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] :
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Management of GTN requires pathology review, centralization of care, and monitoring of human chorionic gonadotropin (hCG)
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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
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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
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In patients with ultra-high-risk GTN, induction with low-dose etoposide and cisplatin may reduce the risk of early mortality
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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; hysterectomy with pelvic node sampling is recommended for patients presenting with stage I disease within 4 years of their last known pregnancy, while those presenting later or with metastatic disease may be treated with multi-agent and subsequent high-dose chemotherapy
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 a WHO score of 5-6. A subsequent Gynecologic Oncology Group study compared pulse actinomycin D (1.25 mg/m2) to a multi-day (5-day or 8-day with folinic acid) methotrexate regimen. The study was closed due to a low accrual rate. Of the 57 patients entered, the complete response rate for methotrexate was 88%, and it was 79% for actinomycin D. This difference was not statistically significant. However, owing to the small number of patients, the study may have been underpowered. [78]
High-risk GTN (WHO score 7 or higher)
Patients with high-risk GTN have good prognosis if treated aggressively as follows:
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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.
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At least 6 weeks of maintenance of EMA-CO or EMA-EP are administered after a normal serum hCG level.
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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]
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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]
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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.
Surgical Care
Note the following:
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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]
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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]
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Histologic section of a complete hydatidiform mole stained with hematoxylin and eosin. Villi of different sizes are present. The large villous in the center exhibits marked edema with a fluid-filled central cavity known as cisterna. Marked proliferation of the trophoblasts is observed. The syncytiotrophoblasts stain purple, while the cytotrophoblasts have a clear cytoplasm and bizarre nuclei. No fetal blood vessels are in the mesenchyme of the villi.
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In this microphotograph of a choriocarcinoma metastatic to the brain, the neuropil is seen on the right and the biphasic (2 cell populations) choriocarcinoma is seen to the left with hemorrhage at the left border of the photograph (H&E stain).
Tables
Prognostic Factor |
Points |
Age ≥40 y |
1 |
Antecedent pregnancy terminated in abortion |
1 |
Antecedent full-term pregnancy |
2 |
Interval of 4-7 mo between antecedent pregnancy and start of chemotherapy |
1 |
Interval of 7-12 mo between antecedent pregnancy and start of chemotherapy |
2 |
Interval of more than 12 mo between antecedent pregnancy and start of chemotherapy |
4 |
Beta-hCG level in serum is 1,000 to < 10,000 mIU/mL |
1 |
Beta-hCG level in serum is 10,000 to < 100,000 mIU/mL |
2 |
Beta-hCG level in serum is ³100,000 mIU/mL |
4 |
Largest tumor is 3 cm to < 5 cm |
1 |
Largest tumor is 5 cm or greater |
2 |
Site of metastases is spleen or kidney |
1 |
Site of metastases is gastrointestinal tract |
2 |
Site of metastases is brain or liver |
4 |
Number of metastases is 1-4 |
1 |
Number of metastases is 5-8 |
2 |
Number of metastases is >8 |
4 |
Prior chemotherapy with single drug |
2 |
Prior chemotherapy with multiple drugs |
4 |
