Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. The overall cure rate in treating these tumors is currently >90%. Thorough evaluation and staging allow selection of appropriate therapy that maximizes chances for cure while minimizing toxicity. Nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN can be treated with single-agent chemotherapy resulting in a survival rate approaching 100%. High-risk GTN (stages II-IV, score ≥7) requires initial multiagent chemotherapy with or without adjuvant radiation and surgery to achieve a survival rate of 80-90%.
Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). The epidemiology, pathology, clinical presentation, and diagnosis of these tumors were discussed in part I of this review. The overall cure rate in treating these tumors is currently >90%. This success is the result of the inherent sensitivity of trophoblastic neoplasms to chemotherapy, the effective use of the tumor marker human chorionic gonadotropin (hCG) for diagnosing disease and monitoring therapy, the referral of patients to or consultation with clinicians who have special expertise in management of these diseases, the identification of prognostic factors that predicts treatment response and enhances individualization of therapy, and the use of combined modality treatment with chemotherapy, radiation, and surgery in the highest risk patients. PSTT and its related ETT remain therapeutic challenges, since they are more frequently chemotherapy resistant and do not have the same hCG marker relationship as invasive mole and choriocarcinoma.
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Classification/staging
When the diagnosis of GTN is suspected or established, a metastatic workup and an evaluation for risk factors is undertaken. Along with a complete history and physical examination, the following laboratory tests should be obtained: complete blood cell count including platelets, coagulation studies, serum chemistries including renal and liver function panels, blood type and antibody screen, and quantitative serum hCG level. Recommended radiologic studies include chest x-ray with computed tomography (CT) scan of the chest if the chest x-ray is negative, CT scans of the abdomen and pelvis, and CT scan or magnetic resonance imaging of the brain ( Figure ). If the physical examination and chest x-ray are normal in the absence of symptoms, other sites of metastasis are uncommon. Measurement of hCG in cerebrospinal fluid may be helpful in detecting brain involvement. Pelvic ultrasound or magnetic resonance imaging may also be useful in detecting extensive uterine disease for which hysterectomy may be of benefit. Repeat curettage after hydatidiform mole evacuation is generally not recommended unless there is excessive uterine bleeding and evidence of intracavitary molar tissue exists on scan, because it does not often induce remission or influence treatment and it may result in uterine perforation and hemorrhage.
In 2002, the International Federation of Gynecology and Obstetrics (FIGO) defined criteria for the diagnosis of postmolar disease and adopted a combined anatomic staging and modified World Health Organization (WHO) risk-factor scoring system for GTN. The components needed to diagnose postmolar GTN include at least 1 of the following: (1) hCG plateau for 4 consecutive values over 3 weeks; (2) hCG rise of ≥10% for 3 values over 2 weeks; (3) hCG persistence 6 months after molar evacuation; (4) histopathologic diagnosis of choriocarcinoma; or (5) presence of metastatic disease. The FIGO stage ( Table 1 ) is designated by a Roman numeral followed by the modified WHO score ( Table 2 ) designated by an Arabic numeral, separated by a colon. PSTTs and ETTs are classified separately.
| Stage | Description |
|---|---|
| I | Disease confined to uterus |
| II | Disease extends outside uterus but is limited to genital structures (adnexa, vagina, broad ligament) |
| III | Disease extends to lungs with or without genital tract involvement |
| IV | Disease involves other metastatic sites |
| Risk factor | Score | |||
|---|---|---|---|---|
| 0 | 1 | 2 | 4 | |
| Age, y | ≤39 | >39 | − | − |
| Antecedent pregnancy | Mole | Abortion | Term | |
| Pregnancy event to treatment interval, mo | <4 | 4-6 | 7-12 | >12 |
| Pretreatment hCG, mIU/mL | <10 3 | 10 3 -10 4 | 10 4 -10 5 | >10 5 |
| Largest tumor mass, including uterus, cm | <3 | 3-4 | ≥5 | − |
| Site of metastases | − | Spleen, kidney | GI tract | Brain, liver |
| No. of metastases | − | 1-4 | 5-8 | >8 |
| Previous failed chemotherapy | − | − | Single drug | ≥2 drugs |
Treatment is based on classification into risk groups defined by the stage and scoring system. Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN can be treated with single-agent chemotherapy, with resulting survival rates approaching 100%. Patients classified as having high-risk metastatic disease (stage IV and stages II-III, score ≥7) should be treated in a more aggressive manner with multiagent chemotherapy ± adjuvant radiation or surgery to achieve cure rates of 80-90%. Use of the FIGO staging system is essential for determining initial therapy for patients with GTN to assure the best possible outcomes with the least morbidity.
Treatment
Low-risk disease
Patients with nonmetastatic (stage I) and low-risk metastatic (stages II and III, score <7) GTN should be treated with single-agent methotrexate or actinomycin D chemotherapy. Several different outpatient chemotherapy protocols have been used, which in mostly nonrandomized, retrospective studies have yielded fairly comparable overall results ( Table 3 ). The variability in primary remission rates reflects differences in drug dosages, schedules, and routes of administration, as well as patient selection criteria. In general, the weekly intramuscular (IM) or intermittent intravenous (IV) infusion methotrexate and the biweekly single-dose actinomycin D protocols are less effective than one of the 5-day methotrexate or actinomycin D protocols and the 8-day methotrexate-folinic acid regimen. Also, older patient age, higher hCG levels, nonmolar antecedent pregnancy, histopathologic diagnosis of choriocarcinoma, presence of metastatic disease, and higher FIGO score are each associated with an increased risk of initial chemotherapy resistance. Despite these differences in primary remission rates with initial chemotherapy, almost all patients are eventually cured with most being able to preserve fertility.
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