Molar Pregnancy

  • Dana-Farber/Brigham and Women's Cancer Care

    Molar pregnancy refers to a slow-growing tumor that develops from trophoblastic cells (cells that help an embryo attach to the uterus and help form the placenta) after fertilization of an egg by a sperm. Learn about molar pregnancy and find information on how we support and care for women with molar pregnancy before, during, and after treatment.

Treatment 

Whether you’ve been diagnosed with a gynecologic cancer or are at high risk of developing one, the specialists in the Susan F. Smith Center for Women's Cancers Gynecologic Oncology Program provide expert, compassionate care.

Because gynecologic cancers can have a wide range of physical and emotional effects, we’ve assembled a team of experts from many disciplines to help you and your family cope with cancer and its treatment. Our doctors and other caregivers will work closely with you to develop an individualized treatment plan suited to your situation.

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Learn more about our treatment and care for women with gynecologic cancers 

Our clinicians are experts in treating all types of gynecologic cancers, including: 

  • Cervical cancer
  • Carcinosarcomas
  • Endometrial cancer
  • Gestational trophoblastic tumor
  • Ovarian cancer
  • Epithelial ovarian cancer
  • Germ cell ovarian cancer
  • Low malignant ovarian cancer
  • Borderline ovarian cancer
  • Primary peritoneal cancer
  • Fallopian tube cancer
  • Vaginal cancer
  • Vulvar cancer
  • Choriocarcinoma
  • Molar pregnancy

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General Information About Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a group of rare diseases in which abnormal trophoblast cells grow inside the uterus after conception.

In gestational trophoblastic disease (GTD), a tumor develops inside the uterus from tissue that forms after conception (the joining of sperm and egg). This tissue is made of trophoblastcells and normally surrounds the fertilized egg in the uterus. Trophoblast cells help connect the fertilized egg to the wall of the uterus and form part of the placenta (the organ that passes nutrients from the mother to the fetus).

Sometimes there is a problem with the fertilized egg and trophoblast cells. Instead of a healthy fetus developing, a tumor forms. Until there are signs or symptoms of the tumor, the pregnancy will seem like a normal pregnancy.

Most GTD is benign (not cancer) and does not spread, but some types become malignant (cancer) and spread to nearby tissues or distant parts of the body.

Gestational trophoblastic disease (GTD) is a general term that includes different types of disease:

  • Hydatidiform Moles (HM)
    • Complete HM.
    • Partial HM.
     
  • Gestational Trophoblastic Neoplasia (GTN)
    • Invasive moles.
    • Choriocarcinomas.
    • Placental-site trophoblastic tumors (PSTT; very rare).
    • Epithelioid trophoblastic tumors (ETT; even more rare).
     

Hydatidiform mole (HM) is the most common type of GTD.

HMs are slow-growing tumors that look like sacs of fluid. An HM is also called a molar pregnancy. The cause of hydatidiform moles is not known.

HMs may be complete or partial:

  • A complete HM forms when sperm fertilizes an egg that does not contain the mother’s DNA. The egg has DNA from the father and the cells that were meant to become the placenta are abnormal.
  • A partial HM forms when sperm fertilizes a normal egg and there are two sets of DNA from the father in the fertilized egg. Only part of the fetus forms and the cells that were meant to become the placenta are abnormal.

Most hydatidiform moles are benign, but they sometimes become cancer. Having one or more of the following risk factors increases the risk that a hydatidiform mole will become cancer:

  • A pregnancy before 20 or after 35 years of age.
  • A very high level of beta human chorionic gonadotropin (β-hCG), a hormone made by the body during pregnancy.
  • A large tumor in the uterus.
  • An ovariancyst larger than 6 centimeters.
  • High blood pressure during pregnancy.
  • An overactive thyroidgland (extra thyroid hormone is made).
  • Severe nausea and vomiting during pregnancy.
  • Trophoblastic cells in the blood, which may block small blood vessels.
  • Serious blood clotting problems caused by the HM.

Gestational trophoblastic neoplasia (GTN) is a type of gestational trophoblastic disease (GTD) that is almost always malignant.

Gestational trophoblastic neoplasia (GTN) includes the following:

Invasive moles

Invasive moles are made up of trophoblast cells that grow into the muscle layer of the uterus. Invasive moles are more likely to grow and spread than a hydatidiform mole. Rarely, a complete or partial HM may become an invasive mole. Sometimes an invasive mole will disappear without treatment.

Choriocarcinomas

A choriocarcinoma is a malignant tumor that forms from trophoblast cells and spreads to the muscle layer of the uterus and nearby blood vessels. It may also spread to other parts of the body, such as the brain, lungs, liver, kidney, spleen, intestines, pelvis, or vagina. A choriocarcinoma is more likely to form in women who have had any of the following:

  • Molar pregnancy, especially with a complete hydatidiform mole.
  • Normal pregnancy.
  • Tubal pregnancy (the fertilized egg implants in the fallopian tube rather than the uterus).
  • Miscarriage.

Placental-site trophoblastic tumors

A placental-site trophoblastic tumor (PSTT) is a rare type of gestational trophoblastic neoplasia that forms where the placenta attaches to the uterus. The tumor forms from trophoblast cells and spreads into the muscle of the uterus and into blood vessels. It may also spread to the lungs, pelvis, or lymph nodes. A PSTT grows very slowly and signs or symptoms may appear months or years after a normal pregnancy.

Epithelioid trophoblastic tumors

An epithelioid trophoblastic tumor (ETT) is a very rare type of gestational trophoblastic neoplasia that may be benign or malignant. When the tumor is malignant, it may spread to the lungs.

Age and a previous molar pregnancy affect the risk of GTD.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn't mean that you will not get cancer. Talk to your doctor if you think you may be at risk. Risk factors for GTD include the following:

  • Being pregnant when you are younger than 20 or older than 35 years of age.
  • Having a personal history of hydatidiform mole.

Signs of GTD include abnormal vaginal bleeding and a uterus that is larger than normal.

These and other signs and symptoms may be caused by gestational trophoblastic disease or by other conditions. Check with your doctor if you have any of the following:

  • Vaginal bleeding not related to menstruation.
  • A uterus that is larger than expected during pregnancy.
  • Pain or pressure in the pelvis.
  • Severe nausea and vomiting during pregnancy.
  • High blood pressure with headache and swelling of feet and hands early in the pregnancy.
  • Vaginal bleeding that continues for longer than normal after delivery.
  • Fatigue, shortness of breath, dizziness, and a fast or irregular heartbeat caused by anemia.

GTD sometimes causes an overactive thyroid. Signs and symptoms of an overactive thyroid include the following:

  • Fast or irregular heartbeat.
  • Shakiness.
  • Sweating.
  • Frequent bowel movements.
  • Trouble sleeping.
  • Feeling anxious or irritable.
  • Weight loss.

Tests that examine the uterus are used to detect (find) and diagnose gestational trophoblastic disease.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. The doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and the other hand is placed over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. A speculum is also inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test or Pap smear of the cervix is usually done. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
    Pelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.  
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
  • Ultrasound exam of the pelvis: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs in the pelvis and make echoes. The echoes form a picture of body tissues called a sonogram. Sometimes a transvaginal ultrasound (TVUS) will be done. For TVUS, an ultrasound transducer (probe) is inserted into the vagina to make the sonogram.
  • Lumbar puncture: A procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle into the spinal column. The CSF is checked for signs of cancer. This procedure is also called an LP or spinal tap.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Blood is also tested to check the liver, kidney, and bone marrow.
  • Serum tumor marker test: A procedure in which a sample of blood is checked to measure the amounts of certain substances made by organs, tissues, or tumor cells in the body. Certain substances are linked to specific types of cancer when found in increased levels in the body. These are called tumor markers. For GTD, the blood is checked for the level of beta human chorionic gonadotropin (β-hCG), a hormone that is made by the body during pregnancy. β-hCG in the blood of a woman who is not pregnant may be a sign of GTD.
  • Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, bacteria, and the level of β-hCG.

Certain factors affect prognosis (chance of recovery) and treatment options.

Gestational trophoblastic disease usually can be cured. Treatment and prognosis depend on the following:

  • The type of GTD.
  • Whether the tumor has spread to the uterus, lymph nodes, or distant parts of the body.
  • The number of tumors and where they are in the body.
  • The size of the largest tumor.
  • The level of β-hCG in the blood.
  • How soon the tumor was diagnosed after the pregnancy began.
  • Whether GTD occurred after a molar pregnancy, miscarriage, or normal pregnancy.
  • Previous treatment for gestational trophoblastic neoplasia.

Treatment options also depend on whether the woman wishes to become pregnant in the future.

Stages of Gestational Trophoblastic Tumors and Neoplasia

After gestational trophoblastic neoplasia has been diagnosed, tests are done to find out if cancer has spread from where it started to other parts of the body.

The process used to find out the extent or spread of cancer is called staging, The information gathered from the staging process helps determine the stage of disease. For GTN, stage is one of the factors used to plan treatment.

The following tests and procedures may be done to help find out the stage of the disease:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body onto film, making pictures of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as brain and spinal cord. A substance called gadolinium is injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if choriocarcinoma spreads to the lung, the cancer cells in the lung are actually choriocarcinoma cells. The disease is metastatic choriocarcinoma, not lung cancer.

There is no staging system for hydatidiform moles.

Hydatidiform moles (HM) are found in the uterus only and do not spread to other parts of the body.

The following stages are used for GTN:

Stage I

In stage I, the tumor is in the uterus only.

Stage II

In stage II, cancer has spread outside of the uterus to the ovary, fallopian tube, vagina, and/or the ligaments that support the uterus.

Stage III

In stage III, cancer has spread to the lung.

Stage IV

In stage IV, cancer has spread to distant parts of the body other than the lungs.

The treatment of gestational trophoblastic neoplasia is based on the type of disease, stage, or risk group.

Invasive moles and choriocarcinomas are treated based on risk groups. The stage of the invasive mole or choriocarcinoma is one factor used to determine risk group. Other factors include the following:

  • The age of the patient when the diagnosis is made.
  • Whether the GTN occurred after a molar pregnancy, miscarriage, or normal pregnancy.
  • How soon the tumor was diagnosed after the pregnancy began.
  • The level of beta human chorionic gonadotropin (β-hCG) in the blood.
  • The size of the largest tumor.
  • Where the tumor has spread to and the number of tumors in the body.
  • How many chemotherapydrugs the tumor has been treated with (for recurrent or resistant tumors).

There are two risk groups for invasive moles and choriocarcinomas: low risk and high risk. Patients with low-risk disease usually receive less aggressive treatment than patients with high-risk disease.

Placental-site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) treatments depend on the stage of disease.

Recurrent and Resistant Gestational Trophoblastic Neoplasia

Recurrent gestational trophoblastic neoplasia (GTN) is cancer that has recurred (come back) after it has been treated. The cancer may come back in the uterus or in other parts of the body.

Gestational trophoblastic neoplasia that does not respond to treatment is called resistant GTN.

Treatment Option Overview

There are different types of treatment for patients with gestational trophoblastic disease.

Different types of treatment are available for patients with gestational trophoblastic disease. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Clinical trials are taking place in many parts of the country. Information about ongoing clinical trials is available from the NCI Web site. Choosing the most appropriate cancer treatment is a decision that ideally involves the patient, family, and health care team.

Three types of standard treatment are used:

Surgery

The doctor may remove the cancer using one of the following operations:

  • Dilatation and curettage (D&C) with suction evacuation: A surgical procedure to remove abnormaltissue and parts of the inner lining of the uterus. The cervix is dilated and the material inside the uterus is removed with a small vacuum-like device. The walls of the uterus are then gently scraped with a curette (spoon-shaped instrument) to remove any material that may remain in the uterus. This procedure may be used for molar pregnancies.
    Dilatation and curettage (D and C). Three-panel drawing showing a side view of the female reproductive anatomy during a D and C procedure. The first panel shows a speculum widening the opening of the vagina. The cervix, uterus with abnormal tissue, bladder, and rectum are also shown; an inset shows the lower half of a woman covered by a drape on an exam table with her legs apart  and her feet in stirrups. The middle panel shows the uterus and a dilator inserted through the vagina into the cervix. The third panel shows a curette scraping out abnormal tissue from the uterus; an inset shows a close up of the curette with the abnormal tissue in it. 
    Dilatation and curettage (D and C). A speculum is inserted into the vagina to widen it in order to look at the cervix (first panel). A dilator is used to widen the cervix (middle panel). A curette is put through the cervix into the uterus to scrape out abnormal tissue (last panel).
  • Hysterectomy: Surgery to remove the uterus, and sometimes the cervix. If the uterus and cervix are taken out through the vagina, the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out through a large incision (cut) in the abdomen, the operation is called a total abdominal hysterectomy. If the uterus and cervix are taken out through a small incision (cut) in the abdomen using a laparoscope, the operation is called a total laparoscopic hysterectomy.
    Hysterectomy; drawing shows the female reproductive anatomy, including the ovaries, uterus, vagina, fallopian tubes, and cervix. Dotted lines show which organs and tissues are removed in a total hysterectomy, a total hysterectomy with salpingo-oophorectomy, and a radical hysterectomy. An inset shows the location of two possible incisions on the abdomen: a low transverse incision is just above the pubic area and a vertical incision is between the navel and the pubic area. 
    Hysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated, or whether the tumor is low-risk or high-risk.

Combination chemotherapy is treatment using more than one anticancer drug.

Even if the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy after surgery to kill any tumor cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

See Drugs Approved for Gestational Trophoblastic Disease for more information.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type of cancer being treated.

New types of treatment are being tested in clinical trials.

Information about ongoing clinical trials is available from the NCI Web site.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Blood levels of beta human chorionic gonadotropin (β-hCG) will be checked for up to 6 months after treatment has ended. This is because a β-hCG level that is higher than normal may mean that the tumor has not responded to treatment or it has become cancer.

Treatment Options for Gestational Trophoblastic Disease

Hydatidiform Moles

Treatment of a hydatidiform mole may include the following:

  • Surgery (Dilatation and curettage with suction evacuation) to remove the tumor.

After surgery, beta human chorionic gonadotropin (β-hCG) blood tests are done every week until the β-hCG level returns to normal. Patients also have follow-up doctor visits monthly for up to 6 months. If the level of β-hCG does not return to normal or increases, it may mean the hydatidiform mole was not completely removed and it has become cancer. Pregnancy causes β-hCG levels to increase, so your doctor will ask you not to become pregnant until follow-up is finished.

For disease that remains after surgery, treatment is usually chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with hydatidiform mole. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Gestational Trophoblastic Neoplasia

Low-risk Gestational Trophoblastic Neoplasia

Treatment of low-risk gestational trophoblastic neoplasia (GTN) (invasive mole or choriocarcinoma) may include the following:

  • Chemotherapy with one or more anticancer drugs. Treatment is given until the beta human chorionic gonadotropin (β-hCG) level is normal for at least 3 weeks after treatment ends.

If the level of β-hCG in the blood does not return to normal or the tumor spreads to distant parts of the body, chemotherapy regimens used for high-risk metastatic GTN are given.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with low risk metastatic gestational trophoblastic tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

High-risk Metastatic Gestational Trophoblastic Neoplasia

Treatment of high-risk metastatic gestational trophoblastic neoplasia (invasive mole or choriocarcinoma) may include the following:

  • Combination chemotherapy.
  • Intrathecal chemotherapy and radiation therapy to the brain (for cancer that has spread to the lung, to keep it from spreading to the brain).
  • High-dose chemotherapy or intrathecal chemotherapy and/or radiation therapy to the brain (for cancer that has spread to the brain).

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with high risk metastatic gestational trophoblastic tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Placental-Site Gestational Trophoblastic Tumors and Epithelioid Trophoblastic Tumors

Treatment of stage I placental-site gestational trophoblastic tumors and epithelioid trophoblastic tumors may include the following:

  • Surgery to remove the uterus.

Treatment of stage II placental-site gestational trophoblastic tumors and epithelioid trophoblastic tumors may include the following:

  • Surgery to remove the tumor, which may be followed by combination chemotherapy.

Treatment of stage III and IV placental-site gestational trophoblastic tumors and epithelioid trophoblastic tumors may include following:

  • Combination chemotherapy.
  • Surgery to remove cancer that has spread to other places, such as the lung or abdomen.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with placental-site gestational trophoblastic tumor and epithelioid trophoblastic tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Recurrent or Resistant Gestational Trophoblastic Neoplasia

Treatment of recurrent or resistant gestational trophoblastic tumor may include the following:

  • Chemotherapy with one or more anticancer drugs for tumors previously treated with surgery.
  • Combination chemotherapy for tumors previously treated with chemotherapy.
  • Surgery for tumors that do not respond to chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent gestational trophoblastic tumor. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Gestational Trophoblastic Disease

For more information from the National Cancer Institute about gestational trophoblastic tumors and neoplasia, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on December 2, 2013.


General Information About Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) is a broad term encompassing both benign and malignant growths arising from products of conception in the uterus.[1]

Incidence and Mortality

The reported incidence of GTD varies widely worldwide, from a low of 23 per 100,000 pregnancies (Paraguay) to a high of 1,299 per 100,000 pregnancies (Indonesia).[2] However, at least part of this variability is caused by differences in diagnostic criteria and reporting. The reported incidence in the United States is about 110 to 120 per 100,000 pregnancies. The reported incidence of choriocarcinoma, the most aggressive form of GTD, in the United States is about 2 to 7 per 100,000 pregnancies. The U.S. age-standardized (1960 World Population Standard) incidence rate of choriocarcinoma is about 0.18 per 100,000 women between the ages of 15 years and 49 years.[2]

Risk Factors

Two factors have consistently been associated with an increased risk of GTD:[2]

  • Maternal age.
  • History of hydatidiform mole (HM).

If a woman has been previously diagnosed with an HM, she carries a 1% risk of HM in subsequent pregnancies. This increases to approximately 25% with more than one prior HM. The risk associated with maternal age is bimodal, with increased risk both for mothers younger than 20 years and older than 35 years (and particularly for mothers >45 years). Relative risks are in the range of 1.1 to 11 for both the younger and older age ranges compared with ages 20 to 35 years. However, a population-based HM registry study suggests that the age-related patterns of the two major types of HM—complete and partial HM—are distinct.[3] (Refer to the Cellular Classification of Gestational Trophoblastic Disease section of this summary for more information.) In that study, the rate of complete HM was highest in women younger than 20 years and then decreased monotonically with age. However, the rates of partial HM increased for the entire age spectrum, suggesting possible differences in etiology. The association with paternal age is inconsistent.[2] A variety of exposures have been examined, with no clear associations found with tobacco smoking, alcohol consumption, diet, and oral contraceptive use.[2]

Clinical Features

GTDs contain paternal chromosomes and are placental, rather than maternal, in origin. The most common presenting symptoms are vaginal bleeding and a rapidly enlarging uterus, and GTD should be considered whenever a premenopausal woman presents with these findings. Because the vast majority of GTD types are associated with elevated human chorionic gonadotropin (hCG) levels, an hCG blood level and pelvic ultrasound are the initial steps in the diagnostic evaluation. In addition to vaginal bleeding and uterine enlargement, other presenting symptoms or signs may include the following:

  • Pelvic pain or sensation of pressure.
  • Anemia.
  • Hyperemesis gravidarum.
  • Hyperthyroidism (secondary to the homology between the beta-subunits of hCG and thyroid-stimulating hormone (TSH), which causes hCG to have weak TSH-like activity).
  • Preeclampsia early in pregnancy.

The most common antecedent pregnancy in GTD is that of an HM.

Choriocarcinoma most commonly follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy, or abortion, and it should always be considered when a patient has continued vaginal bleeding in the postdelivery period. Other possible signs include neurologic symptoms (resulting from brain metastases) in a female within the reproductive age group and asymptomatic lesions on routine chest x-ray.

Prognostic Factors and Survivorship

The prognosis for cure of patients with GTDs is good even when the disease has spread to distant organs, especially when only the lungs are involved. Therefore, the traditional TNM staging system has limited prognostic value.[4] The probability of cure depends on the following:

  • Histologic type (invasive mole or choriocarcinoma).
  • Extent of spread of the disease/largest tumor size.
  • Level of serum beta-hCG.
  • Duration of disease from the initial pregnancy event to start of treatment.
  • Number and 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. The beta-hCG is a sensitive marker to indicate the presence or absence of disease before, during, and after treatment. Given the extremely good therapeutic outcomes of most of these tumors, an important goal is to distinguish patients who need less-intensive therapies from those who require more-intensive regimens to achieve a cure.

References:

  1. Ngan HY, Kohorn EI, Cole LA, et al.: Trophoblastic disease. Int J Gynaecol Obstet 119 (Suppl 2): S130-6, 2012.

  2. Altieri A, Franceschi S, Ferlay J, et al.: Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4 (11): 670-8, 2003.

  3. Altman AD, Bentley B, Murray S, et al.: Maternal age-related rates of gestational trophoblastic disease. Obstet Gynecol 112 (2 Pt 1): 244-50, 2008.

  4. Gestational trophoblastic tumors. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p 439.

Cellular Classification of Gestational Trophoblastic Disease

Gestational trophoblastic disease (GTD) may be classified as follows:[1]

  • Hydatidiform mole (HM).
    • Complete HM.
    • Partial HM.
  • Gestational trophoblastic neoplasia.
    • Invasive mole.
    • Choriocarcinoma.
    • Placental-site trophoblastic tumor (PSTT); (very rare).
    • Epithelioid trophoblastic tumor (ETT); (extremely rare).

Choriocarcinoma, PSTT, and ETT are often grouped under the heading gestational trophoblastic tumors.

HM

HM is defined as products of conception that show gross cyst-like swellings of the chorionic villi that are caused by an accumulation of fluid. There is disintegration and loss of blood vessels in the villous core.

Complete HM

A complete mole occurs when an ovum that has extruded its maternal nucleus is fertilized by either a single sperm, with subsequent chromosome duplication, or two sperm, resulting in either case in a diploid karyotype. The former case always yields a mole with a karyotype of 46 XX, since at least one X chromosome is required for viability and a karyotype of 46 YY is rapidly lethal to the ovum. The latter case may yield a karyotype of 46 XX or 46 XY. About 90% of complete HMs are 46 XX. On ultrasound examination, complete moles rarely reveal a fetus or amniotic fluid.

Partial HM

A partial mole occurs when the ovum retains its nucleus but is fertilized by a single sperm, with subsequent chromosome duplication, or is fertilized by two sperm; the possible resulting triploid karyotypes are 69 XXY, 69 XXX, or 69 XYY. Therefore, in contrast to a complete mole, the partial mole chromosomes of a partial mole are only two-thirds paternal in origin. In contrast to complete moles, partial moles usually show a fetus, which may even be viable, and amniotic fluid is visible.

Complete HMs have a 15% to 25% risk of developing into an invasive mole, but transformation to malignancy is much more rare (<5%) in the case of partial moles.

Gestational Trophoblastic Neoplasias

Invasive mole

Invasive moles (chorioadenoma destruens) are locally invasive, rarely metastatic lesions characterized microscopically by trophoblastic invasion of the myometrium with identifiable villous structures. These may be preceded by either complete or partial molar pregnancy. They are usually diploid in karyotype, but may be aneuploid. Microscopically, these lesions are characterized by hyperplasia of cytotrophoblastic and syncytial elements and persistence of villous structures. They may resemble choriocarcinoma in histologic appearance. Invasive moles have more aggressive behavior than either complete or partial HMs, and they are treated similarly to choriocarcinoma (i.e., with chemotherapy). However, unlike choriocarcinoma, they may regress spontaneously.

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. Most choriocarcinomas have an aneuploid karyotype, and about three-quarters of them contain a Y chromosome. Most follow an HM pregnancy, spontaneous abortion, or ectopic pregnancy; but, about one-quarter of them are preceded by a full-term pregnancy. Nearly all GTDs that are preceded by nonmolar pregnancies are choriocarcinomas; the rare exceptions generally are PSTTs.

PSTT

PSTT disease is the result of a very 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, whereas immunoperoxidase staining for human chorionic gonadotropin (hCG) is positive in only scattered cells, and elevations in serum hCG are relatively low compared with the marked elevations seen in choriocarcinoma. hCG is not a reliable marker of tumor volume.[2][3] PSTTs have much lower growth rates than choriocarcinoma, and presentation after a full-term pregnancy is often delayed by months or years. They are generally resistant to chemotherapy. Therefore, hysterectomy is the standard primary treatment if the tumor is confined to the uterus. However, about 35% of PSTTs have distant metastases at diagnosis.[3][4] Common sites of metastasis include the lungs, pelvis, and lymph nodes. Central nervous system, renal, and liver metastases have also been observed.

ETT

ETT is an extremely rare gestational trophoblastic tumor.[5][6] Although originally termed atypical choriocarcinoma, it appears to be less aggressive than choriocarcinoma and is now regarded as a distinct entity. Pathologically, it has a monomorphic cellular pattern of epithelioid cells and may resemble squamous cell cancer of the cervix when arising in the cervical canal. Its clinical behavior appears to be closer to that of PSTT than to choriocarcinoma. It has a spectrum of clinical behavior from benign to malignant. About one-third of patients present with metastases, usually in the lungs.

References:

  1. Altieri A, Franceschi S, Ferlay J, et al.: Epidemiology and aetiology of gestational trophoblastic diseases. Lancet Oncol 4 (11): 670-8, 2003.

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

  3. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002.

  4. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009.

  5. Shih IM, Kurman RJ: Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma. Am J Surg Pathol 22 (11): 1393-403, 1998.

  6. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008.

Stage Information for Gestational Trophoblastic Disease

Hydatidiform Mole (HM)

HM (molar pregnancy) is disease limited to the uterine cavity.

Gestational Trophoblastic Neoplasia

Definitions: FIGO

The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define gestational trophoblastic neoplasia; the FIGO system is most commonly used.[1][2] Some tumor registrars encourage the recording of staging in both systems.

FIGO staging system (and modified World Health Organization [WHO] prognostic scoring system)

The FIGO staging system is as follows:[1]

Table 1. Gestational Trophoblastic Neoplasia (GTN)a,b

FIGO Anatomical Staging

Stage

I

Disease confined to the uterus.

II

GTN extends outside of the uterus, but is limited to the genital structures (adnexa, vagina, broad ligament).

III

GTN extends to the lungs, with or without known genital tract involvement.

IV

All other metastatic sites.

Modified WHO Prognostic Scoring System as Adapted by FIGOb

Scores

0

1

2

4

Age

<40

≥40

Antecedent pregnancy

mole

abortion

term

Interval months from index pregnancy

<4

4–6

7–12

>12

Pretreatment serum hCG (iu/1)

<103

103–104

104–105

>105

Largest tumor size (including uterus)

<3

3–4 cm

≥5 cm

Site of metastases

lung

spleen, kidney

gastrointestinal

liver, brain

Number of metastases

1–4

5–8

>8

Previous failed chemotherapy

single drug

≥2 drugs

FIGO = Féderation Internationale de Gynécologie et d’Obstétrique; hCG = human chorionic gonadotropin; iu = international unit; WHO = World Health Organization.

aAdapted from FIGO Committee on Gynecologic Oncology.[1]

bTo stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals, i.e., stage II:4, stage IV:9. This stage and score will be allotted for each patient.

In addition, the FIGO staging system incorporates a modified WHO prognostic scoring system. The scores from the eight risk factors are summed and incorporated into the FIGO stage, separated by a colon (e.g., Stage II:4, Stage IV:9, etc.). Unfortunately, a variety of risk scoring systems have been published, making comparisons of results difficult.

References:

  1. FIGO Committee on Gynecologic Oncology: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 105 (1): 3-4, 2009.

  2. Gestational trophoblastic tumors. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, p 439.

Treatment Option Overview

Most hydatidiform moles (HMs) are benign and are treated conservatively by dilation, suction evacuation, and curettage. However, since they carry a risk of persistence or progression to malignant gestational trophoblastic disease (GTD), they must be followed carefully with weekly serum human chorionic gonadotropin (hCG) levels to normalization. Monthly follow-up for 6 months is generally recommended, although the duration of this phase of follow-up is not based on empiric study.[1]

Prompt institution of therapy for GTD and continuing follow-up at very close intervals until normal beta-hCG titers are obtained is the cornerstone of management. When chemotherapy is instituted, the interval between courses should rarely exceed 14 to 21 days, depending on the regimen used. It is recommended that patients receive one to three courses of chemotherapy after the first normal beta-hCG titer, depending on the extent of disease. The modified World Health Organization (WHO) Prognostic Scoring System (see Table 1) should be utilized, and combination chemotherapy should be initiated when warranted by the patient's score. If a diagnosis of GTD is made, routine work-up includes the following:

  • Serum beta-hCG.
  • Blood work of liver, renal, and marrow function.
  • Chest x-ray.
  • Pelvic ultrasound.
  • Head computed tomography or magnetic resonance imaging (in the case of choriocarcinoma or central nervous system signs).

Treatment of GTD depends on the risk category determined by the Modified WHO Prognostic Scoring System as adapted by the International Federation of Gynecology and Obstetrics (see Table 1). Since the very rare placental-site trophoblastic tumors and the even more rare epithelioid trophoblastic tumors are biologically distinct entities, their management is discussed separately.

Low Levels of hCG

Accurate monitoring of hCG is critical to successfully diagnose and monitor the treatment course of gestational trophoblastic disease. False-positive results may lead to inappropriate diagnoses and treatment, and must be minimized. The following are possible alternate diagnoses to be considered in cases of low-level hCG.

False-positive hCG

Serum hCG testing relies on detecting two antibodies on the hCG molecule. The antibodies are polyclonal or monoclonal antibodies derived from various animals: mouse, rabbit, goat or sheep. Humans with heterophilic (or cross-species) antibodies bind the antibodies in the assay, leading to a false-positive result. This was a common problem with one of the commercially available assays until it was re-engineered in 2003. Heterophilic antibodies cannot cross the glomerular filtration barrier, so the performance of a urinary hCG can eliminate this source for a positive test result. The urine sample should be run using the same system generally reserved for serum, as opposed to over-the-counter urine-pregnancy tests, to avoid decreased sensitivity in the latter.

Pituitary hCG

The anterior stalk of the pituitary secretes luteinizing hormone (LH), which shares an alpha subunit with hCG. In normal menstrual cycles, pituitary-generated hCG may be detectable at the time of the LH surge. Estrogen provides negative feedback for this LH secretion and acts as a suppressing agent. In patients in low-estrogen states (perimenopause, menopause, and status postoophorectomy), pituitary hCG may be secreted in increasing amounts, although only levels between 1 to 32 mIU/mL have been recorded.[2] To confirm a pituitary source for the hCG, patients are started on high-dose oral contraceptive pills to produce an exogenous source of estrogen. In general, patients with pituitary hCG will have their hCG levels suppressed after 3 weeks on this regimen.[2]

References:

  1. Sita-Lumsden A, Short D, Lindsay I, et al.: Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009. Br J Cancer 107 (11): 1810-4, 2012.

  2. Muller CY, Cole LA: The quagmire of hCG and hCG testing in gynecologic oncology. Gynecol Oncol 112 (3): 663-72, 2009.

Hydatidiform Mole Management

Treatment of hydatidiform mole (HM) is within the purview of the obstetrician/gynecologist and will not be discussed separately here. However, following the diagnosis and treatment of HM, patients should be monitored to rule out the possibility of metastatic gestational trophoblastic neoplasia. In almost all cases, this can be performed with routine monitoring of serum beta human chorionic gonadotropin (beta-hCG) to document its return to normal. An effective form of contraception is important during the follow-up period to avoid the confusion that can occur with a rising beta-hCG as a result of pregnancy.

Chemotherapy is necessary when there is the following:

  1. A rising beta-hCG titer for 2 weeks (3 titers).
  2. A tissue diagnosis of choriocarcinoma.
  3. A plateau of the beta-hCG for 3 weeks.
  4. Persistence of detectable beta-hCG 6 months after mole evacuation.
  5. Metastatic disease.
  6. An elevation in beta-hCG after a normal value.
  7. Postevacuation hemorrhage not caused by retained tissues.

Chemotherapy is ultimately required for persistence or neoplastic transformation in about 15% to 20% of patients after evacuation of a complete HM but for fewer than 5% of patients with partial HM. Chemotherapy is determined by the patient's modified World Health Organization score.

In women with complete HM, risk of persistence or neoplastic transformation is approximately doubled in the setting of certain characteristics, which include the following:

  • Age older than 35 years or age younger than 20 years.
  • Pre-evacuation serum beta-hCG greater than 100,000 IU/L.
  • Large-for-date uterus.
  • Large uterine molar mass.
  • Large (>6 cm) ovarian cysts.
  • Pre-eclampsia.
  • Hyperthyroidism.
  • Hyperemesis of pregnancy.
  • Trophoblastic embolization.
  • Disseminated intravascular coagulation.

Studies have shown that a single course of prophylactic dactinomycin or methotrexate can decrease the risk of a postmolar gestational trophoblastic disease (GTD).[1][2][3] However, there is concern that chemoprophylaxis increases tumor resistance to standard therapy in the women who subsequently develop GTD.[1] Therefore, this practice is generally limited to countries in which a large number of women do not return for follow-up.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.

References:

  1. Kim DS, Moon H, Kim KT, et al.: Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. Obstet Gynecol 67 (5): 690-4, 1986.

  2. Limpongsanurak S: Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 46 (2): 110-6, 2001.

  3. Uberti EM, Fajardo Mdo C, Ferreira SV, et al.: Reproductive outcome after discharge of patients with high-risk hydatidiform mole with or without use of one bolus dose of actinomycin D, as prophylactic chemotherapy, during the uterine evacuation of molar pregnancy. Gynecol Oncol 115 (3): 476-81, 2009.

Low-Risk Gestational Trophoblastic Neoplasia (FIGO Score 0–6) Treatment

There is no consensus on the best chemotherapy regimen for initial management of low-risk gestational trophoblastic neoplasia (GTN), and first-line regimens vary by geography and institutional preference. Most regimens have not been compared head-to-head, and the level of evidence for efficacy is often limited to 3iiDii except as noted below. Even if there are differences in initial remission rate among the regimens, salvage with alternate regimens is very effective, and the ultimate cure rates are generally 99% or more. The initial regimen is generally given until a normal beta human chorionic gonadotropin (beta-hCG) (for the institution) is achieved and sustained for 3 consecutive weeks (or at least for one treatment cycle beyond normalization of the beta-hCG). A salvage regimen is instituted if any of the following occur:

  • A plateau of the beta-hCG for 3 weeks (defined as a beta-hCG decrease of 10% or less for 3 consecutive weeks).
  • A rise in beta-hCG of greater than 20% for 2 consecutive weeks.
  • Appearance of metastases.

The use of chemotherapy in the first-line management of low-risk GTN has been assessed in a Cochrane Collaboration systematic review.[1] In that systematic review, four randomized controlled trials were identified.[2][3][4][5]

Three of the randomized trials [3][4][5] compared the same two commonly used regimens:

  • Biweekly (pulsed) dactinomycin (1.25 mg/m2 intravenously [IV]).
  • Weekly intramuscular methotrexate (30 mg/m2).

These three trials included a total of 392 patients. All three trials showed better primary complete response (CR) rates without the need for additional salvage therapy associated with pulsed dactinomycin (relative risk [RR] of cure, 3.00; 95% confidence interval [CI], 1.10–8.17), even though the magnitude of benefit showed substantial heterogeneity (I2 statistic = 79%).[3][4][5][Level of evidence: 1iiDii] Fewer courses of therapy were needed to achieve CR and cure with dactinomycin treatment. As expected, salvage chemotherapy was nearly uniformly successful, because almost all low-risk GTN patients are ultimately cured, irrespective of the initial chemotherapeutic regimen. There were no statistically significant differences in most toxicities, including the following:

  • Nausea and vomiting.
  • Diarrhea.
  • Hematologic toxicity.
  • Hepatic toxicity.

There was a statistically significant increase in dermatologic toxicity, including alopecia, associated with dactinomycin. However, in the largest study,[5] there was statistically significantly more low-grade gastrointestinal toxicity, grade 2 nausea, grade 1 to 2 vomiting, and grades 1 to 3 neutropenia in the dactinomycin group. In that study, choriocarcinoma patients and patients with a risk score of 5 to 6 had a worse CR rate to initial treatment with single-agent therapy, and methotrexate was virtually ineffective.[5]

The fourth randomized trial was a very small study of 45 patients and compared a 5-day regimen of dactinomycin (10 μg/kg) with an 8-day regimen of methotrexate (1 mg/kg) and folinic acid (0.1 mg/kg) on alternate days. There was a statistically significant decrease in risk of failure to achieve primary cure without the need for salvage therapy in the dactinomycin arm (RR, 0.57; 95% CI, 0.40–0.81).[2][Level of evidence: 1iiDii] There was less alopecia associated with methotrexate but more hepatic toxicity.

The Cochrane systematic review also summarized the evidence from four nonrandomized trials, but comparisons across studies are difficult. The regimens evaluated in those studies are included in the lists below.[1][Level of evidence: 3iiDii]

Commonly used treatment regimens include the following:

  1. The 8-day Charing Cross regimen. Methotrexate (50 mg intramuscularly [IM] on days 1, 3, 5, and 7) and folinic acid (7.5 mg orally on days 2, 4, 6, and 8). This may be the most common regimen worldwide,[1][6] but it has not been directly compared with other regimens.
  2. Biweekly pulsed dactinomycin (1.25 mg/m2 IV).
  3. Weekly methotrexate (30 mg/m2 IM). Efficacy of this regimen appears to be low for choriocarcinoma and for patients with Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) risk scores of 5 to 6.

Other regimens in less-common use include the following:

  • An 8-day regimen of methotrexate (1 mg/kg IM days 1, 3, 5, and 7) and folinic acid (0.1 mg/kg IM days 2, 4, 6, and 8).
  • Methotrexate 20 mg/m2 IM days 1 to5, repeated every 14 days.
  • Dactinomycin 12 μg/kg/day IV days 1 to 5, repeated every 2 to 3 weeks. This regimen has fallen out of favor because of substantial alopecia and nausea.
  • Methotrexate 20 mg IM daily, days 1 to 5; and dactinomycin 500 μg IV daily, days 1 to 5, repeated every 14 days.
  • Dactinomycin 10 μg/kg/day, days 1 to 5, repeated every 2 weeks.
  • Methotrexate 0.4 mg/kg/day IM daily on days 1 to 5, repeated after 7 days.
  • Etoposide 100 mg/m2/day IV on days 1 to 5, or 250 mg/m2 IV on days 1 and 3, at 10-day intervals.[7]

The unusual patient with a tumor that becomes refractory to single-agent chemotherapy is treated with one of the combination regimens described below for high-risk GTN. (Refer to the High-Risk Gestational Trophoblastic Neoplasia (FIGO Score ≥7) Treatment section of this summary for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with low risk 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.

References:

  1. Alazzam M, Tidy J, Hancock BW, et al.: First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev (1): CD007102, 2009.

  2. Lertkhachonsuk AA, Israngura N, Wilailak S, et al.: Actinomycin d versus methotrexate-folinic acid as the treatment of stage I, low-risk gestational trophoblastic neoplasia: a randomized controlled trial. Int J Gynecol Cancer 19 (5): 985-8, 2009.

  3. Gilani MM, Yarandi F, Eftekhar Z, et al.: Comparison of pulse methotrexate and pulse dactinomycin in the treatment of low-risk gestational trophoblastic neoplasia. Aust N Z J Obstet Gynaecol 45 (2): 161-4, 2005.

  4. Yarandi F, Eftekhar Z, Shojaei H, et al.: Pulse methotrexate versus pulse actinomycin D in the treatment of low-risk gestational trophoblastic neoplasia. Int J Gynaecol Obstet 103 (1): 33-7, 2008.

  5. Osborne RJ, Filiaci V, Schink JC, et al.: Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. J Clin Oncol 29 (7): 825-31, 2011.

  6. Khan F, Everard J, Ahmed S, et al.: Low-risk persistent gestational trophoblastic disease treated with low-dose methotrexate: efficacy, acute and long-term effects. Br J Cancer 89 (12): 2197-201, 2003.

  7. Hitchins RN, Holden L, Newlands ES, et al.: Single agent etoposide in gestational trophoblastic tumours. Experience at Charing Cross Hospital 1978-1987. Eur J Cancer Clin Oncol 24 (6): 1041-6, 1988.

High-Risk Gestational Trophoblastic Neoplasia (FIGO Score ≥7) Treatment

Multiagent chemotherapy is standard for the initial management of high-risk gestational trophoblastic neoplasia (GTN). A systematic literature review revealed only one randomized controlled trial (and no high-quality trials)—conducted in the 1980s—comparing multiagent chemotherapy regimens for high-risk GTN.[1] In the trial, only 42 women were randomly assigned to either a CHAMOMA regimen (i.e., methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin) or MAC (i.e., methotrexate, dactinomycin, and chlorambucil).[2] There was substantially more life-threatening toxicity in the CHAMOMA arm and no evidence of higher efficacy. However, there were serious methodologic problems with this trial. It was reportedly designed as an equivalency trial, but owing to the small sample size, the trial was inadequately powered to assess equivalence. In addition, the characteristics of the patients randomly assigned to the two study arms were not reported (although the authors stated that there were no major differences in the patient populations assigned to each arm), nor was the method of randomization or allocation concealment described.

There are no randomized trials comparing regimens in common use to establish the superiority of one over another. Therefore, the literature does not permit firm conclusions about the best chemotherapeutic regimen.[1][Level of evidence 3iiiDii] However, since EMA/CO (i.e., etoposide, methotrexate, and dactinomycin/cyclophosphamide and vincristine) is the most commonly used regimen, the specifics are provided in Table 2 below.[3][4][5]

Table 2. Specifics of the EMA/CO Regimena,b,c

Day

Drug

Dose

1

Etoposide

100 mg/m2 IV for 30 min

Dactinomycin

0.5 mg IV push

Methotrexate

300 mg/m2 IV for 12 h

2

Etoposide

100 mg/m2 IV for 30 min

Dactinomycin

0.5 mg IV push

Folinic Acid

15 mg or PO every 12 h × 4 doses, beginning 24 h after the start of methotrexate

8

Cyclophosphamide

600 mg/m2 IV infusion

Vincristine

0.8–1.0 mg/m2 IV push (maximum dose 2 mg)

IV = intravenously; PO = orally.

aAdapted from Bower et al.[3]

bAdapted from Escobar et al.[4]

cAdapted from Lurain et al.[5]

Cycles are repeated every 2 weeks (on days 15, 16, and 22) until any metastases present at diagnosis disappear and serum beta-human chorionic gonadotropin (beta-hCG) has normalized, then the treatment is usually continued for an additional three to four cycles.

Results of a large, consecutive case series of 272 patients with up to 16 years of follow-up showed a complete remission rate of 78% using this regimen, and these results are consistent with other case series in the literature that employed EMA/CO.[3] More than two-thirds of the women who did not have a complete response or subsequently had disease recurrence could be salvaged with cisplatin-containing regimens (with or without resection of metastases), yielding a long-term cure rate of 86.2% (95% CI, 81.9%–90.5%).[3][Level of evidence: 3iiA] Moreover, routinely when the addition of cisplatin plus etoposide was added to EMA/CO, a 9% improvement was reported in the survival results of these high-risk patients.[6] Among the women who had an intact uterus, about 50% of them retained their fertility. Patients with documented brain metastases received higher doses of systemic methotrexate as part of the EMA component (i.e., etoposide, methotrexate, folinic acid, and dactinomycin) of EMA/CO (1 g/m2 intravenously [IV] for 24 hours, followed by folinic-acid rescue, 15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with brain metastases received an increased dose of systemic methotrexate of 1 g/m2 for 24 hours followed by folinic acid (15 mg orally every 6 hours for 12 doses starting 32 hours after methotrexate). Patients with lung metastases received cranial prophylaxis with irradiation and intrathecal methotrexate 12.5 mg every 2 weeks with the CO (i.e., cyclophosphamide and vincristine) cycles.

Examples of other regimens that have been used include the following:[1]

  • MAC: Methotrexate, folinic acid, dactinomycin, and cyclophosphamide.
  • Another MAC: Methotrexate, dactinomycin, and chlorambucil.
  • EMA: Etoposide, methotrexate, folinic acid, and dactinomycin (EMA/CO without the CO).
  • CHAMOCA: Methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine.
  • CHAMOMA: Methotrexate, folinic acid, hydroxyurea, dactinomycin, vincristine, melphalan, and doxorubicin.

Brain metastases are associated with poor prognosis, particularly when liver metastases are also present.[7][8][9] However, even patients with brain metastases may achieve long-term remission in 50% to 80% of cases.[3][4][9] Patients with central nervous system (CNS) metastases receive additional therapy simultaneously with the initiation of systemic chemotherapy. Some centers utilize whole-brain irradiation (30 Gy in 2 Gy fractions) with or without intrathecal methotrexate.[7] However, some investigators omit the cranial radiation, relying on replacement of the standard dose of methotrexate in the EMA/CO regimen with the higher dose of 1,000 mg/m2 IV for 24 hours on the first day, as noted above, to achieve therapeutic CNS levels.[9]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with high risk 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.

References:

  1. Deng L, Yan X, Zhang J, et al.: Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev (2): CD005196, 2009.

  2. Curry SL, Blessing JA, DiSaia PJ, et al.: A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study. Obstet Gynecol 73 (3 Pt 1): 357-62, 1989.

  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. Escobar PF, Lurain JR, Singh DK, et al.: Treatment of high-risk gestational trophoblastic neoplasia with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy. Gynecol Oncol 91 (3): 552-7, 2003.

  5. Lurain JR, Singh DK, Schink JC: Management of metastatic high-risk gestational trophoblastic neoplasia: FIGO stages II-IV: risk factor score > or = 7. J Reprod Med 55 (5-6): 199-207, 2010 May-Jun.

  6. Alifrangis C, Agarwal R, Short D, et al.: EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. J Clin Oncol 31 (2): 280-6, 2013.

  7. Small W Jr, Lurain JR, Shetty RM, et al.: Gestational trophoblastic disease metastatic to the brain. Radiology 200 (1): 277-80, 1996.

  8. 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.

  9. Newlands ES, Holden L, Seckl MJ, et al.: Management of brain metastases in patients with high-risk gestational trophoblastic tumors. J Reprod Med 47 (6): 465-71, 2002.

Placental-Site Trophoblastic Tumor Treatment

Given the rarity of the placental-site trophoblastic tumor (PSTT), reports of therapeutic results are confined to relatively small case series with accrual extending for very long time periods. Therefore, few reliable comparisons among surgical approaches or chemotherapeutic regimens can be made. Nevertheless, there are distinctions in underlying biology between PSTTs and the other gestational trophoblastic tumors—particularly resistance to chemotherapy—that justify specific treatment strategies, such as the following:

  1. Tumors confined to the uterus (Féderation Internationale de Gynécologie et d’Obstétrique [FIGO] Stage I).

    Hysterectomy is the treatment of choice.[1][2] In a relatively large, retrospective, population-based, consecutive, case series of 62 women with PSTT, 33 had disease confined to the uterus and were treated with hysterectomy (n = 17) or with hysterectomy plus chemotherapy (n = 16). Overall survival at 10 years was virtually identical between the two groups (90% and 91%, respectively). There was only one recurrence in the surgery group and two in the combination therapy group.[2][Level of evidence 3iDii] There is little evidence to guide the optimal extent of surgery (e.g., lymph node resection or oophorectomy).

  2. Tumors with extrauterine spread to genital structures (FIGO stage II).

    Complete resection with or without adjuvant chemotherapy. Because the relapse rate is high after surgery and overall mortality in patients is high, adjuvant multiple-agent chemotherapy should be considered.[1][2][Level of evidence 3iDii] However, the impact of adjuvant therapy on overall mortality is uncertain.

  3. Metastatic tumors (FIGO stages III and IV).

    Polyagent chemotherapy. A variety of regimens have been used with no direct comparisons to determine whether one is superior. Some of the regimens include the following:[1][2]

    • EMA/CO: Etoposide, methotrexate with folinic acid rescue, dactinomycin, cyclophosphamide, and vincristine. This appears to be the most commonly used regimen.
    • EP/EMA: Etoposide and cisplatin with etoposide, methotrexate, and dactinomycin.
    • MAE: Methotrexate with folinic acid rescue, dactinomycin, and etoposide.

In part because of the inherent chemoresistance of PSTTs, resection of tumors is often considered in addition to chemotherapy regimens used for high-risk gestational trophoblastic neoplasias. In retrospective series, adjuvant surgery, such as hysterectomy, excision of lung metastases, or removal of obstructing abdominal lesions, has been associated with favorable disease control. However, it is not clear which component of the favorable outcomes is attributable to the surgery or to patient selection factors.[2][3][Level of evidence 3iiiDii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.

References:

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

  2. Schmid P, Nagai Y, Agarwal R, et al.: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective observational study. Lancet 374 (9683): 48-55, 2009.

  3. Feltmate CM, Genest DR, Goldstein DP, et al.: Advances in the understanding of placental site trophoblastic tumor. J Reprod Med 47 (5): 337-41, 2002.

Epithelioid Trophoblastic Tumor Treatment

Epithelioid trophoblastic tumors (ETTs) are exceedingly rare, and there is little information to guide therapy. However, these tumors are similar in behavior and prognosis to placental-site trophoblastic tumors, so it is reasonable to manage them similarly. (Refer to the Placental-Site Gestational Trophoblastic Tumor Treatment section of this summary for more information.) Only a minority of ETTs are malignant in behavior, but they are not very responsive to systemic therapy. A variety of chemotherapy regimens have been used.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with epithelioid 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.

References:

  1. Palmer JE, Macdonald M, Wells M, et al.: Epithelioid trophoblastic tumor: a review of the literature. J Reprod Med 53 (7): 465-75, 2008.

Recurrent or Chemoresistant Gestational Trophoblastic Neoplasia Treatment

Recurrent disease indicates failure of prior chemotherapy unless initial therapy was surgery alone. One 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] Nearly all recurrences occur within 3 years of remission (85% before 18 months). A patient whose disease progresses after primary surgical therapy is generally treated with single-agent chemotherapy unless one of the poor-prognosis factors that requires combination chemotherapy supervenes. Relapse after failure of prior chemotherapy automatically places the patient in the high-risk category. These patients should be treated with aggressive chemotherapy.

Reports of combination chemotherapy come from small retrospective case series. Long-term disease-free survival, in excess of 50%, is achievable with combination drug regimens.[2][Level of evidence: 3iiiDii] A variety of regimens have been reported that include combinations of the following:[3][4][5][6][7]

  • Cisplatin.
  • Etoposide.
  • Bleomycin.
  • Ifosfamide.
  • Paclitaxel.
  • 5-fluorouracil.
  • Floxuridine.

A select group of patients with chemotherapy-resistant and clinically detectable gestational trophoblastic neoplasia may benefit from salvage surgery.[8][Level of evidence: 3iiiDii]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.

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. Newlands ES: The management of recurrent and drug-resistant gestational trophoblastic neoplasia (GTN). Best Pract Res Clin Obstet Gynaecol 17 (6): 905-23, 2003.

  3. Matsui H, Iitsuka Y, Suzuka K, et al.: Salvage chemotherapy for high-risk gestational trophoblastic tumor. J Reprod Med 49 (6): 438-42, 2004.

  4. Xiang Y, Sun Z, Wan X, et al.: EMA/EP chemotherapy for chemorefractory gestational trophoblastic tumor. J Reprod Med 49 (6): 443-6, 2004.

  5. Lurain JR, Nejad B: Secondary chemotherapy for high-risk gestational trophoblastic neoplasia. Gynecol Oncol 97 (2): 618-23, 2005.

  6. Wan X, Xiang Y, Yang X, et al.: Efficacy of the FAEV regimen in the treatment of high-risk, drug-resistant gestational trophoblastic tumor. J Reprod Med 52 (10): 941-4, 2007.

  7. Wang J, Short D, Sebire NJ, et al.: Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE). Ann Oncol 19 (9): 1578-83, 2008.

  8. Lehman E, Gershenson DM, Burke TW, et al.: Salvage surgery for chemorefractory gestational trophoblastic disease. J Clin Oncol 12 (12): 2737-42, 1994.


This information is provided by the National Cancer Institute.

This information was last updated on April 25, 2014.

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