Gestational Trophoblastic Diseases
Gestational trophoblastic diseases (GTDs) encompass a spectrum of neoplastic disorders that arise from placental trophoblastic tissue after abnormal fertilization. In the United States, GTDs account for less than 1% of gynecologic malignancies. Forty years ago, women with choriocarcinoma had a 95% mortality rate. Today, with the advent of effective chemotherapy and the development of a reliable tumor marker (β-subunit human chorionic gonadotropin [β-hCG]), the cure rate for choriocarcinoma is 90% to 95%.
Clinical Presentation
Complete mole
The classic signs of a molar pregnancy include the absence of fetal heart sounds, physical evidence of a uterus that is larger than expected for gestational age, and vaginal bleeding. Although an intact fetus may coexist with a partial mole, this occurs in fewer than 1 in 100,000 pregnancies.
The most common presenting symptom of molar pregnancy is vaginal bleeding, reported in up to 97% of patients. Intrauterine clots may undergo oxidation and liquefaction, producing pathognomonic prune juice–like fluid. Prolonged or recurrent bleeding may result in iron-deficiency anemia. Symptoms of anemia occur in approximately 50% of patients at the time of diagnosis. Early toxemia (hypertension, proteinuria, and edema) presenting during the first or second trimester is common (20% to 30% of cases) in molar pregnancy.
Hyperthyroidism is seen clinically in approximately 7% of molar pregnancies. An elevation of triiodothyronine (T3) and thyroxine (T4) levels is observed more commonly than are the clinical manifestations of tachycardia, sweating, weight loss, and tremor. These hormonal elevations are presumed to be secondary to the structural similarity of hCG to thyroid-stimulating hormone (TSH).
Partial mole
Patients with partial mole have clinical features different from those with complete mole. Fewer than 10% of patients with partial mole have uterine enlargement. Patients with partial mole do not have prominent theca-lutein cysts, hyperthyroidism, or respiratory insufficiency. They experience toxemia only rarely. The diagnosis of partial mole is usually made after histologic review of curettage specimens.
Gestational trophoblastic neoplasia
Gestational trophoblastic neoplasia (GTN) develops in 6% to 19% of patients after molar evacuation. Metastases sometimes have a histology identical to that of molar disease, but the vast majority are choriocarcinomas. Metastatic spread is hematogenous. Because of its extensive vascular network, metastatic GTN often produces local, spontaneous bleeding. The New England Trophoblastic Disease Center reported that the common metastatic sites of GTD are the lungs (80%); vagina (30%); pelvis (20%); liver (10%); brain (10%); and bowel, kidneys, and spleen (5% each).
Pulmonary metastases are common (80% of patients with metastatic disease) and occur when trophoblastic tissue enters the circulation via uterine venous sinuses. The radiologic features may be protean or subtle and include alveolar, nodular, and miliary patterns. Pleural effusions may also be present. Pulmonary metastases can be extensive and can cause respiratory failure and death.
Right upper-quadrant pain has been observed when hepatic metastases stretch Glisson's capsule. GI lesions may result in severe hemorrhage or in perforation with peritonitis, both of which require emergency intervention. Vaginal examination may reveal bluish metastatic deposits; these and other metastatic sites should not undergo biopsy because severe uncontrolled bleeding may occur.
CNS involvement from metastatic GTN suggests widespread disease and has a poor prognosis. CNS metastases are clinically evident in 7% to 28% of patients with metastatic choriocarcinoma. Cerebral metastases tend to respond favorably to both radiotherapy and chemotherapy.
Diagnostic studies
Although the clinical presentation may suggest a diagnosis of GTN, certain laboratory studies, particularly a determination of the patient's β-hCG level, and radiographic studies are needed to confirm this diagnosis.
Laboratory studies. Thyroid function studies should be performed in all patients with a clinical history or physical examination suggestive of hyperthyroidism. Abnormal thyroid function, manifested as an elevated T4 level, is common in GTD. Metastatic deposits in the kidneys or GI tract may reveal themselves by hematuria or hematochezia.
Tumor markers. A well-characterized glycoprotein hormone secreted by the syncytiotrophoblast, hCG is essential to maintaining normal function of the corpus luteum during pregnancy. Because all trophoblastic tumors secrete β-hCG, this hormone serves as an excellent marker for tumor activity in the nonpregnant patient. Serial β-hCG levels should be monitored during therapy to ensure adequate treatment. The level of β-hCG is roughly proportional to the tumor burden and inversely proportional to the therapeutic outcome.
Radiologic studies. A chest x-ray should always be performed because 70% to 80% of patients with metastatic GTN have lung involvement. Although this x-ray usually demonstrates nodular metastases, the patterns of metastatic disease can range from atelectatic areas to subtle pleural abnormalities. A CT scan is often helpful in evaluating these nonspecific findings.
Since it has been demonstrated that 97% to 100% of patients with CNS disease from choriocarcinoma have concomitant pulmonary metastases, a CNS workup in asymptomatic patients with normal chest x-rays is not routinely warranted. If the chest x-ray is abnormal, or if β-hCG levels plateau or rise during treatment, a more thorough evaluation for metastatic disease is indicated. MRI of the brain, brain stem, and cerebellum as well as CT scans of the abdomen and pelvis should be performed to evaluate other likely sites of metastatic spread. The presence of intrauterine or ovarian disease also may be detected by MRI of the pelvis. Ultrasonography is a reliable, safe, economical, and relatively simple method for confirming the diagnosis of intrauterine GTD. It is also useful in identifying embryonic remnants.
The proposed FIGO 2000 anatomic staging system is a straightforward system based on anatomic criteria. In GTD, stage I disease is confined to the uterus; stage II disease is outside the uterus but limited to the genital structures; stage III disease extends to the lungs with or without known genital tract involvement; and stage IV disease includes all other metastatic sites. The FIGO 2000 scoring system is based on a method (adapted from the World Health Organization [WHO]) to identify patients at high risk for treatment failure. With the FIGO 2000 scoring system, patients are classified as being in a low-, middle-, or high-risk category. A total score of up to 4 is considered low risk; 5 to 7, middle risk; and 8 or greater, high risk. (Some centers recommend a low-risk score of 6 or less, a high-risk score of 7 or greater, and no middle-risk score.)
Treatment
The treatment strategy for GTD must be individualized for each patient. The stratification of risk groups enables physicians to direct an appropriate treatment strategy. Low-risk disease responds readily to single-agent chemotherapy and is virtually 100% curable. High-risk disease is not likely to be cured with single-agent therapy and therefore requires multidrug regimens.
Molar pregnancy. For patients with complete or partial hydatidiform mole, evacuation of the mole by suction and sharp curettage should be performed. Oxytocics also are given to produce uterine involution and to control bleeding. However, these agents should be used judiciously, as they may cause hyponatremia and fluid overload. A baseline chest x-ray and β-hCG measurement should be obtained prior to surgery. After molar evacuation, 80% of patients will need no further intervention.
Follow-up. As mentioned previously, all patients with molar disease should obtain a baseline chest x-ray. Serial β-hCG levels should be obtained every 1 to 2 weeks until the level is normal for three consecutive assays. Complete remission is defined by three consecutive normal β-hCG levels. Once this has occurred, β-hCG levels should be checked monthly for 12 months, every 4 months for the following year, and then yearly for 2 years. However, a single undetectable human chorionic gonadotropin level after evacuation is sufficient follow-up to ensure remission in patients with partial hydatidiform moles.
Although the use of OCs during the surveillance period remains controversial, strict contraception is required, because pregnancy would obviate the usefulness of β-hCG as a tumor marker. In general, once 12-month surveillance establishes a disease-free status, conception is acceptable. These women are always at high risk for future molar disease and will require close observation during future pregnancies. A pelvic ultrasonographic examination should be performed during the first trimester of all subsequent pregnancies to confirm that gestation is normal.
Chemotherapy is indicated when there is a plateau or increase in β-hCG levels on consecutive measurements, failure to reach normal levels by 16 weeks, or metastatic disease. Such patients are usually at low risk and will respond to single-agent chemotherapy. Methotrexate is the most commonly initiated single agent. Therapy is continued for one to two courses after a normal β-hCG level is achieved.
Low-risk metastatic disease
In more than 30 years of experience, single-agent chemotherapy with methotrexate has produced a high cure rate in patients with low-risk GTN. Likewise, methotrexate plus leucovorin induces remission in 90% of patients with low-risk metastatic disease with low toxicity. The GOG conducted two phase II trials; both showed that a single dose of dactinomycin every other week (GOG0069) or weekly intramuscular methotrexate (GOG0079) had good compliance, comparable activity, and tolerable toxicity. The use of dactinomycin in methotrexate-resistant patients increased the cure rate to more than 95%. As reported by Osborne, GOG0174 was the first randomized prospective front-line chemotherapy trial in 240 patients with GTN. The primary endpoint was normalization of the β-hCG levels. Eligible patients were those with untreated, histologically confirmed low-risk GTN (WHO risk score, 0-6) defined as one of the following: < 10% decrease in β-hCG level over 3 consecutive weeks, persistently elevated β-hCG level for more than 4 months following initial curettage, or histologically proven nonmetastatic choriocarcinoma. Among eligible patients, complete response was observed in 53% of those given methotrexate and 69% of those given dactinomycin (P = .015). Both regimens were well tolerated; only two patients experienced grade 4 toxicity, and no patient experienced grade 5 toxicity. This study demonstrates that biweekly dactinomycin (at 1.25 mg/m2) is statistically superior to weekly parenteral methotrexate (at 30 mg/m2) as initial management for low-risk GTN. The first prospective multicenter phase II trial of salvage therapy for failed low-risk GTN, GOG0176 found that pulse actinomycin D (1.24 mg/m2 IV every 2 weeks) is an active regimen.
High-risk metastatic disease
The discovery that etoposide is an effective agent against trophoblastic disease led to the development of the EMA-CO regimen (etoposide, methotrexate, actinomycin D [dactinomycin], cyclophosphamide(Drug information on cyclophosphamide), Oncovin [vincristine]), with a reported survival rate of 83% in patients with high-risk choriocarcinoma.
EMA-CO is the preferred regimen for high-risk GTN. This regimen is also used for patients with middle-risk GTN, as defined by the FIGO 2000 criteria. EMA-CO is generally well tolerated, with no life-threatening toxic effects. Alopecia occurs universally, and anemia, neutropenia, and stomatitis are mild. Reproductive function is preserved in approximately 75% of patients.
Within hours of receiving chemotherapy, patients with a significant tumor burden are at risk of hemorrhage into tumors and surrounding tissues. Thus, any acute organ toxicity that begins shortly after the induction of chemotherapy should be considered as possibly related to this phenomenon. Some researchers have advocated a reduction in dosage at the beginning of therapy in patients with large-volume disease to minimize these sequelae.
Salvage therapy
Unfortunately, about 25% of women with high-risk metastatic disease become refractory to EMA-CO and fail to achieve a complete remission. Currently, there is no standard salvage chemotherapy regimen for patients not responding to EMA-CO. However, salvage regimens that combine cisplatin(Drug information on cisplatin), etoposide, vinca alkaloids, and bleomycin have been administered.
Early studies show cisplatin-based regimens to be an effective salvage therapy in GTD. A recent dose-intensive regimen, EMA-CE, utilizes cisplatin (100 mg/m2) and etoposide (200 mg/m2) combined with EMA, with favorable results.
Another alternative is to give cisplatin in the EMA-POMB regimen (Platinol [cisplatin], Oncovin [vincristine], methotrexate, bleomycin). POMB is administered as vincristine, at 1 mg/m2 IV, and methotrexate, 300 mg/m2 IV (day 1); bleomycin, at 15 mg IV over 24 hours by continuous infusion, and folinic acid, at 15 mg twice daily for four doses (day 2); bleomycin, at 15 mg IV over a 24-hour continuous infusion (day 3); and cisplatin, at 120 mg/m2 IV (day 4).
A PEBA regimen (cisplatin, etoposide, bleomycin, doxorubicin(Drug information on doxorubicin)) reported from China (Chen LP et al: Gynecol Oncol 1995) and was found to be effective in EMA-CO–resistant disease. A complete remission was achieved in 96% of the women, and 73% had a sustained complete remission that lasted at least 1 year. In a small study (Lurain JR et al: J Reprod Med 2012), ifosfamide(Drug information on ifosfamide) alone and combined in the VIP regimen (VePesid [etoposide], ifosfamide, and Platinol [cisplatin]) showed promise as being an effective salvage drug in GTD. The experience of the Brewer Trophoblastic Disease Center in patients with persistent or recurrent high-risk GTN showed that those who develop resistance to methotrexate-containing treatment protocols should be treated with drug combinations employing a platinum agent and etoposide with or without bleomycin or ifosfamide.
Another consideration in the treatment of refractory GTN is the use of high-dose chemotherapy with autologous bone marrow transplantation.
