Gestational Trophoblastic Neoplasia

Practice Essentials

Gestational trophoblastic neoplasia (GTN) is a collective term for gestational trophoblastic diseases that invade locally or metastasize. Hydatidiform mole is the most common form of GTN (see the image below); others are invasive mole (chorioadenoma destruens), choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT).

View Image

Histologic section of a complete hydatidiform mole stained with hematoxylin and eosin. Villi of different sizes are present. The large villous in the ....

Signs and symptoms

Most cases of GTN are diagnosed when the serum hCG levels plateau or rise in patients being observed after the diagnosis of hydatidiform mole. If metastases have developed, the following signs and symptoms may be noted:

• Metastasis to the lower genital tract presents as purple to blue-black papules or nodules, which are extremely vascular and may bleed profusely if biopsied^[1]
• Abdominal tenderness, if liver or gastrointestinal metastases have occurred
• Abdominal guarding and rebound tenderness, if a hemoperitoneum has occurred due to bleeding from an abdominal metastasis
• Bleeding from a metastasis could also result in signs and symptoms of hemorrhagic shock^{[2, 3]}
• Neurologic deficits, from lethargy to coma, if brain metastasis has occurred
• Jaundice, if liver metastasis causes biliary obstruction

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies used in the diagnosis of GTN are as follows:

• Serum quantitative hCG – To assess response to therapy and disease status
• CBC – May help detect anemia secondary to bleeding
• Liver enzymes – May become elevated in patients with metastasis to the liver

Imaging studies

• Pelvic ultrasonography – May show persistent molar tissue in the uterus
• Chest radiograph – Recommended because the lung is the most frequent site of metastasis
• CT scan of the chest (optional)
• CT scan of the abdomen and pelvis with contrast
• MRI of the head (preferable to CT)

CT and MRI are recommended if the patient has hydatidiform mole with metastasis to the lungs, choriocarcinoma, or persistent hydatidiform mole. The lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract are common sites of metastases.

Procedures

• Suction and careful sharp curettage could be performed in patients being observed for a hydatidiform mole who have persistent vaginal bleeding and tissue within the endometrial cavity on pelvic ultrasonography
• Uterine dilatation and curettage (D&C) performed in a woman with abnormal vaginal bleeding and a positive pregnancy test result may reveal a choriocarcinoma

Features of a D&C are as follows:

• A D&C may be part of the evaluation of a patient with an elevated serum hCG level of unknown origin
• The tissue is sent for histopathologic examination
• Examination may reveal a hydatidiform mole (complete or partial) or a choriocarcinoma
• Rarely is a histopathologic diagnosis of an invasive mole made on a D&C specimen, because this requires the identification of destructive invasion of the myometrium by the trophoblasts
• Typically, scant or no myometrium is recovered on a D&C specimen
• Rarely is the diagnosis of PSTT made on a D&C specimen, since this usually presents as intermediate trophoblasts infiltrating the myometrium

Staging and prognostic scoring

The official International Federation of Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows^{[4, 5]} :

• Stage I – Confined to the uterus
• Stage II – Limited to the genital structures
• Stage III – Lung metastases
• Stage IV – Other metastases

The currently used prognostic scoring index is a modification of the World Health Organization (WHO) classification. Scores are determined by adding up points from a list of 19 prognostic factors.

See Workup for more detail.

Management

Patients with GTN are subdivided into 2 groups: those with a WHO score of less than 7 (low-risk) and those with a score of 7 or higher and who are at high risk of therapy failure. Patients with nonmetastatic GTN or metastatic low-risk GTN are treated with single-agent chemotherapy, as follows^{[6, 7, 8, 9, 10, 11]} ​^[12] :

• Methotrexate is preferred by many US specialists, but actinomycin D can be used in patients with poor liver function
• During treatment, the serum hCG levels are monitored every week
• Six weeks of maintenance chemotherapy is administered after a normal serum hCG level
• After 3-4 normal serum hCG levels, the levels are observed once per month for 1 year
• A switch from methotrexate to actinomycin D is made if the serum hCG levels rise or plateau and the WHO score remains less than 7

 Treatment in patients with WHO scores of 7 or higher is as follows:

• EMA-CO regimen – A combination of etoposide, methotrexate, and actinomycin D administered in the first week of a 2-week cycle, and cyclophosphamide and vincristine (Oncovin) administered in the second week^{[13, 14, 15, 16]}
• EMA-EP regimen – Cisplatin and etoposide are substituted for cyclophosphamide and vincristine during the second week^[17] ; sometimes reserved for patients in whom EMA-CO fails
• At least 6 weeks of maintenance EMA-CO or EMA-EP are administered after a normal serum hCG level
• Patients with liver metastasis are considered for liver irradiation (2000 cGy)^[18]

Brain metastasis treatment

• Whole brain irradiation (3000 cGy) is given in combination with chemotherapy^{[19, 20, 21]} ; dexamethasone is administered to reduce brain edema (most common approach in US)
• Early neurosurgical intervention for solitary lesions or stereotactic radiotherapy for multiple lesions or solitary lesions in locations at high risk for surgical morbidity,^[22] followed by moderate- and high-dose intravenous methotrexate and, at some centers, intrathecal methotrexate (approach used in selected institutions)
• A therapeutic level of methotrexate is achieved in the cerebrospinal fluid at IV doses of >600 mg/m^2[22]
• In patients not receiving whole brain irradiation, the dose of methotrexate on day 1 of the EMA-CO or EMA-EP regimen is increased to 1000 mg/m²
• Instead of 4 doses of folinic acid (15 mg every 12 hours), 12 doses (15 mg every 6 hours) are given, starting 24 hours after the initiation of methotrexate infusion

Stage IV GTN

• Patients with stage IV GTN are most often treated with multiagent chemotherapy, even when the WHO score is less than 7, which is uncommon
• After achieving 3-4 consecutive weekly normal serum hCG levels, patients with stage IV GTN are observed with monthly serum hCG levels for 2 years
• If the levels begin to rise during follow-up, the patient is evaluated for possible intervening pregnancy, or persistent or recurrent disease

Surgical care

• Uterine or hypogastric artery ligation or embolization of feeding vessels may be needed to control hemorrhage; hepatic artery embolization has been used successfully to control hemorrhage from hepatic metastases^[2]
• A hysterectomy may be necessary in case of uncontrolled vaginal bleeding
• Craniotomy may be needed to control bleeding and provide decompression^{[15, 22]}
• Resection of solitary metastasis (eg, thoracotomy) or disease within the myometrium may help achieve a remission^{[23, 24, 25]}
• A complete response (normalization of serum hCG) occurs in 30-40% of patients with newly diagnosed low-risk non-metastatic GTN who undergo a repeat D&C
• Hysterectomy,^{[26, 27]} or a repeat D&C in patients with persistent tissue on pelvic ultrasonography, may reduce the number of chemotherapy cycles needed to achieve remission^[28]
• A hysterectomy is the treatment of choice for PSTT; the ovaries do not need to be removed if the patient is premenopausal^[29]

See Treatment and Medication for more detail.

• References

Background

Gestational trophoblastic disease (GTD) can be benign or malignant. Histologically, it is classified into hydatidiform mole, invasive mole (chorioadenoma destruens), choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). Those that invade locally or metastasize are collectively known as gestational trophoblastic neoplasia (GTN). Hydatidiform mole is the most common form of GTN. While invasive mole and choriocarcinoma are malignant, a hydatidiform mole can behave in a malignant or benign fashion.

View Image

Histologic section of a complete hydatidiform mole stained with hematoxylin and eosin. Villi of different sizes are present. The large villous in the ....

No methods exist to accurately predict the clinical behavior of a hydatidiform mole by histopathology. The clinical course is defined by the patient's serum human chorionic gonadotropin (hCG) curve after evacuation of the mole. In 80% of patients with a benign hydatidiform mole, serum hCG levels steadily drop to normal within 8-12 weeks after evacuation of the molar pregnancy. In the other 20% of patients with a malignant hydatidiform mole, serum hCG levels either rise or plateau.^{[4, 30]}

The International Federation of Gynecology and Obstetrics considers an elevated serum hCG level 6 or more months after evacuation of a hydatidiform mole to be diagnostic of malignancy (ie, GTN). However, serum hCG levels spontaneously return to normal without chemotherapy in most patients with elevated but still declining serum hCG levels 6 months after diagnosis of a hydatidiform mole. Therefore, continuing to follow these patients is reasonable as long as the hCG levels do not rise or plateau.^[31]

For more information on hydatidiform mole, see the Medscape Reference article Hydatidiform Mole.

• References

Pathophysiology

A hydatidiform mole is considered malignant when the serum hCG levels plateau or rise during the follow-up period and an intervening pregnancy is excluded. This occurs in 15-20% of hydatidiform moles.^{[4, 30, 32]}

A hydatidiform mole with a fetus or fetal tissue and a triploid karyotype is known as a partial or incomplete mole. Partial moles also have malignant potential, but only 2-3% become malignant.^{[33, 34, 35]} Cases of partial hydatidiform moles with lung metastasis have been reported and at least one case of choriocarcinoma on a biopsy from a vaginal metastasis has been reported in a patient being observed for a partial hydatidiform mole.^{[36, 37]}

An invasive mole has the same histopathologic characteristics of a hydatidiform mole, but invasion of the myometrium with necrosis and hemorrhage occurs or pulmonary metastases are present.

Histologically, choriocarcinomas have no villi, but they have sheets of trophoblasts and hemorrhage. Choriocarcinomas are aneuploid and can be heterozygous depending on the type of pregnancy from which the choriocarcinoma arose. If a hydatidiform mole preceded the choriocarcinoma, the chromosomes are of paternal origin. Maternal and paternal chromosomes are present if a term pregnancy precedes the choriocarcinoma. Of choriocarcinomas, 50% are preceded by a hydatidiform mole, 25% by an abortion, 3% by ectopic pregnancy, and the other 22% by a full-term pregnancy.^[4] Choriocarcinoma has also been associated with ectopic pregnancy with a theoretic incidence of 1 in 5333 ectopic pregnancies.^[38]

Placental site trophoblastic tumor is a rare form of gestational trophoblastic neoplasia.^{[39, 40]} In patients with PSTT, intermediate trophoblasts are found infiltrating the myometrium without causing tissue destruction. The intermediate trophoblasts contain human placental lactogen (hPL).^[41] These patients have persistent low levels of serum hCG (100-1000 mIU/mL). However, serum hCG levels as high as 108,000 mIU/mL have been reported in patients with PSTT.^[42] The treatment of PSTT is hysterectomy with ovarian conservation.^[29] If the tumor recurs or metastases are present at initial diagnosis, chemotherapy is administered with variable results.^{[43, 44]} Radiation therapy may provide local control.

Like PSTT, epithelioid trophoblastic tumor (ETT) is comprised of intermediate trophoblasts, but they have an epithelioid appearance.^[39] The monomorphic epithelioid cells form nests or cords. ETT frequently involves the lower uterine segment and endocervix, which could be misdiagnosed as a squamous cell carcinoma. When the ETT replaces the endocervical glands it could be confused with high grade squamous cervical intraepithelial neoplasia. ETT stains focally for hCG and human placental lactogen (hPL).  Serum levels of hCG are usually less than 1000 mIU/ml. Measuring serum levels hPL is not clinically useful. Similar to PSST the treatment is surgical with total hysterectomy with ovarian preservation in young women if the ovaries are not involved.

Both PSST and ETT may be diagnosed years after the antecedent pregnancy. They are characterized by slow growth and remain at stage I for a long time. The WHO score is not as useful as in other types of GTN in determining prognosis. Factors associated with poor prognosis include time from antecedent pregnancy, deep myometrial invasion, tumor necrosis, and mitotic count >6/10 high power fields. The prognosis is worse when the interval from the antecedent pregnancy is >4 years. Chemotherapy is administered to patients with metastatic disease or high risk factors. EMA-EP seems to be the most effective regimen.

The most frequent sites of metastases of malignant gestational trophoblastic neoplasia are the lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract.

View Image

In this microphotograph of a choriocarcinoma metastatic to the brain, the neuropil is seen on the right and the biphasic (2 cell populations) chorioca....

• References

Frequency

United States

Gestational trophoblastic neoplasia is diagnosed in 15-20% of patients with a complete hydatidiform mole and 2% of partial hydatidiform moles. Lung metastases are found in 4-5% of patients with complete hydatidiform moles and rarely in cases of partial hydatidiform moles.

Choriocarcinoma occurs in 1 out of 40 hydatidiform moles and in 1 out of 20,000-40,000 pregnancies.^{[4, 45]} However, only 1 out of 160,000 term pregnancies is followed by a choriocarcinoma.^[46]

International

The international rate of choriocarcinoma has been reported to be as high as 1 in 500-600 pregnancies in India to 1 in 50,000 pregnancies in Mexico, Paraguay, and Sweden.^{[45, 47, 48]} These differences are probably due to differences in methodology (eg, identification of cases, accuracy of denominator).^{[45, 47]}

Race-, sex-, age-related demographics

Little information is available on international ethnic or racial differences of the incidence of choriocarcinoma. In the United States, African Americans have the highest incidence of choriocarcinoma and the lowest survival rates.^[49]

Gestational trophoblastic neoplasia affects women during their reproductive years. However, placental site trophoblastic tumors have been diagnosed when patients were postmenopausal.

The incidence of choriocarcinoma increases with age and is 5-15 times higher in women 40 years and older than in younger women.^[47]

• References

Prognosis

Nonmetastatic GTN has a cure rate of close to 100% with chemotherapy treatment.

Metastatic low-risk GTN has a cure rate of close to 100% with chemotherapy treatment. Metastatic high-risk GTN has a cure rate of approximately 75% with chemotherapy treatment.

Currently, prognosis and treatment is decided using the WHO prognostic score. Patients with a WHO score of 6 or less have excellent prognosis and are initially treated with single agent chemotherapy. Patients with WHO score >6 have a prognosis similar to that of patients previously classified as having metastatic high-risk disease. These patients with high-risk disease are treated initially with multiagent chemotherapy. Patients with WHO score of 5-6 have a higher probability of failing initial single agent chemotherapy but a complete response is usually achieved when switching to the alternate agent if the serum hCG is below 300 IU//L.^[50]

After 12 months of normal hCG levels, less than 1% of patients with GTN have recurrences.

Morbidity/mortality

Patients who have a malignant hydatidiform mole, an invasive mole, or a choriocarcinoma should undergo a systematic search for metastases. Prior to the WHO scoring system as revised by FIGO in 2000, patients who had metastases were classified as high-risk or low-risk according to the National Institutes of Health (NIH) classification.^[30] The NIH criteria for high-risk metastatic gestational trophoblastic neoplasia included hepatic or brain metastasis, serum hCG levels greater than 40,000 mIU/mL prior to the initiation of chemotherapy, duration of disease longer than 4 months, prior unsuccessful chemotherapy, and malignant gestational trophoblastic neoplasia following a term pregnancy.

As noted above, patients with malignant nonmetastatic or metastatic low-risk gestational trophoblastic neoplasia have an almost 100% probability of cure with chemotherapy. The probability of cure after chemotherapy for patients with metastatic high-risk gestational trophoblastic neoplasia is approximately 75%.^[51]  The WHO score as modified by FIGO 2000 classifies patients into low risk if the score is 6 or less and high-risk if the score is >6. The reported cure rate for patients with low-risk disease (WHO score of 6 or less) is almost 100%.^[52] The survival of patients with high-risk disease (score >6) treated aggressively at specialized centers is better than 90%.^{[53, 54, 55]}

The probability of a late recurrence after the patient has been in remission (normal serum beta-hCG titers) for 1 year is less than 1%.^{[30, 56]}

See Prognosis section for more information on recurrence rate.

Complications

Plateauing or rising serum hCG levels during the period of follow-up care may indicate a normal intrauterine pregnancy or GTN with or without metastasis.

Etoposide is associated with an increased risk of developing leukemia. It should be used only in patients with high-risk disease.^[57]

The rate of abnormal pregnancies (spontaneous abortions, stillbirths, repeat GTD) is higher if a subsequent pregnancy occurs within 6 months of completing chemotherapy, compared with pregnancies that occur after 12 months.^[58]

• References

History

Most cases of gestational trophoblastic neoplasia are diagnosed when the serum hCG levels plateau or rise in patients being observed after the diagnosis of hydatidiform mole. If metastases are present, signs and symptoms associated with the metastatic disease, such as hemoptysis, abdominal pain, hematuria, and neurologic symptoms, may be present.

The FIGO 2000 criteria for the diagnosis of GTN after evacuation of a hydatidiform mole include: Serum hCG plateau over 4 weekly measurements (day 1, 7, 14 and 21), more than 10% rise in serum hCG level of three consecutive weekly measurements, elevated serum hCG 6 or more months after evacuation of the mole, or a histologic diagnosis of choriocarcinoma.^[59]

• References

Physical

Note the following:

• Metastasis to the lower genital tract present as purple to blue-black papules or nodules. These are extremely vascular and might bleed profusely if biopsied.^[1]
• Abdominal tenderness may be present if liver or gastrointestinal metastases have occurred.
• Abdominal guarding and rebound tenderness may be present if a hemoperitoneum has occurred due to bleeding from an abdominal metastasis. Bleeding from a metastasis could also result in signs and symptoms of hemorrhagic shock.^{[2, 3]}
• Neurologic deficits, from lethargy to coma, can be encountered if brain metastasis has occurred.
• Jaundice may be present if liver metastasis causes biliary obstruction.

• References

Causes

Why some hydatidiform moles become malignant and others do not is unknown. However, mounting evidence shows different molecular profiles between nonmalignant and malignant gestational trophoblastic disease.^{[60, 61, 62]}

• References

Laboratory Studies

Serum quantitative hCG is used to assess response to therapy and disease status.

A CBC may help detect anemia secondary to bleeding.

Liver enzymes levels may become elevated in the presence of metastasis to the liver.

• References

Imaging Studies

Pelvic ultrasonography

This may show persistent molar tissue in the uterus.

Chest radiography

This test is recommended because the lung is the most frequent site of metastasis.

Computed tomography scanning and magnetic resonance imaging

Chest computed tomography (CT) scanning (optional)

Micrometastases are present in approximately 40-45% of women with nonmetastatic gestational trophoblastic neoplasia (GTN) who have normal chest radiograph findings.^{[68, 69]} The significance of this is not clear. However, having metastasis elsewhere is extremely rare if pulmonary or lower genital tract metastases has not occurred.

If metastases are found on chest CT and not on chest radiograph, they cannot be used for purpose of staging.^{[4, 5, 30]}  Only lesions seen on chest radiograph are used to assign the WHO score. However, it has been suggested that a retrocardiac lesion that measures 1 cm or greater on CT can be used for scoring since this may be difficult to detect on a plain chest radiograph.^[70]

CT scan of the abdomen and pelvis with contrast and MRI of the head (preferable to CT)

CT and MRI are recommended if the patient has GTN (hydatidiform mole with metastasis to the lungs, choriocarcinoma, or persistent hydatidiform mole).

The lungs, lower genital tract, brain, liver, kidney, and gastrointestinal tract are common sites of metastases.

• References

Procedures

Note the following:

• Suction and careful sharp curettage could be performed in patients being observed for a hydatidiform mole who have persistent vaginal bleeding and tissue within the endometrial cavity on pelvic ultrasonography.
• A uterine dilatation and curettage (D&C) performed in a woman with abnormal vaginal bleeding and a positive pregnancy test result may reveal a choriocarcinoma.
• A D&C may be part of the evaluation of a patient with an elevated serum hCG levels of unknown origin: The tissue is sent for histopathologic examination; examination may reveal a hydatidiform mole (complete or partial) or a choriocarcinoma.
• Rarely is a histopathologic diagnosis of an invasive mole made on a D&C specimen because this requires the identification of destructive invasion of the myometrium by the trophoblasts. Typically, scant or no myometrium is recovered on a D&C specimen.
• Rarely is the diagnosis of placental site trophoblastic tumor (PSTT) made on a D&C specimen since this usually presents as intermediate trophoblasts infiltrating the myometrium.
• A complete response (normalization of serum hCG) occurs in 30-40% of patients with newly diagnosed low-risk non-metastatic GTN who undergo a repeat D&C.^[71]
• In a patient with GTN, a hysterectomy will likely reduce the total number of chemotherapy cycles required to achieve a remission.^{[26, 27]}
• A hysterectomy is the treatment of choice for PSTT and epithelioid trophoblastic tumor (ETT); the ovaries do not need to be removed if the patient is premenopausal.^[29]

• References

Histologic Findings

Complete hydatidiform moles have edematous placental villi, hyperplasia of the trophoblasts, and lack or scarcity of fetal blood vessels.

In the incomplete or partial hydatidiform mole, scalloping of the villi and trophoblastic inclusions occur within the villi. Fetal blood vessels are present.

In a hydropic degeneration of a normal pregnancy, edema of the villi is present, but no trophoblastic hyperplasia. Ghost villi may be observed.

Immunohistochemical staining for p57 may help differentiate between a complete mole and hydropic degeneration. P57 is a paternally imprinted gene that is only expressed in maternal chromosomes. Because all chromosomes of a complete mole are paternal in origin, the nuclei of the villous stroma and the cytotrophoblasts of complete moles do not stain for p57. Hydropic degeneration and partial moles do stain for p57 because they contain maternal chromosomes.^[72]

The invasive mole has the same appearance as the hydatidiform mole, but the myometrium is invaded with the presence of hemorrhage and tissue necrosis.

Although the choriocarcinoma has no chorionic villi, it has sheets of trophoblasts, hemorrhage, and necrosis.

In placental site trophoblastic tumor (PSTT), intermediate trophoblasts are found between myometrial fibers, without tissue necrosis.^[39]  

The epithelioid trophoblastic tumor (ETT) displays nodular nests and cords growth of monomorphic epithelioid cells.^[39]

• References

Staging

The official International Federation of Gynecology and Obstetrics staging of gestational trophoblastic neoplasia is as follows^{[4, 5]} :

• Stage I – Confined to the uterus
• Stage II – Limited to the genital structures
• Stage III – Lung metastases
• Stage IV – Other metastases

Each anatomical stage (roman numeral) is followed by the sum of the prognostic scores (see table below) separated by a colon (eg, stage III:5).^[73] The FIGO oncology committee at its 2000 meeting recommended that patients could be assigned to a low-risk group if the prognostic score was 0-6 and a high-risk group if the score was 7 or higher.

For patients who relapse, a full restaging to include response to previous chemotherapy can be done. This is different from other gynecologic cancers.

The currently used prognostic scoring index is a modification of the World Health Organization (WHO) classification. It provides points for the presence of a number of prognostic factors.

Table. Prognostic Scoring Index

View Table

See Table

• References

Approach Considerations

In September 2013, the European Society of Medical Oncology issued clinical practice guidelines for the diagnosis and treatment of gestational trophoblastic disease. Recommendations include the following^{[74, 50]} :

• Management of GTN requires pathology review, centralization of care, and monitoring of human chorionic gonadotropin (hCG)
• After staging with the FIGO scoring system, treatment may include either single-agent methotrexate or single-agent actinomycin D for low-risk disease or multiagent chemotherapy for patients with high-risk disease
• Low-risk disease requires 6 weeks of maintenance therapy after normalization of hCG, while high-risk disease with liver or brain metastases requires 8 weeks of maintenance therapy
• In patients with ultra-high-risk GTN, induction with low-dose etoposide and cisplatin may reduce the risk of early mortality
• Management of PSTT/epithelioid trophoblastic tumor (PSTT/ETT) varies according to disease stage and risk factors for poor outcome, which include the interval from last known pregnancy; patients presenting within 4 years of their last known pregnancy may need hysterectomy with pelvic node sampling, while those presenting later may be treated with multi-agent and subsequent high-dose chemotherapy

• References

Medical Care

Patients with gestational trophoblastic disease (GTD) do not require medical therapy. Because 20% of patients with hydatidiform mole develop malignant disease, such as persistent hydatidiform mole with or without metastasis, some have suggested the use of a prophylactic dose of methotrexate in noncompliant patients.^{[75, 76]} However, observing patients with weekly serum hCG levels is preferable, and only patients with rising or plateauing titers, as occurs in patients with gestational trophoblastic neoplasia (GTN), should be treated with chemotherapy.^[4]

Low-risk GTN (WHO score <7)

Patients with low-risk GTN are treated with single-agent chemotherapy.^{[6, 7, 8, 9, 10, 11, 12]} Many in the United States prefer methotrexate. However, actinomycin D can be used in patients with poor liver function. During treatment, the serum hCG levels are monitored every week. Six weeks of maintenance chemotherapy is administered after a normal serum hCG level. After 3-4 normal serum hCG levels, the levels are observed once per month for 1 year. A switch from methotrexate to actinomycin D is made if the patient receiving methotrexate for nonmetastatic or metastatic low-risk GTN develops rising or plateauing serum hCG levels.

A randomized clinical trial comparing 30 mg/m² methotrexate given weekly to patients with low-risk GTN versus 1.25 mg/m² of actinomycin D given every other week showed a higher complete response rate with actinomycin D.^[77]  The difference was most marked among patients with WHO score of 5-6. The results of a Gynecologic Oncology Group trial that compared pulsed actinomycin D to a more intense dosing of methotrexate are not yet available (https://clinicaltrials.gov/ct2/show/NCT01535053?cond=Gestational+Trophoblastic+Neoplasia&rank=9).

High-risk GTN (WHO score 7 or higher)

Patients with high-risk GTN have good prognosis if treated aggressively as follows:

• These patients are treated with a combination of etoposide, methotrexate, and actinomycin D administered in the first week of a 2-week cycle and cyclophosphamide and vincristine (Oncovin) administered in the second week.^{[13, 14, 15, 16]} This is known as the EMA-CO regimen.
• Some substitute cisplatin and etoposide for cyclophosphamide and vincristine during the second week. This is known as the EMA-EP regimen.^[17] Some reserve the EMA-EP regimen for patients in whom EMA-CO fails.
• At least 6 weeks of maintenance of EMA-CO or EMA-EP are administered after a normal serum hCG level.
• Patients with metastasis to the brain receive whole brain irradiation (3000 cGy) in combination with chemotherapy.^{[19, 20, 21]} Corticosteroids (dexamethasone) with systemic effect are administered to reduce brain edema. This is the most common approach in the United States.
• Early neurosurgical intervention for solitary lesions or stereotactic radiotherapy for multiple lesions or solitary lesions in locations at high risk for surgical morbidity is used at the Charing Cross Hospital in the United Kingdom and has been reported by physicians from Duke University in North Carolina.^[22] At Charing Cross, neurosurgery is followed by moderate- and high-dose intravenous methotrexate and intrathecal methotrexate. However, intrathecal methotrexate is not routinely used by others. A therapeutic level of methotrexate is achieved in the cerebrospinal fluid at doses of methotrexate >600 mg/m² given intravenously to patients with brain metastases.^[22]
• In patients not receiving whole brain irradiation, the dose of methotrexate on day 1 of the EMA-CO or EMA-EP regimen is increased to 1000 mg/m². Instead of 4 doses of folinic acid (15 mg every 12 hours), 12 doses (15 mg every 6 hours) are given starting 24 hours after the initiation of methotrexate infusion. Patients with liver metastasis are considered for liver irradiation (2000 cGy).^[18]
• Patients at high risk of early death (WHO score >12, large disease burden, major bleeding) are treated with low-dose induction etoposide/cisplatin (EP) consisting of 100 mg/m² of etoposide and 20 mg/m² of cisplatin on days 1 and 2, repeated weekly for 1-2 cycles before commencing EMA/CO.^[50]

Stage IV GTN

Patients with stage IV GTN are most often treated with multiagent chemotherapy, even when the WHO score is less than 7, which is uncommon.

After achieving 3-4 consecutive weekly normal serum hCG levels, patients with stage IV GTN are observed with monthly serum hCG levels for 2 years. If the levels begin to rise during follow-up, the patient is evaluated for possible intervening pregnancy, or persistent or recurrent disease.

Consultations

A gynecologic oncologist experienced in managing GTN should be consulted.

Transfer

Patients with resistant disease may benefit from consultation at a regional trophoblastic disease center.

Diet and activity

There are no dietary and activity restrictions.

• References

Surgical Care

Note the following:

• A hysterectomy may be necessary in case of uncontrolled vaginal bleeding. Hysterectomy may reduce the total number of chemotherapy cycles needed to achieve remission.^{[26, 27]}
• Uterine or hypogastric artery ligation or embolization of feeding vessels may be needed to control hemorrhage. Hepatic artery embolization has been used successfully to control hemorrhage from hepatic metastases.^[2]
• A repeat D&C in the presence of persistent tissue on pelvic ultrasonography may reduce the number of chemotherapy cycles needed to achieve remission.^[28]
• Craniotomy may be needed to control bleeding and provide decompression.^{[15, 22]}
• Resection of solitary metastasis (eg, thoracotomy) or disease within the myometrium may help achieve a remission.^{[23, 24, 25]}

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to eradicate the neoplasm.

• References

Methotrexate (Folex PFS, Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Used both as single agent and in multiagent regimens for the treatment of malignant GTN.

• References

Actinomycin D (Dactinomycin)

• Dosing, Interactions, etc.

Clinical Context:  Intercalates between guanine and cytosine base pairs, inhibiting DNA and RNA synthesis and protein synthesis. Use as single agent or as part of multiagent regimen for treatment of malignant GTN.

• References

Cyclophosphamide (Cytoxan, Neosar)

• Dosing, Interactions, etc.

Clinical Context:  Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Part of multiagent chemotherapy regimens used to treat high-risk metastatic GTN.

• References

Etoposide (Toposar, VePesid)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G₂ portion of cell cycle. One of the drugs in multiagent chemotherapy regimens used to treat patients with high-risk metastatic GTN.

• References

Vincristine (Oncovin, Vincasar PFS)

• Dosing, Interactions, etc.

Clinical Context:  Blocks mitosis; one of the drugs included in multiagent chemotherapy regimens used to treat patients with high-risk metastatic GTN.

• References

Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits DNA synthesis and, thus, cell proliferation, by causing DNA cross-links and denaturation of double helix. Effective antineoplastic used in patients with chemotherapy-resistant malignant GTN.

• References

Class Summary

Gestational trophoblastic tumors are sensitive to many antineoplastic agents, especially those that act in the S phase or the M phase of the cell cycle.

• References

Leucovorin (Wellcovorin)

• Dosing, Interactions, etc.

Clinical Context:  Used to prevent toxicity from high doses of MTX.

• References

Class Summary

May be used to alleviate toxic adverse effects of MTX. MTX blocks conversion of uridine to thymidine, one of the building blocks of DNA. Folinic acid provides a methyl group to uridine monophosphate, thus forming thymidine monophosphate, overcoming effects of MTX on tetrahydrofolic acid reductase.

• References

Further Outpatient Care

Patients with gestational trophoblastic neoplasia (GTN) should have follow-up serum hCG levels measured once per week until 4 normal values are obtained. Then, hCG levels should be obtained once per month for 1 year. Patients with stage IV disease are observed with monthly serum hCG level monitoring for 2 years after 3-4 consecutive weekly normal levels. Patients should use a reliable method of contraception.

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Inpatient & Outpatient Medications

During the period of follow-up care, patients with GTN should use a reliable method of contraception, such as oral contraceptives or depot progesterone. The serum hCG levels are critical in monitoring the status of the disease, and a normal intrauterine pregnancy interferes with this critical monitoring tool.

• References

Deterrence/Prevention

The early diagnosis of GTN by the close follow-up of serum hCG levels after the evacuation of a hydatidiform mole results in therapeutic intervention prior to the development of high-risk disease.

In patients with a history of gestational trophoblastic disease (GTD), measuring serum hCG levels 6 weeks after any subsequent pregnancy should be strongly considered to exclude occult GTN.

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Patient Education

The pregnancy rate after chemotherapy with methotrexate and cyclophosphamide is 80%. Of women treated with EMA-CO, 46% have had at least 1 live birth after chemotherapy.^{[78, 79]}

Patients who become pregnant after treatment for GTN should have pelvic ultrasonography early during the pregnancy to confirm that the pregnancy is normal.

A serum hCG level should be obtained 6 weeks after delivery of a subsequent pregnancy to exclude repeat GTN.

• References