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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gestational trophoblastic tumors. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Gestational trophoblastic tumors (GTTs) are rare but highly curable tumors arising from the products of conception in the uterus. 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. The probability of cure depends on the following:
Selection of treatment depends on these factors plus the patient’s desire for future pregnancies. The hCG, produced normally during pregnancy, is abnormally elevated in the blood and urine of patients with this group of diseases and is a sensitive marker to indicate the presence or absence of disease before, during, and after treatment.
The most common antecedent pregnancy is that of a hydatidiform mole, usually a genetic disorder of pregnancy in which only placental-like tissue is present. The patient will present with abnormal bleeding from onset of pregnancy and may have a uterus which is much larger than expected. Sonography is the preferred method of diagnosis, and suction dilation and curettage (D & C) is the preferred method of evacuation. Of utmost importance is careful follow-up with serum beta hCG (BhCG) weekly until less than 100 mIU/mL and then every 2 weeks. The patient should have a careful pelvic examination every other week and a chest x-ray every 4to 6 weeks. Once the titer of serum BhCG has fallen to normal levels, these two examinations need no longer be done; however, BhCG titers need to be repeated every 2 weeks for 3 months, then monthly for 3 months, then every 2 months for 6 months, then every 6 months for 3 years. Each patient should be counseled in the use of a reliable birth control method. Any patient who develops an increasing level of serum BhCG, a plateau of the BhCG over 3 weeks, or persistent elevation of BhCG after 16 weeks of follow-up should be considered as having gestational trophoblastic neoplasia and should undergo the appropriate work-up and treatment. Similarly, any patient who develops metastatic disease during follow-up should be staged and undergo treatment.
Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other common signs include bizarre neurologic symptoms in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.
Gestational trophoblastic tumors may be classified as follows: [1]
Hydatidiform mole
Hydatidiform mole is defined as products of conception that lack an intact fetus and show gross cyst-like swellings of the chorionic villi caused by an accumulation of fluid. There is disintegration and loss of blood vessels in the villous core.
Invasive mole
Invasive mole (chorioadenoma destruens) is a locally invasive, rarely metastatic lesion characterized microscopically by trophoblastic invasion of the myometrium with identifiable villous structures. Microscopically, this lesion is characterized by hyperplasia of cytotrophoblastic and syncytial elements and persistence of villous structures.
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.
Placental-site trophoblastic tumor
Placental-site trophoblastic disease is an extremely 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, while immunoperoxidase staining for human chorionic gonadotropin (hCG) is positive in only scattered cells, and serum hCG is relatively low. [1]
Hydatidiform mole (molar pregnancy) is disease limited to the uterine cavity.
Invasive mole (chorioadenoma destruens) is a locally invasive, rarely metastatic lesion.
The FIGO staging system is as follows: [1]
The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification. [1]
Risk factors affecting staging include the following:
Most major U.S. Trophoblastic Disease Centers have used a clinical classification system based on prognostic groups to determine treatment and report results. In the staging system below, GTT is divided into metastatic and nonmetastatic, with the former further divided into low-risk and high-risk based on: [2] [3]
Nonmetastatic GTT is defined as no disease outside the uterus. A diagnosis of nonmetastatic trophoblastic disease is made when there are persistently elevated hCG titers or a tissue diagnosis of uterine choriocarcinoma in the absence of detectable metastatic disease. One criterion used to make the diagnosis relates tumor load to the length of the hCG plateau. [4]
Indicated by the following factors:
Indicated by any of the following factors:
Metastatic GTTs are also categorized by the WHO scoring system as low-risk, medium-risk, and high-risk. [5] This scoring system has been suggested for use in identifying the especially (“ultra”) high-risk patient who is best treated by the most dose-intensive and efficacious combination chemotherapy protocol. The WHO scoring system based on prognostic factors is listed below. The individual scores for each prognostic factor are added together to obtain a total score. [6] A total score less than or equal to four is considered low risk, a total score of five to seven is considered middle risk, and a total score of eight or greater is considered high risk. A study also examined the use of the WHO scoring system for reporting results of treatment; the results suggested that risk categories be redefined as low (<8), medium (8–12), and high (>12). Failure of treatment was limited to patients in the latter group. [7]
| Prognostic Factor | Score |
|---|---|
| Age | |
| <39 | 0 |
| >39 | 1 |
| Antecedent pregnancy | |
| hydatidiform mole | 0 |
| abortion | 1 |
| term | 2 |
| Interval between end of antecedent pregnancy and start of chemotherapy | |
| <4 mo | 0 |
| 4–6 mo | 1 |
| 7–12 mo | 2 |
| >12 mo | 4 |
| hCG (IU/mL) | |
| <1000 | 0 |
| 1,000–10,000 | 1 |
| 10,000–100,000 | 2 |
| >100,000 | 4 |
| ABO groups (female × male) | |
| O × A or A × O | 1 |
| B or AB | 2 |
| Largest tumor, including uterine | |
| 3–5 cm | 1 |
| >5 cm | 2 |
| Site of metastases | |
| spleen, kidney | 1 |
| gastrointestinal tract or liver | 2 |
| brain | 4 |
| Number of metastases identified | |
| 1–4 | 1 |
| 4–8 | 2 |
| >8 | 4 |
| Prior chemotherapy | |
| single drug | 2 |
| 2 or more drugs | 4 |
Treatment depends on the:
Of utmost importance in treating patients with gestational trophoblastic tumors is instituting therapy as quickly as possible and continuing chemotherapy at very close intervals until normal BhCG titers are obtained. The interval between courses should rarely exceed 14 to 21 days depending on the treatment. It is recommended that patients receive one to three courses of chemotherapy after the first normal BhCG titer, depending on the extent of disease. Regardless of stage, if one of the high-risk factors is present, the patient should be treated with combination chemotherapy.
Hydatidiform mole (molar pregnancy) is 100% curable. The selection of treatment is based on the desire to preserve reproductive capability.
Standard treatment options:
Following this initial treatment, patients should be monitored with determination of serum BhCG to document its return to normal. Follow-up with a urinary pregnancy test is inadequate, and a sensitive radioimmunoassay is mandatory. Chemotherapy is necessary when there is:
Chemotherapy is required in only 20% of patients after evacuation of a molar pregnancy. Chemotherapy is the same as for nonmetastatic gestational trophoblastic tumor.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
Hysterectomy is the treatment of choice for patients with placental-site trophoblastic tumors. Although most reports have noted a benign course for these tumors, they are relatively resistant to chemotherapy and can be fatal. [1]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
This is the most common presentation of gestational trophoblastic tumors and usually requires treatment with cytotoxic therapy, primarily single agents.
Standard treatment options:
Treatment usually consists of single-agent chemotherapy though hysterectomy has been used in the occasional patient where preservation of reproductive function is not an issue. Single-agent chemotherapy is usually methotrexate unless the patient has abnormal liver function, in which case dactinomycin is used.
Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use. They are:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with nonmetastatic 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.
This group of patients has disease outside the uterus, but it does not have any of the adverse prognostic factors detailed in stage information. In general, these patients should be treated with single-agent chemotherapy as described for nonmetastatic disease. Patients who do not tolerate methotrexate or who become resistant to it can often be salvaged with dactinomycin. Development of intercurrent poor-risk factors dictates the need for combination chemotherapy. Cure rates should approach 100%, but approximately 40% to 50% of these patients will develop resistance to the first chemotherapeutic agent and require alternate treatment. Careful monitoring is mandatory.
Standard treatment options:
Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use. They are:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with good prognosis 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.
Patients with any of the high-risk factors fall into this category. Patients with a WHO score greater than eight are considered to be especially (“ultra”) high-risk. Therapy needs to be instituted quickly and should consist of multiple-agent chemotherapy. Additional therapy (including radiation to central nervous system metastases and adjuvant surgery) is often necessary. These patients should be treated at a regional Trophoblastic Disease Center or by a physician with prior experience in treating poor-risk patients. Radiation to liver metastasis is contraindicated since it has no clear value and leads to myelosuppression that may make administration of cytotoxic chemotherapy more difficult.
Standard treatment options:
For patients with a WHO prognostic score less than eight:
For patients with a WHO prognostic score greater than eight:
Other regimens that may produce similar outcome but have been studied less extensively or are in less common use include:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with poor prognosis 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.
Recurrent disease indicates failure of prior chemotherapy unless initial therapy was surgery alone. A 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] All recurrences were within 36 months of remission (85% before 18 months). Prior chemotherapy failure automatically places the patient into the high-risk (poor prognosis) category. These patients should be treated with aggressive chemotherapy. For resistant high-risk gestational trophoblastic tumors (GTTs), combinations of etoposide, cisplatin, and either dactinomycin or bleomycin have shown promising results. [2] [3] A patient who has failed primary surgical therapy is generally treated with single-agent chemotherapy unless one of the poor-prognosis factors that requires combination chemotherapy supervenes.
A select group of patients with chemotherapy-resistant and clinically detectable GTT may benefit from salvage surgery. [4]
When central nervous system metastases are identified, whole brain radiation therapy (30 Gy in 2 Gy fractions) is given simultaneously with the initiation of systemic chemotherapy. Approximately 50% to 60% of patients will achieve sustained remission using this treatment approach. The outcome for women presenting with hepatic metastases from GTT disease is poor with an even worse prognosis if cerebral metastases are also present. [5] [6] Chemotherapy with ifosfamide, carboplatin, and etoposide may be considered for patients with recurrent GTTs metastatic to the brain. [7]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.
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