the possibility of metastatic gestational trophoblastic neoplasia (GTN). In almost all cases, this can be performed with routine monitoring of serum beta human chorionic gonadotropin (beta-hCG) to document its return to normal. An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.

Chemotherapy is necessary when there is the following:

1. A rising beta-hCG titer for 2 weeks (3 titers).
2. A tissue diagnosis of choriocarcinoma.
3. A plateau of the beta-hCG for 3 weeks.
4. Persistence of detectable beta-hCG 6 months after mole evacuation.
5. Metastatic disease.
6. An elevation in beta-hCG after a normal value.
7. Postevacuation hemorrhage not caused by retained tissues.

Chemotherapy is ultimately required for persistence or neoplastic transformation in about 15% to 20% of patients after evacuation of a complete HM but for fewer than 5% of patients with partial HM. Chemotherapy is the same as for nonmetastatic GTN.

In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:

• Age older than 35 years or age younger than 20 years.
• Pre-evacuation serum beta-hCG greater than 100,000 IU/L.
• Large-for-date uterus.
• Large uterine molar mass.
• Large (>6 cm) ovarian cysts.
• Pre-eclampsia.
• Hyperthyroidism.
• Hyperemesis of pregnancy.
• Trophoblastic embolization.
• Disseminated intravascular coagulation.

Studies have shown that a single course of prophylactic dactinomycin or methotrexate can decrease the risk of a postmolar GTN. 1 2 3 However, there is concern that chemoprophylaxis increases tumor resistance to standard therapy in the women who subsequently develop GTN. 1 Therefore, this practice is generally limited to countries in which a large number of women do not return for follow-up.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with hydatidiform mole. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Kim DS, Moon H, Kim KT, et al.: Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. Obstet Gynecol 67 (5): 690-4, 1986. [PUBMED Abstract]
2. Limpongsanurak S: Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 46 (2): 110-6, 2001. [PUBMED Abstract]
3. Uberti EM, Fajardo Mdo C, Ferreira SV, et al.: Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy. Gynecol Oncol 115 (3): 476-81, 2009. [PUBMED Abstract]

Low-Risk Gestational Trophoblastic Neoplasia (FIGO Score 06) Treatment

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There is no consensus on the best chemotherapy regimen for initial management of low-risk gestational trophoblastic neoplasia (GTN), and first-line regimens vary by geography and institutional preference. Most regimens have not been compared head-to-head, and the level of evidence for efficacy is therefore often limited to 3iiDii except as noted below. Importantly, even if there are differences in initial remission rate among the regimens, salvage with alternate regimens is very effective, and the ultimate cure rates are generally 99% or more. The initial regimen is generally given until a normal beta human chorionic gonadotropin (beta-hCG) (for the institution) is achieved and sustained for 3 consecutive weeks (or at least for one treatment cycle beyond normalization of the beta-hCG). A salvage regimen is instituted if any of the following occur:

• A plateau of the beta-hCG for 3 weeks (defined as a hCG decrease of 10% or less for 3 consecutive weeks).
• A rise in beta-hCG of greater than 20% for 2 consecutive weeks.
• Metastases appear.

The use of chemotherapy in the first-line management of low-risk GTN has been assessed in a Cochrane Collaboration systematic review. 1 In that systematic review, four randomized controlled trials were identified. 2 3 4 5

Three of the randomized trials 3 4 5 compared the same two commonly used regimens:

• Biweekly (pulsed) dactinomycin (1.25 mg/m² intravenously [IV]) .
• Weekly intramuscular methotrexate (30 mg/m²).

These three trials included a total of 392 patients. All three trials showed better primary complete response (CR) rates without the need for additional salvage therapy associated with pulsed dactinomycin (relative risk [RR] of cure = 3.00; 95% confidence interval (CI), 1.108.17), even though the magnitude of benefit showed substantial heterogeneity (I² statistic = 79%). 3 4 5[Level of evidence: 1iiDii] Fewer courses of therapy were needed to achieve CR and cure with dactinomycin treatment as well. As expected, salvage chemotherapy was nearly uniformly successful, since almost all low-risk GTN patients are ultimately cured, irrespective of the initial chemotherapeutic regimen. There were no statistically significant differences in most toxicities, including the following:

• Nausea and vomiting.
• Diarrhea.
• Hematologic toxicity.
• Hepatic toxicity.

There was a statistically significant increase in dermatologic toxicity, including alopecia, associated with dactinomycin. However, in the largest study, 5 there was statistically significantly more low-grade gastrointestinal toxicity, grade 2 nausea, grade 1 to 2 vomiting, and grades 1 to 3 neutropenia in the dactinomycin group. In that study, choriocarcinoma patients and patients with a risk score of 5 to 6 had a worse CR rate to initial treatment with single-agent therapy, and methotrexate was virtually ineffective. 5

The fourth randomized trial was a very small study of 45 patients, comparing a 5-day regimen of dactinomycin (10 ¼g/kg) to an 8-day regimen of methotrexate (1 mg/kg) and folinic acid (0.1 mg/kg) on alternate days. There was a statistically significant decrease in risk of failure to achieve primary cure without the need for salvage therapy in the dactinomycin arm (RR = 0.57; 95% CI, 0.400.81). 2[Level of evidence: 1iiDii] There was less alopecia associated with methotrexate but more hepatic toxicity.

The Cochrane systematic review also summarized the evidence from four nonrandomized trials, but comparisons across studies are difficult. The regimens evaluated in those studies are included in the lists below. 1[Level of evidence: 3iiDii]

Commonly used treatment regimens include the following:

1. The 8-day Charing Cross regimen. Methotrexate (50 mg intramuscularly (IM) on days 1, 3, 5, and 7) and folinic acid (7.5 mg orally on days 2, 4, 6, and 8). This may be the most common regimen worldwide, 1 6 but it has not been directly compared to other regimens.
2. Biweekly pulsed dactinomycin (1.25 mg/m² intravenously [IV]).
3. Weekly methotrexate (30 mg/m² IM). Efficacy of this regimen appears to be low for choriocarcinoma and for patients with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) risk scores of 5 to 6.

Other regimens in less-common use include the following: 1

• An 8-day regimen of methotrexate (1 mg/kg IM days 1, 3, 5, and 7) and folinic acid (0.1 mg/kg IM days 2, 4, 6, and 8).
• Methotrexate 20 mg/m² IM days 1 to5, repeated every 14 days.
• Dactinomycin 12 ¼g/kg/day IV days 1 to 5, repeated every 2 to 3 weeks. This regimen has fallen out of favor because of substantial alopecia and nausea.
• Methotrexate 20 mg IM daily, days 1 to 5; and dactinomycin 500 ¼g IV daily, days 1 to 5, repeated every 14 days.
• Dactinomycin 10 ¼g/kg/day, days 1 to 5, repeated every 2 weeks.
• Methotrexate 0.4 mg/kg/day IM daily on days 1 to 5, repeated after 7 days.
• Etoposide 100 mg/m²/day IV on days 1 to 5, or 250 mg/m² IV on days 1 and 3, at 10-day intervals. 7

The unusual patient with a tumor that becomes refractory to single-agent chemotherapy is treated with one of the combination regimens described below for high-risk GTN. (Refer to the High-Risk Gestational Trophoblastic Neoplasia (FIGO Score 7) Treatment section of this summary for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with low risk metastatic gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Alazzam M, Tidy J, Hancock BW, et al.: First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev (1): CD007102, 2009. [PUBMED Abstract]
2. Lertkhachonsuk AA, Israngura N, Wilailak S, et al.: Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 19 (5): 985-8, 2009. [PUBMED Abstract]
3. Gilani MM, Yarandi F, Eftekhar Z, et al.: Comparison of pulse methotrexate and pulse dactinomycin in the treatment of low-risk gestational trophoblastic neoplasia. Aust N Z J Obstet Gynaecol 45 (2): 161-4, 2005. [PUBMED Abstract]
4. Yarandi F, Eftekhar Z, Shojaei H, et al.: Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynaecol Obstet 103 (1): 33-7, 2008. [PUBMED Abstract]
5. Osborne RJ, Filiaci V, Schink JC, et al.: Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol 29 (7): 825-31, 2011. [PUBMED Abstract]
6. Khan F, Everard J, Ahmed S, et al.: Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects. Br J Cancer 89 (12): 2197-201, 2003. [PUBMED Abstract]
7. Hitchins RN, Holden L, Newlands ES, et al.: Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987. Eur J Cancer Clin Oncol 24 (6): 1041-6, 1988. [PUBMED Abstract]

High-Risk Gestational Trophoblastic Neoplasia (FIGO Score 7) Treatment

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Multi-agent chemotherapy is standard for the initial management of high-risk gestational trophoblastic neoplasia (GTN). A systematic literature review revealed only one randomized controlled trial (and no high-quality trials)conducted in the 1980scomparing multiagent chemotherapy regimens for high-risk GTN. 1 In the trial, only 42 women were randomly assigned to either a CHAMOMA regimen (i.e., methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin) or MAC (i.e., methotrexate, dactinomycin, and chlorambucil). 2 There was substantially more life-threatening toxicity in the CHAMOMA arm and no evidence of higher efficacy. However, there were serious methodologic problems with this trial. It was reportedly designed as an equivalency trial, but owing to the small sample size, the trial was inadequately powered to assess equivalence. In addition, the characteristics of the patients randomly assigned to the two study arms were not reported (although the authors stated that there were no major differences in the patient populations assigned to each arm), nor was the method of randomization or allocation concealment described.

There are no randomized trials comparing regimens in common use to establish the superiority of one over another. Therefore, the literature does not permit firm conclusions about the best chemotherapeutic regimen. 1[Level of evidence 3iiiDii] However, since EMA/CO (i.e., etoposide, methotrexate, and dactinomycin/cyclophosphamide and vincristine) is the most commonly used regimen, the specifics are provided in Table 2 below. 3 4 5

Table 2. Specifics of the EMA/CO Regimen^a,b,c

^aAdapted from Bower et al. ^bAdapted from Escobar et al.^cAdapted from Lurain et al.

Day	Drug	Dose
1	Etoposide	100 mg/m2 IV for 30 min
	Dactinomycin	0.5 mg IV push
	Methotrexate	300 mg/m2 IV for 12 h
2	Etoposide	100 mg/m2 IV for 30 min
	Dactinomycin	0.5 mg IV push
	Folinic Acid	15 mg or PO every 12 h í 4 doses, beginning 24 h after the start of methotrexate
8	Cyclophosphamide	600 mg/m2 IV infusion
	Vincristine	0.81.0 mg/m2 IV push (maximum dose 2 mg)
IV = intravenously; PO = orally.
3
4
5

Cycles are repeated every 2 weeks (on days 15, 16, and 22) until any metastases present at diagnosis disappear and serum beta-human chorionic gonadotropin (beta-hCG) has normalized, then the treatment is usually continued for an additional three to four cycles.

Results of a large, consecutive case series of 272 patients with up to 16 years of follow-up showed a complete remission rate of 78% using this regimen, results that are consistent with other case series in the literature that employed EMA/CO. 3 More than two-thirds of the women who did not have a complete response or subsequently had disease recurrence could be salvaged with cisplatin-containing regimens (with or without resection of metastases), yielding a long-term cure rate of 86.2% (95% CI, 81.9%90.5%). 3[Level of evidence: 3iiA] Among the women who had an intact uterus, about one-half of them retained their fertility. Patients with documented brain metastases received higher doses of systemic methotrexate as part of the EMA component (i.e., etoposide, methotrexate, folinic acid, and dactinomycin) of EMA/CO (1 g/m² IV for 24 hours, followed by folinic-acid rescue, 15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with brain metastases received an increased dose of systemic methotrexate of 1 g/m² for 24 hours followed by folinic acid (15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with lung metastases received cranial prophylaxis with irradiation and intrathecal methotrexate 12.5 mg every 2 weeks with the CO (i.e., cyclophosphamide and vincristine) cycles.

Examples of other regimens that have been used include the following: 1

• MAC: Methotrexate, folinic acid, dactinomycin, and cyclophosphamide.
• Another MAC: methotrexate, dactinomycin, and chlorambucil.
• EMA: etoposide, methotrexate, folinic acid, and dactinomycin (EMA/CO without the CO).
• CHAMOCA: methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine.
• CHAMOMA: methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin.

Brain metastases are associated with poor prognosis, particularly when liver metastases are also present. 6 7 8 However, even patients with brain metastases may achieve long-term remission in 50% to 80% of cases. 3 4 8 Patients with central nervous system (CNS) metastases receive additional therapy simultaneously with the initiation of systemic chemotherapy. Some centers utilize whole-brain irradiation (30 Gy in 2 Gy fractions) with or without intrathecal methotrexate. 6 However, some investigators omit the cranial radiation, relying on replacement of the standard dose of methotrexate in the EMA/CO regimen with the higher dose of 1000 mg/m² IV for 24 hours on the first day, as noted above, to achieve therapeutic CNS levels. 8

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with high risk metastatic gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Deng L, Yan X, Zhang J, et al.: Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev (2): CD005196, 2009. [PUBMED Abstract]
2. Curry SL, Blessing JA, DiSaia PJ, et al.: A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 73 (3 Pt 1): 357-62, 1989. [PUBMED Abstract]
3. Bower M, Newlands ES, Holden L, et al.: EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 15 (7): 2636-43, 1997. [PUBMED Abstract]
4. Escobar PF, Lurain JR, Singh DK, et al.: Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol 91 (3): 552-7, 2003. [PUBMED Abstract]
5. Lurain JR, Singh DK, Schink JC: Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score > or = 7. J Reprod Med 55 (5-6): 199-207, 2010 May-Jun. [PUBMED Abstract]
6. Small W Jr, Lurain JR, Shetty RM, et al.: Gestational trophoblastic disease metastatic to the brain. Radiology 200 (1): 277-80, 1996. [PUBMED Abstract]
7. Crawford RA, Newlands E, Rustin GJ, et al.: Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gynaecol 104 (1): 105-9, 1997. [PUBMED Abstract]
8. Newlands ES, Holden L, Seckl MJ, et al.: Management of brain metastases in patients with high-risk gestational trophoblastic tumors. J Reprod Med 47 (6): 465-71, 2002. [PUBMED Abstract]

Placental-Site Gestational Trophoblastic Tumor Treatment

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Given the rarity of this tumor, reports of therapeutic results are confined to relatively small case series with accrual extending for very long time periods. Therefore, few reliable comparisons among surgical approaches or chemotherapeutic regimens can be made. Nevertheless, there are distinctions in underlying biology between placental-site gestational trophoblastic tumors (PSTTs) and the other gestational trophoblastic tumorsparticularly resistance to chemotherapythat justify specific treatment strategies, such as the following:

1. Tumors confined to the uterus (Féderation Internationale de Gynécologie et d'Obstétrique [FIGO] Stage I).

   Hysterectomy is the treatment of choice. 1 2 In a relatively large retrospective population-based consecutive case series of 62 women with PSTT, 33 had disease confined to the uterus and were treated with hysterectomy (n = 17) or with hysterectomy plus chemotherapy (n = 16). Overall survival at 10 years was virtually identical between the two groups (90% and 91%, respectively). There was only one recurrence in the surgery group and two in the combination therapy group. In a relatively large retrospective population-based consecutive case series of 62 women with PSTT, 33 had disease confined to the uterus and were treated with hysterectomy (n = 17) or with hysterectomy plus chemotherapy (n = 16). Overall survival at 10 years was virtually identical between the two groups (90% and 91%, respectively). There was only one recurrence in the surgery group and two in the combination therapy group. 2[[Level of evidence 3iDiiLevel of evidence 3iDii] There is little evidence to guide the optimal extent of surgery (e.g., lymph node resection or oophorectomy).] There is little evidence to guide the optimal extent of surgery (e.g., lymph node resection or oophorectomy).

2. Tumors with extrauterine spread to genital structures (FIGO stage II).

   Complete resection with or without adjuvant chemotherapy. Because the relapse rate is high after surgery and overall mortality in patients is high, adjuvant multiple-agent chemotherapy should be considered. 1 2[Level of evidence 3iDii][Level of evidence 3iDii] However, the impact of adjuvant therapy on overall mortality is uncertain. However, the impact of adjuvant therapy on overall mortality is uncertain.

3. Metastatic tumors (FIGO stages III and IV).

   Polyagent chemotherapy. A variety of regimens have been used, with no direct comparisons to determine whether one is superior. Some of the regimens include the following: 1 2

   • EMA/CO: Etoposide, methotrexate with folinic acid rescue, dactinomycin, cyclophosphamide, and vincristine. This appears to be the most commonly used regimen.
   • EP/EMA: Etoposide and cisplatin with etoposide, methotrexate, and dactomycin.
   • MAE: methotrexate with folinic acid rescue, dactinomycin, and etoposide.

In part because of the inherent chemoresistance of PSTTs, resection of tumors is often considered in addition to chemotherapy regimens used for high-risk gestational trophoblastic neoplasias. In retrospective series, adjuvant surgery, such as hysterectomy, excision of lung metastases, or removal of obstructing abdominal lesions, has been associated with favorable disease control. However, it is not clear as to what component of the favorable outcomes is attributable to the surgery versus patient selection factors. 2 3[Level of evidence 3iiiDii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with placental-site gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990. [PUBMED Abstract]
2. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009. [PUBMED Abstract]
3. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002. [PUBMED Abstract]

Epithelioid Trophoblastic Tumor Treatment

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These tumors are exceedingly rare. There is little information to guide therapy. However, they are similar in behavior and prognosis to placental-site trophoblastic tumors, so it is reasonable to manage them similarly. (Refer to the Placental-Site Gestational Trophoblastic Tumor Treatment section of this summary for more information.) Only a minority of these tumors are malignant in behavior, but they are not very responsive to systemic therapy. A variety of chemotherapy regimens have been used. 1

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with epithelioid trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008. [PUBMED Abstract]

Recurrent or Chemoresistant Gestational Trophoblastic Tumor Treatment

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Recurrent disease indicates failure of prior chemotherapy unless initial therapy was surgery alone. One study found recurrence of disease in 2.5% of patients with nonmetastatic disease, 3.7% of patients with good-prognosis metastatic disease, and 13% of patients with poor-prognosis metastatic disease. 1 Nearly all recurrences occur within 3 years of remission (85% before 18 months). A patient whose disease progresses after primary surgical therapy is generally treated with single-agent chemotherapy unless one of the poor-prognosis factors that requires combination chemotherapy supervenes. Relapse after prior chemotherapy failure automatically places the patient into the high-risk category. These patients should be treated with aggressive chemotherapy.

Reports of combination chemotherapy come from small retrospective case series. Long-term disease-free survival, in excess of 50%, is achievable with combination drug regimens. 2[Level of evidence: 3iiiDii] A variety of regimens have been reported that include combinations of the following: 3 4 5 6 7

• Cisplatin.
• Etoposide.
• Bleomycin.
• Ifosfamide.
• Paclitaxel.
• 5-fluorouracil.
• Floxuridine.

A select group of patients with chemotherapy-resistant and clinically detectable gestational trophoblastic tumors may benefit from salvage surgery. 8[Level of evidence: 3iiiDii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent gestational trophoblastic tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Mutch DG, Soper JT, Babcock CJ, et al.: Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center.