Gestational trophoblastic tumors: Treatment - Health Professional Information [NCI PDQ]

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Gestational Trophoblastic Tumors (PDQ®)

General Information

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:

• Histologic type (mole, invasive mole, or choriocarcinoma).
• Extent of spread of the disease.
• Level of the human chorionic gonadotropin (HCG) titer.
• Duration of disease from the initial pregnancy event to start of treatment.
• Specific sites of metastases.
• Nature of antecedent pregnancy.
• Extent of prior treatment.

Selection of treatment depends on these factors plus the patient’s desire for future pregnancies. Human chorionic gonadotropin, 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 two weeks. The patient should have a careful pelvic examination every other week and a chest x-ray every 4-6 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.

Cellular Classification

Gestational trophoblastic tumors may be classified as follows: [1]

• Hydatidiform mole.
• Invasive mole (chorioadenoma destruens).
• Choriocarcinoma.
• Placental-site trophoblastic tumor.

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 due to 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 HCG is positive in only scattered cells, and serum HCG is relatively low.[1]

References:

1. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990.

Stage Information

Hydatidiform mole

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]

• Stage I: Disease confined to the uterus
  • Stage IA: Disease confined to the uterus with no risk factors.
  • Stage IB: Disease confined to the uterus with one risk factor.
  • Stage IC: Disease confined to the uterus with two risk factors.
• Stage II: GTT extends outside of the uterus but is limited to the genital structures (ovary, tube, vagina, broad ligament)
  • Stage IIA: GTT involving genital structures without risk factors.
  • Stage IIB: GTT extends outside of the uterus but limited to genital structures with one risk factor.
  • Stage IIC: GTT extends outside of the uterus but limited to the genital structures with two risk factors.
• Stage III: GTT extends to the lungs, with or without known genital tract involvement
  • Stage IIIA: GTT extends to the lungs, with or without genital tract involvement and with no risk factors.
  • Stage IIIB: GTT extends to the lungs, with or without genital tract involvement and with one risk factor.
  • Stage IIIC: GTT extends to the lungs, with or without genital tract involvement and with two risk factors.
• Stage IV: All other metastatic sites
  • Stage IVA: All other metastatic sites, without risk factors.
  • Stage IVB: All other metastatic sites, with one risk factor.
  • Stage IVC: All other metastatic sites, with two risk factors.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[1]

TNM definitions

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• T1: Disease limited to uterus
• T2: Disease outside of uterus but is limited to genital structures (ovary, tube, vagina, broad ligaments)

Distant metastasis (M)

• M0: No clinical metastasis
• M1a: Lung metastasis
• M1b: All other distant metastasis

Risk factors affecting staging include the following:

1. hCG > 100,000 IU/24-hour urine.
2. The detection of disease more than 6 months from termination of the antecedent pregnancy.

AJCC stage groupings

Stage IA

• T1, M0, no risk factors

Stage IB

• T1, M0, one risk factor

Stage IC

• T1, M0, two risk factors

Stage IIA

• T2, M0, no risk factors

Stage IIB

• T2, M0, one risk factor

Stage IIC

• T2, M0, two risk factors

Stage IIIA

• Any T, M1a, no risk factors

Stage IIIB

• Any T, M1a, one risk factor

Stage IIIC

• Any T, M1a, two risk factors

Stage IVA

• Any T, M1b, no risk factors

Stage IVB

• Any T, M1b, one risk factor

Stage IVC

• Any T, M1b, two risk factors

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]

1. Duration of disease.
2. Presence or absence of liver or brain metastasis.
3. HCG titer level.
4. Presence or absence of prior chemotherapy.
5. Occurrence after a full-term pregnancy.

Nonmetastatic gestational trophoblastic tumors

Nonmetastatic gestational trophoblastic tumor 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]

Good-prognosis metastatic gestational trophoblastic tumors

1. Last pregnancy less than 4 months ago.
2. HCG titer low (<100,000 IU [24 hour urine] or <40,000 mIU/mL blood).
3. No liver or brain metastases.
4. No prior chemotherapy.

Poor-prognosis metastatic gestational trophoblastic tumors

Any of the following factors positive:

1. Last pregnancy more than 4 months ago.
2. HCG titer high (>100,000 IU [24 hour urine] or >40,000 mIU/mL blood).
3. Liver or brain metastases.
4. Prior chemotherapy.
5. Occurrence after a full-term pregnancy.

Metastatic GTTs are also categorized by the WHO scoring system as low-, medium-, 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 4 is considered low risk, a total score of 5-7 is considered middle risk, and a total score of 8 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 Factors Based on the WHO Scoring System

References:

1. Gestational trophoblastic tumors. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, pp 211-214.
2. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990.
3. Bagshawe KD: Risk and prognostic factors in trophoblastic neoplasia. Cancer 38 (3): 1373-85, 1976.
4. Kohorn EI: Evaluation of the criteria used to make the diagnosis of nonmetastatic gestational trophoblastic neoplasia. Gynecol Oncol 48 (2): 139-47, 1993.
5. World Health Organization Scientific Group.: Gestational trophoblastic diseases. Geneva: World Health Organization, 1983.
6. Tumors of the placental trophoblast. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 315-353.
7. Dubuc-Lissoir J, Sweizig S, Schlaerth JB, et al.: Metastatic gestational trophoblastic disease: a comparison of prognostic classification systems. Gynecol Oncol 45 (1): 40-5, 1992.

Treatment Option Overview

Treatment depends on the:

• Cell type.
• Stage.
• Level of serum BHCG.
• Duration of the disease.
• Specific sites of metastasis.
• Extent of prior treatment.

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 1 to 3 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.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Hydatidiform Mole

Hydatidiform mole (molar pregnancy) is 100% curable. The selection of treatment is based on the desire to preserve reproductive capability.

STANDARD TREATMENT OPTIONS:

1. Removal of the hydatidiform mole (dilation, suction evacuation, and curettage).
2. Removal of the uterus (hysterectomy). Only in rare situations do the ovaries require removal.

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 radio-immunoassay is mandatory. Chemotherapy is necessary when there is:

1. A rising BHCG titer for 2 weeks (3 titers).
2. A tissue diagnosis of choriocarcinoma.
3. A plateau of the BHCG for 3 weeks.
4. Metastatic disease (good prognosis).
5. An elevation in BHCG after a normal value.
6. Postevacuation hemorrhage not caused by retained tissues.

This is required in only 20% of patients after evacuation of a molar pregnancy. Chemotherapy is the same as for nonmetastatic gestational trophoblastic tumor.

Placental-Site Gestational Trophoblastic Tumors

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]

References:

1. Lurain JR: Gestational trophoblastic tumors. Semin Surg Oncol 6 (6): 347-53, 1990.

Nonmetastatic Gestational Trophoblastic Tumors

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 although 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.

1. Methotrexate with leucovorin. [1]
2. Dactinomycin. [2]

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use. They are:

1. Methotrexate. [2,3,4]
2. Etoposide. [5]

References:

1. Berkowitz RS, Goldstein DP, Bernstein MR: Ten year's experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 23 (1): 111-8, 1986.
2. Tumors of the placental trophoblast. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 315-353.
3. Homesley HD, Blessing JA, Rettenmaier M, et al.: Weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease. Obstet Gynecol 72 (3 Pt 1): 413-8, 1988.
4. Homesley HD, Blessing JA, Schlaerth J, et al.: Rapid escalation of weekly intramuscular methotrexate for nonmetastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Gynecol Oncol 39 (3): 305-8, 1990.
5. Wong LC, Choo YC, Ma HK: Primary oral etoposide therapy in gestational trophoblastic disease. An update. Cancer 58 (1): 14-7, 1986.

Good-Prognosis Metastatic Gestational Trophoblastic Tumors

This group of patients has disease outside the uterus but none 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, however, 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 therefore mandatory.

STANDARD TREATMENT OPTIONS:

1. Methotrexate with leucovorin. [1]
2. Dactinomycin. [2]
3. Primary hysterectomy followed by single-agent chemotherapy with methotrexate or dactinomycin (if patient has completed family).
4. Primary chemotherapy followed by secondary hysterectomy for persistent uterine disease (must verify that metastatic disease has totally regressed).
5. For refractory disease:
   • MAC: methotrexate + dactinomycin + chlorambucil.[2]

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use. They are:

1. Methotrexate. [2]
2. EMA-CO: etoposide + methotrexate + dactinomycin and vincristine + cyclophosphamide. [3]

References:

1. Berkowitz RS, Goldstein DP, Bernstein MR: Ten year's experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 23 (1): 111-8, 1986.
2. Tumors of the placental trophoblast. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 315-353.
3. Bagshawe KD: High-risk metastatic trophoblastic disease. Obstet Gynecol Clin North Am 15 (3): 531-43, 1988.

Poor-Prognosis Metastatic Gestational Trophoblastic Tumors

Patients with any of the high-risk factors fall into this category. Patients with a WHO score greater than 8 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 8:

• EMA-CO: etoposide + methotrexate + dactinomycin and vincristine + cyclophosphamide.[1,2,3] A dose-intensive regimen, EMA-CE, in which etoposide and cisplatin are substituted for vincristine and cyclophosphamide of the EMA-CO regimen, may offer additional benefits.[4]

FOR PATIENTS WITH A WHO PROGNOSTIC SCORE GREATER THAN 8:

• EMA-CO.[1] A dose-intensive regimen, EMA-CE, may offer additional benefits.[4]

Other regimens that may produce similar outcome but have been studied less extensively or are in less common use include:

• APE: dactinomycin + cisplatin + etoposide. [5]
• PVB: cisplatin + vinblastine + bleomycin. [6]
• PEBA: cisplatin + etoposide + bleomycin + adriamycin. [7]
• Ifosfamide + carboplatin + etoposide with autologous bone marrow transplant. [8]

References:

1. Soper JT, Evans AC, Clarke-Pearson DL, et al.: Alternating weekly chemotherapy with etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine for high-risk gestational trophoblastic disease. Obstet Gynecol 83 (1): 113-7, 1994.
2. Newlands ES, Bagshawe KD, Begent RH, et al.: Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol 98 (6): 550-7, 1991.
3. Bower M, Newlands ES, Holden L, et al.: EMA/CO for high-risk gestational trophoblastic tumors: results from a cohort of 272 patients. J Clin Oncol 15 (7): 2636-43, 1997.
4. Surwit EA, Childers JM: High-risk metastatic gestational trophoblastic disease. A new dose-intensive, multiagent chemotherapeutic regimen. J Reprod Med 36 (1): 45-8, 1991.
5. Theodore C, Azab M, Droz JP, et al.: Treatment of high-risk gestational trophoblastic disease with chemotherapy combinations containing cisplatin and etoposide. Cancer 64 (9): 1824-8, 1989.
6. Azab M, Droz JP, Theodore C, et al.: Cisplatin, vinblastine, and bleomycin combination in the treatment of resistant high-risk gestational trophoblastic tumors. Cancer 64 (9): 1829-32, 1989.
7. Chen LP, Cai SM, Fan JX, et al.: PEBA regimen (cisplatin, etoposide, bleomycin, and adriamycin) in the treatment of drug-resistant choriocarcinoma. Gynecol Oncol 56 (2): 231-4, 1995.
8. Lotz JP, André T, Donsimoni R, et al.: High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults. Cancer 75 (3): 874-85, 1995.

Recurrent Gestational Trophoblastic Tumors

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 (GTT), 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 gray in 2 gray fractions) is given simultaneously with the initiation of systemic chemotherapy. Approximately 50%-60% of patients will achieve sustained remission using this treatment approach. The outcome for women presenting with hepatic metastases from gestational trophoblastic 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 gestational trophoblastic tumors metastatic to the brain.[7]

References:

1. Mutch DG, Soper JT, Babcock CJ, et al.: Recurrent gestational trophoblastic disease. Experience of the Southeastern Regional Trophoblastic Disease Center. Cancer 66 (5): 978-82, 1990.
2. Theodore C, Azab M, Droz JP, et al.: Treatment of high-risk gestational trophoblastic disease with chemotherapy combinations containing cisplatin and etoposide. Cancer 64 (9): 1824-8, 1989.
3. Surwit EA: Management of high-risk gestational trophoblastic disease. J Reprod Med 32 (9): 657-62, 1987.
4. Lehman E, Gershenson DM, Burke TW, et al.: Salvage surgery for chemorefractory gestational trophoblastic disease. J Clin Oncol 12 (12): 2737-42, 1994.
5. Small W Jr, Lurain JR, Shetty RM, et al.: Gestational trophoblastic disease metastatic to the brain. Radiology 200 (1): 277-80, 1996.
6. Crawford RA, Newlands E, Rustin GJ, et al.: Gestational trophoblastic disease with liver metastases: the Charing Cross experience. Br J Obstet Gynaecol 104 (1): 105-9, 1997.
7. Piamsomboon S, Kudelka AP, Termrungruanglert W, et al.: Remission of refractory gestational trophoblastic disease in the brain with ifosfamide, carboplatin, and etoposide (ICE): first report and review of literature. Eur J Gynaecol Oncol 18 (6): 453-6, 1997.

Changes to This Summary (06/05/2003)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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Date Last Modified: 2003-06-05