Initial Management of High-risk Gestational Trophoblastic Neoplasia

8/16/2019 Initial Management of High-risk Gestational Trophoblastic Neoplasia

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2/4/2015 Ini ti al manag ement of hi gh- ri sk g es tati onal tr ophobl asti c neopl as i a

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Official reprint from UpToDatewww.uptodate.com ©2015 UpToDate

Authors

Ross S Berkowitz, MDDonald Peter Goldstein,

MD

Neil S Horowitz, MD

Section Editor

Barbara Goff, MD

Deputy Editors

Don S Dizon, MD, FACPSandy J Falk, MD, FACOG

Initial management of high-risk gestational trophoblastic neoplasia

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review cur rent through: Jan 2015. | This topic last updated: Jan 06, 2015.

INTRODUCTION — Gestational trophoblastic disease (GTD) defines a group of conditions that arise from an

aberrant fertilization event. When GTD recurs or there is evidence of metastatic disease, it is called gestational

trophoblastic neoplasia (GTN) and comprises four subtypes of disease:

The initial treatment of high-risk GTN is discussed here. The pathol ogy, epidemiology, clinical manifestations,

and staging of GTD are discussed separ ately. In addition, the management of low-risk and recurrent GTN are

also discuss ed separately.

DEFINITION OF HIGH-RISK DISEASE — High-risk gestational trophoblastic neoplasia (GTN) is characterized

by the International Federation of Gynecology and Obstetrics (FIGO) stage and the World Health Organization

(WHO) risk score (table 1) (see "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis,

staging, and risk stratification", section on 'Staging and risk assessment'):

Of note, the WHO Prognostic Scoring System is not applicable to patients with placental site trophoblastic

tumor (PSTT) or epithel ioid trophoblastic tumor (ETT), and those patients are not categorized as either low risk

or high risk . They are, however, st aged based on the FIGO Stage. The management of these patients is

discussed below. (See 'Placental site or epithelioid trophoblastic tumor' below.)

APPROACH TO TREATMENT — Gestational trophoblastic neoplasia (GTN) is uniquely sensitive to

chemotherapy, which is the major treatment modality for patients with high-risk disease. The exception to this

is women with placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT), in which case,

the primary treatment may be a combination of surgery and chemotherapy, primarily because PSTT and ETT

are relatively resistant to chemotherapy as compared with choriocarcinoma and invasive mole. Regardless, in

the treatment of high-risk GTN, other modalities such as surgery and radiation therapy (RT) may be indicated in

addition to chemotherapy.

For patients in whom combination chemotherapy is indicated, treatment may result in ovarian insufficiency.

Therefore, we advocate for the use of oral contraceptives to suppress the pituitary glands' production of

luteinizing hormone which aims to protect the ovaries from the toxicity of chemotherapy and also suppress the

production of human chorionic gonadotropin (hCG), which in our clinical experience, could falsely suggest the

®

®

Invasive mole●

Choriocarcinoma●

Placental site trophoblastic tumor (PSTT)●

Epithelioid trophoblastic tumor (ETT)●

(See "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)●

(See "Gestational trophoblastic disease: Pathology" .)●

(See "Hydatidiform mole: Management" .)●

(See "Initial management of low-risk gestational trophoblastic neoplasia" .)●

Stage IV disease●

Stages II and III with risk score >6●

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presence of active disease if not suppressed [ 1]. (See "Fertility preservation in patients undergoing gonadotoxic

treatment or gonadal resection", section on 'Gonadal suppression' and"Hydatidiform mole: Management",

section on 'Contraception'.)

Chemotherapy — Patients with high-risk GTN are likely to develop drug resistance if single-agent therapy is

administered. Therefore, these patients are commonly treated with multi-agent regimens. Evidence of the

greater likelihood of resistance to single-agent chemotherapy comes from a retrospective study that included

over 300 patients treated for nonmetastatic GTN [ 2]. Although all patients were cured, 27 of 253 patients (11

percent) initially treated with methotrexate (MTX) developed resistance. In this series, only six patientsexperienced a relapse after obtaining a remission; of these, five patients had a choriocarcinoma.

Our preferred regimen for these patients is etoposide, MTX, plus actinomycin D (ActD) alternating with

cyclophosphamide andvincristine (EMA-CO) because it results in complete response rates between 71 and 78

percent and long-term survival rates of 85 to 94 percent [ 3-11]. However, a 2012 Cochrane review has found that

regimens that incorporate etoposide and cisplatin are effective options, though the lack of randomized trials

prevented an analysis to define the optimal regimen [ 12].

EMA-CO — EMA-CO has emerged as the regimen of choice for initial treatment of high-risk GTN. This is

predominantly based on retrospective data that consistently show it is active in high-risk GTN and is associated

with a low toxicity profile [ 12,13].

The components of this regimen are [ 11]:

Although EMA-CO is the most widely used regimen, there have been no randomized trials to demonstrate that it

should be the preferred regimen. However, compared with other combination regimens, it appears to be as

effective (if not more so) and better tolerated.

This was shown in one report that included over 200 women with high-risk GTN treated with [ 13]:

Of these four regimens, EMA-CO resulted in [ 13]:

In a 2012 systematic review, the administration of EMA-CO was associated with primary remission rates

ranging from 54 to 91 percent of patients [ 12]. These data support the use of EMA-CO as a primary treatment

for high-risk GTN.

Administration — Treatment with EMA-CO should be administered every two to three weeks. Although a

treatment delay or dose reduction may be required due to side effects, these should be avoided as both have

Etoposide – 100 mg/m IV over 30 minutes on days 1 and 2● 2

MTX – 100 mg/m IV bolus followed by 200 mg/m IV over 12 hours on day 1● 2 2

ActD – 0.5 mg IV bolus on days 1 and 2●

Leucovorin calcium – 15 mg orally every 12 hours for four doses, starting 24 hours after start of MTX●

Cyclophosphamide – 600 mg/m IV on day 8● 2

Vincristine – 1.0 mg/m IV on day 8● 2

MTX plus ActD and folinic acid (MA, administered between 1971 and 1995)●

MTX, ActD, cyclophosphamide , doxorubicin, melphalan, hydroxyurea, and vincristine (CHAMOCA,

administered between 1982 and 1995)

●

MTX, ActD, and chlorambucil (MAC, administered between 1971 and 1982)●

EMA-CO (administered between 1985 and 1995)●

The highest remission rate (91 percent) compared with MA, CHAMOCA, and MAC (63, 76, and 68

percent, respectively) and required the fewest number of courses to attain remission

●

The lowest mortality rate (9 percent versus 37, 22, and 33 percent, respectively)●

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been associated with less than optimal outcomes.

Treatment should be continued until the hCG level becomes undetectable and remains undetectable for three

consecutive weeks. Finally, we administer at least three courses of EMA-CO after the patient achieves

undetectable hCG levels as consolidation therapy to reduce the risk of relapse, which is supported by the

limited data. (See "Initial management of low-risk gestational trophoblastic neoplasia", section on 'Consolidation

therapy'.)

The Charing Cross Group has reported the use of induction low-dose etoposide (100 mg/m ) andcisplatin (20

mg/m ) on days 1 and 2 every seven days in selec ted patients with high tumor burden. This has almost

completely eliminated early mortality from respiratory compromise and hemorrhage. They also report a 94

percent remission rate with EMA-CO by carefully excluding non-gestational tumors using genetic analysis [ 14].

Patients with brain metastases — For patients with brain metastases, a neurosurgical consult should be

obtained prior to treatment. These patients are at risk for complications directly related to their brain metastases

or as a consequence of treatment, which may require urgent or emergent treatment (eg, craniotomy for

intracerebral bleeding). For these patients, we administer a modification of systemic EMA-CO that uses a

higher MTX dose (1000 mg/m over 24 hours) than what is routinely adminis tered [15]. The higher dose of

parenteral MTX allows for adequate levels of MTX within the cerebrospinal fluid (CSF) [ 15-18]. In addition, these

patients should receive dexamethasone to decreasecerebral edema; however, prophylactic anti-epileptic drugsare generally not recommended in most patients, provided there is no history of an antecedent seizure. (See

"Seizures in patients with primary and metastatic brain tumors" .)

A typical regimen is as follows [ 18]:

Finally, these patients should be closely followed during treatment, which can be done using serial imaging.

Role for intrathecal therapy — The need for intrathecal (IT) therapy in these patients is controversial

[ 16,18-20], and its use alongside high-dose EMA-CO is based on institutional preferences. If administered, MTX

is given as a 12.5 mg dose IT on day 8, followed by leucovorin calcium 15 mg at 24 and 36 hours. However, one

small study that included 15 patients treated with EMA-CO plus IT MTX reported that 87 percent (13 patients)

achieved a sustained remission without the use of whole-brain irradiation [ 18].

Concomitant whole-brain radiation therapy — At the New England Trophoblastic Disease Center

(NETDC), we administer cranial RT (20 to 30 Gy in 2 Gy daily fractions) concurrently with high-dose MTX

chemotherapy. As with the role of IT MTX, the role of cranial RT is also controversial. In addition to shrinking the

brain metastases, concomitant cranial irradiation increases the MTX concentration within the central nervous

system (CNS) [ 21] and reduces the risk of cerebral hemorrhage prior to eradication of tumor, and may improve

survival [ 22,23]. However, the use of concurrent MTX and cranial irradiation also increased the likelihood of

treatment-related toxicity, especially leukoencephalopathy. (See "Delayed complications of cranial irradiation",

section on 'Neurocognitive effects'.)

Cisplatin-containing regimens — In some centers, a modified EMA-CO regimen that incorporatescisplatin is preferentially administered to patients with a risk score >12. The most commonly used combination

replaces vincristine andcyclophosphamide (used in EMA-CO) withetoposide and cisplatin on day 8 (EMA-EP).

EMA-EP alone or in combination with surgery induced complete remission in 16 (76 percent) of 21 patients with

EMA-CO resistance [ 5].

2

2

2

Etoposide – 100 mg/m IV over 60 minutes on days 1 and 2● 2

MTX – 1000 mg/m IV over 24 hours on day 1● 2

ActD – 0.5 mg IV bolus on days 1 and 2●

Leucovorin calcium – 30 mg intramuscular (IM) or orally every 12 hours for three days, starting 32 hours

after treatment with MTX

●

Cyclophosphamide – 600 mg/m IV on day 8● 2

Vincristine – 1.0 mg/m IV on day 8● 2

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While no randomized trials compared EMA-CO with cisplatin-containing regimens, a retrospective study

evaluated outcomes among 83 patients treated with cisplatin-containing treatment and 103 patients treated with

EMA-CO [ 24]. Compared with EMA-CO, incorporation of cisplatin was associated with:

APE — Given the activity ofcisplatin for GTN, one group reported their experience using ActD, cisplatin, and

etoposide (APE) for high-risk GTN that included 59 patients (out of a total of 96) who were treated with this

regimen as initial therapy between 1985 and 2013 [ 25]. Patients with brain metastases or placental site

trophoblastic tumors (PSTT) were excluded from treatment. The overall remission rate for these patients was 95

percent. One patient required treatment discontinuation after four cycles due to grade 2 ototoxicity. The final two

had refractory disease to this regimen, but all three entered remission with second-line EMA-CO therapy. The

five-year disease-free survival rate was 98 percent.

Surgery — Approximately 50 percent of patients with high-risk, metastatic GTN will require adjuvant surgery to

achieve cure, even in the presence of multi-organ involvement [ 26-39]. As an example, in one study of 50

patients with high-risk, metastatic GTN treated with EMA-CO between 1986 and 2005, among 24 patients whounderwent a total of 28 surgical procedures, the cure rate was 87.5 percent. These procedures included

hysterectomy, pulmonary resection, uterine wedge resection, small bowel resection, and selective uterine artery

embolization [ 33]. Surgery is generally performed to resect foci of chemotherapy-resistant disease or to control

complications such as bleeding or infection.

PLACENTAL SITE OR EPITHELIOID TROPHOBLASTIC TUMOR — Although universally accepted guidelines

are not available, patients with placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT)

should be treated with a combination of surgery and chemotherapy. Multi-agent regimens are usually

administered, including etoposide, methotrexate (MTX), plus actinomycin D (ActD) alternating with

cyclophosphamide andvincristine (EMA-CO) [40] or EMA plus etoposide and cisplatin (EMA-EP) [41]. There

are no prospective data to inform whether one or the other is the preferred regimen. (See "Management of resistant or recurrent gestational trophoblastic neoplasia", section on 'High-risk gestational trophoblastic

neoplasia'.)

Unfortunately, patients with metastatic disease have a poor prognosis and a high fatality rate [ 42-44]. In a 2012

review of the literature that reported on the deaths from gestational trophoblastic neoplasia (GTN), 30 percent

had placental site trophoblastic tumors (PSTT) [ 44]. In addition, one single-institution series of 18 patients with

PSTT reported that five of six who had extrauterine disease ultimately died despite the administration of multi-

agent chemotherapy [ 43]. Survival with PSTT is strongly related to the number of years since the antecedent

pregnancy. Papadopoulos et al, reporting on 34 patients, found that while all 27 patients diagnosed within four

years of the antecedent pregnancy survived, all seven patients died when the antecedent pregnancy was more

than four years [ 42].

MONITORING DURING TREATMENT — As with women who are treated for low-risk gestational trophoblastic

neoplasia (GTN), all women with high-risk GTN should be monitored with serial measurements of serum human

chorionic gonadotropin (hCG) at the start of treatment and then at weekly intervals during therapy. This and

other considerations for patients during treatment are discussed separately. (See "Initial management of low-

risk gestational trophoblastic neoplasia", section on 'Monitoring during treatment'.)

The approximate biologic half-life of hCG is 1.5 to 3 days, and serum levels should fall exponentially (by at least

one log within 18 days). A slower rate of decline suggests the possibility of chemoresistance, although there is

no consensus or clear guideline as to the optimal cutoff for determining chemoresistance or the management of

patients with a slower than expected tumor marker decline [ 45-47].

Definition of remission — Remission is achieved when the quantitative hCG level becomes undetectable for

three consecutive weeks. Given the sensitivity of this tumor marker, no imaging is required if levels are

consistent with remission because abnormalities on imaging can persist despite the attainment of undetectable

A slightly lower remission rate (85 versus 92 percent, respectively)●

A lower number of cycles to achieve a normal hCG level (three versus five courses)●

More toxicity, including fever, nephropathy, nausea, and diarrhea●

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hCG levels, representing fibrosis rather than active tumor.

Persistent or progressive disease — The French Trophoblastic Disease Reference Center in Lyon defines

chemotherapy resistance as an increase or a plateau in two consecutive hCG values over a two-week interval

[ 48]. As described above, other generally accepted criteria include detection of new metastases [ 49]. For

patients who appear to have persistent disease, surgery may be a curative option. The approach to patients who

experience disease progression is discussed separately. (See "Gestational trophoblastic neoplasia:

Epidemiology, clinical features, diagnosis, staging, and risk stratification" .)

PROGNOSIS — The overall cure rate for patients with high-risk gestational trophoblastic neoplasia (GTN) (stage

II to III) ranges between 95 and 100 percent [ 50]. At the New England Trophoblastic Disease Center (NETDC),

we treated 90 patients between July 1965 and December 2013, of whom 77.8 percent had a sustained complete

remission with primary chemotherapy (table 2). As depicted in the table, of those who developed resistance,

second-line therapy ultimately resulted in sustained remission in 85 percent of patients. Overall, 87 (96.7

percent) of 90 patients with high-risk stage II and III GTN achieved complete remission.

For patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV high-risk GTN, the

prognosis is not as good, though complete remission can be expected in 60 to 70 percent of patients [ 50].

Much of this success is due to the use of combination chemotherapy. After combination chemotherapy was

introduced as primary treatment in this group, the survival rate dramatically improved. Since the introduction of

intensive primary combination chemotherapy with adjunctive surgery and radiation therapy (RT), survival at the

NETDC increased from 30 to 84 percent ( table 3) [ 26].

Prognostic factors — For patients with high-risk GTN, long-term survival appeared to be associated with

variables related to disease extent [ 51]:

Data from the Charing Cross Hospital indicate that survival with hepatic metastases appears to have improvedover time. Excluding early deaths (within four weeks of presentation) and two deaths unrelated to GTN, the

cause-specific survival in 25 patients was 68 percent [ 52,53].

POSTTREATMENT SURVEILLANCE — After remission is achieved, serum human chorionic gonadotropin

(hCG) should be measured monthly until there have been undetectable hCG levels for 12 months [ 54,55].

The follow-up of patients treated for high-risk gestational trophoblastic neoplasia (GTN) is similar to that of

women treated for low-risk GTN and includes considerations of contraception and the timing of subsequent

pregnancies. These issues are discussed separately. (See "Initial management of low-risk gestational

trophoblastic neoplasia", section on 'Posttreatment surveillance' and"Initial management of low-risk gestational

trophoblastic neoplasia", section on 'Fertility and pregnancy' .)

Uterine arteriovenous malformation — Patients treated for GTN that invaded the myometrium (both low-risk

and high-risk) are at risk of developing a uterine artery malformation (also known as an arteriovenous fistula),

which can persist for months or years after remission is achieved. A fistula may remain asymptomatic and

undiagnosed or may present with menorrhagia. The presence of an arteriovenous malformation has also been

associated with recurrent miscarriage. (See "Differential diagnosis of genital tract bleeding in women", section

on 'Arteriovenous malformation'.)

The diagnosis is made with the use of color Doppler transabdominal or endovaginal ultrasonography. Selective

pelvic arteriography clearly identifies the abnormal vascular malformation and helps in evaluating possible

treatment modalities. If symptomatic, treatment consists of hysterectomy or, when preservation of reproductive

function is desired, treatment consists of selective uterine artery embolization [ 56-58].

DIAGNOSIS OF RECURRENT OR RESISTANT DISEASE — Patients whose human chorionic gonadotropin

(hCG) level re-elevates after becoming undetectable for three consecutive weeks are considered to have

recurrent disease. In contrast, patients whose hCG level remains elevated despite treatment are considered to

In the presence of liver metastases, only 27 percent were alive●

If brain metastases were present, the survival rate was 70 percent●

If both were present, only 10 percent were alive●

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have resistant disease. Despite the success of combination chemotherapy, patients treated for high-risk

gestational trophoblastic neoplasia (GTN) have an 8 to 10 percent risk of recurrence, dependent on stage and

risk score [ 59]. This is often detected by a re-elevation in the quantitative serum hCG levels after three

consecutive weeks of undetectable quantitative hCG levels. The approach to patients with recurrent or resistant

disease is discussed separately. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features,

diagnosis, staging, and risk stratification" .)

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement .

REFERENCES

Gestational trophoblastic neoplasia (GTN) is characterized by the International Federation of Gynecology

and Obstetrics (FIGO) stage and the World Health Organization (WHO) risk score (table 1). Patients are

defined as having high-risk GTN if they have stage IV disease or stage II to III disease with a risk score >6.

(See 'Definition of high-risk disease' above.)

●

The WHO Prognostic Scoring System is not applicable to patients with placental site trophoblastic tumor

(PSTT) or epithelioid trophoblastic tumor (ETT). Therefore, patients with these subtypes of GTN are not

categorized as either low risk or high risk. They should be characterized by their FIGO Stage. (See

'Definition of high-risk disease' above.)

●

GTN is uniquely sensitive to chemotherapy, which is the major treatment modality for patients with high-

risk disease. The exception to this is women with PSTT or ETT, in which case, the primary treatment maybe a combination of surgery and chemotherapy, primarily because PSTT and ETT are relatively resistant to

chemotherapy as compared with choriocarcinoma and invasive mole. (See 'Approach to treatment' above.)

●

For patients with high-risk GTN, we recommend multi-agent chemotherapy rather than single-agent

therapy (Grade 1B). We suggest a combination of etoposide, methotrexate (MTX), plus actinomycin D

(ActD) alternating with cyclophosphamide andvincristine (EMA-CO) (Grade 2C). (See 'EMA-CO' above.)

●

For patients with high-risk GTN and brain metastases, a neurosurgical consult should be obtained prior to

treatment. We suggest EMA-CO as the primary systemic treatment, using a higher MTX dose (1000

mg/m over 24 hours) than what is routinely adminis tered otherwise (Grade 2C). We also suggest cranial

radiation therapy (RT) for these patients (Grade 2C). However, for patients who do not wish to proceedwith cranial RT, we suggest additional chemotherapy using intrathecal MTX (Grade 2C). (See 'Patients

with brain metastases' above.)

●

2

Approximately 50 percent of patients with high-risk, metastatic GTN will require adjuvant surgery to

achieve cure, even in the presence of multi-organ involvement. (See 'Surgery' above.)

●

Although universally accepted guidelines are not available, for patients with PSTT or ETT, we suggest a

combination of surgery and chemotherapy (Grade 2C). Multi-agent regimens are usually administered,

including EMA-CO or EMA plus etoposide andcisplatin (EMA-EP). There are no prospective data to

inform whether one or the other is the preferred regimen, and a choice between them is based on

institutional preferences. (See 'Placental site or epithelioid trophoblastic tumor' above.)

●

As with women who are treated for low-risk GTN, all women with high-risk GTN should be monitored with

serial measurements of serum human chorionic gonadotropin (hCG) at the start of treatment and then at

weekly intervals during therapy. (See 'Monitoring during treatment' above.)

●

The overall cure rate for patients with high-risk GTN (stage II to III) ranges between 95 and 100 percent.

The extent of disease is a prognostic factor among these patients. (See 'Prognosis' above.)

●

After remission is achieved, serum hCG should be measured monthly until monitoring has shown one year

of normal hCG levels. (See 'Posttreatment surveillance' above.)

●

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1. Cole LA, Sasaki Y, Muller CY. Normal production of human chorionic gonadotropin in menopause. N Engl

J Med 2007; 356:1184.

2. Lurain JR, Elfstrand EP. Single-agent methotrexate chemotherapy for the treatment of nonmetastatic

gestational trophoblastic tumors. Am J Obstet Gynecol 1995; 172:574.

3. Schink JC, Singh DK, Rademaker AW, et al. Etoposide, methotrexate, actinomycin D,

cyclophosphamide, and vincristine for the treatment of metastatic, high-risk gestational trophoblastic

disease. Obstet Gynecol 1992; 80:817.

4. Bolis G, Bonazzi C, Landoni F, et al. EMA/CO regimen in high-risk gestational trophoblastic tumor (GTT).

Gynecol Oncol 1988; 31:439.

5. 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 1997; 15:2636.

6. Kim SJ, Bae SN, Kim JH, et al. Risk factors for the prediction of treatment failure in gestational

trophoblastic tumors treated with EMA/CO regimen. Gynecol Oncol 1998; 71:247.

7. Matsui H, Suzuka K, Iitsuka Y, et al. Combination chemotherapy with methotrexate, etoposide, and

actinomycin D for high-risk gestational trophoblastic tumors. Gynecol Oncol 2000; 78:28.

8. 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 2003; 91:552.

9. Turan T, Karacay O, Tulunay G, et al. Results with EMA/CO (etoposide, methotrexate, actinomycin D,

cyclophosphamide, vincristine) chemotherapy in gestational trophoblastic neoplasia. Int J Gynecol Cancer

2006; 16:1432.

10. Cagayan MS. High-risk metastatic gestational trophoblastic neoplasia. Primary management with EMA-

CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy. J Reprod

Med 2012; 57:231.

11. Lurain JR, Singh DK, Schink JC. Primary treatment of metastatic high-risk gestational trophoblastic

neoplasia with EMA-CO chemotherapy. J Reprod Med 2006; 51:767.

12. Deng L, Zhang J, Wu T, Lawrie TA. Combination chemotherapy for primary treatment of high-risk

gestational trophoblastic tumour. Cochrane Database Syst Rev 2013; 1:CD005196.

13. Kim SJ, Bae SN, Kim JH, et al. Effects of multiagent chemotherapy and independent risk factors in the

treatment of high-risk GTT--25 years experiences of KRI-TRD. Int J Gynaecol Obstet 1998; 60 Suppl

1:S85.

14. 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 2013; 31:280.

15. Newlands ES, Holden L, Seckl MJ, et al. Management of brain metastases in patients with high-risk

gestational trophoblastic tumors. J Reprod Med 2002; 47:465.

16. Newlands ES. The management of recurrent and drug-resistant gestational trophoblastic neoplasia (GTN).

Best Pract Res Clin Obstet Gynaecol 2003; 17:905.

17. Small W Jr, Lurain JR, Shetty RM, et al. Gestational trophoblastic disease metastatic to the brain.

Radiology 1996; 200:277.

18. Rustin GJ, Newlands ES, Begent RH, et al. Weekly alternating etoposide, methotrexate, andactinomycin/vincristine and cyclophosphamide chemotherapy for the treatment of CNS metastases of

choriocarcinoma. J Clin Oncol 1989; 7:900.

19. Bakri Y, Berkowitz RS, Goldstein DP, et al. Brain metastases of gestational trophoblastic tumor. J

Reprod Med 1994; 39:179.

20. Altintaş A, Vardar MA. Central nervous syst em involvement in gestational trophoblastic neoplasia. Eur J

Gynaecol Oncol 2001; 22:154.

21. Herrington S. Enhancing cure and palliation: radiation therapy in the treatment of metastatic gestational

trophoblastic neoplasia. Semin Oncol 1995; 22:185.

22. Yordan EL Jr, Schlaerth J, Gaddis O, Morrow CP. Radiation therapy in the management of gestational

choriocarcinoma metastatic to the central nervous system. Obstet Gynecol 1987; 69:627.

23. Athanassiou A, Begent RH, Newlands ES, et al. Central nervous syst em metastases of choriocarcinoma.

23 years' experience at Charing Cross Hospital. Cancer 1983; 52:1728.

http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/5http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/4http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/18http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/11http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/13http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/2http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/3http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/22http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/21http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/20http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/9http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/16http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/8http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/1http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/10http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/12http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/23http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/17http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/6http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/19http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/15http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/7http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/14


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2/4/2015 Initial management of high- ri sk gestational trophoblastic neoplasia


24. Lybol C, Thomas CM, Blanken EA, et al. Comparing cisplatin-based combination chemotherapy with

EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia. Eur J Cancer

2013; 49:860.

25. Even C, Pautier P, Duvillard P, et al. Actinomycin D, cisplatin, and etoposide regimen is associated with

almost universal cure in patients with high-risk gestational trophoblastic neoplasia. Eur J Cancer 2014;

50:2082.

26. Berkowitz RS, Goldstein DP. Current management of gestational trophoblastic diseases. Gynecol Oncol

2009; 112:654.

27. Tomoda Y, Arii Y, Kaseki S, et al. Surgical indications for resection in pulmonary metastasis of

choriocarcinoma. Cancer 1980; 46:2723.

28. Fleming EL, Garrett L, Growdon WB, et al. The changing role of thoracotomy in gestational trophoblastic

neoplasia at the New England Trophoblastic Disease Center. J Reprod Med 2008; 53:493.

29. Jones WB, Romain K, Erlandson RA, et al. Thoracotomy in the management of gestational

choriocarcinoma. A clinicopathologic study. Cancer 1993; 72:2175.

30. Hoekstra AV, Lurain JR, Rademaker AW, Schink JC. Gestational trophoblastic neoplasia: treatment

outcomes. Obstet Gynecol 2008; 112:251.

31. Alazzam M, Hancock BW, Tidy J. Role of hysterectomy in managing persistent gestational trophoblastic

disease. J Reprod Med 2008; 53:519.

32. Doumplis D, Al-Khatib K, Sieunarine K, et al. A review of the management by hysterectomy of 25 cases

of gestational trophoblastic tumours from March 1993 to January 2006. BJOG 2007; 114:1168.

33. Lurain JR, Singh DK, Schink JC. Role of surgery in the management of high-risk gestational trophoblastic

neoplasia. J Reprod Med 2006; 51:773.

34. Pisal N, North C, Tidy J, Hancock B. Role of hysterectomy in management of gestational trophoblasticdisease. Gynecol Oncol 2002; 87:190.

35. Xu LT, Sun CF, Wang YE, Song HZ. Resection of pulmonary metastatic choriocarcinoma in 43 drug-

resistant patients. Ann Thorac Surg 1985; 39:257.

36. Wang YA, Song HZ, Xia ZF, Sun CF. Drug resistant pulmonary choriocarcinoma metastasis treated by

lobectomy: report of 29 cases. Chin Med J (Engl) 1980; 93:758.37. Cagayan MS, Magallanes MS. The role of adjuvant surgery in the management of gestational

trophoblastic neoplasia. J Reprod Med 2008; 53:513.

38. Soper JT. Role of surgery and radiation therapy in the management of gestational trophoblastic disease.

Best Pract Res Clin Obstet Gynaecol 2003; 17:943.

39. Clark RM, Nevadunsky NS, Ghosh S, et al. The evolving role of hysterectomy in gestational trophoblastic

neoplasia at the New England Trophoblastic Disease Center. J Reprod Med 2010; 55:194.

40. Newlands ES, Mulholland PJ, Holden L, et al. Etoposide and cisplatin/etoposide, methotrexate, and

actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory

to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic

placental site trophoblastic tumors. J Clin Oncol 2000; 18:854.

41. Newlands ES, Bower M, Fisher RA, Paradinas FJ. Management of placental site trophoblastic tumors. J

Reprod Med 1998; 43:53.

42. Papadopoulos AJ, Foskett M, Seckl MJ, et al. Twenty-five years' clinical experience with placental site

trophoblastic tumors. J Reprod Med 2002; 47:460.

43. Hyman DM, Bakios L, Gualtiere G, et al. Placental site trophoblastic tumor: analysis of presentation,

treatment, and outcome. Gynecol Oncol 2013; 129:58.

44. Kingdon SJ, Coleman RE, Ellis L, Hancock BW. Deaths from gestational trophoblastic neoplasia: any

lessons to be learned? J Reprod Med 2012; 57:293.

45. van Trommel NE, Massuger LF, Schijf CP, et al. Early identification of resistance to first-line single-agent

methotrexate in patients with persistent trophoblastic disease. J Clin Oncol 2006; 24:52.46. You B, Pollet-Villard M, Fronton L, et al. Predictive values of hCG clearance for risk of methotrexate

resistance in low-risk gestational trophoblastic neoplasias. Ann Oncol 2010; 21:1643.

47. Kerkmeijer LG, Thomas CM, Harvey R, et al. External validation of serum hCG cutoff levels for prediction

of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease. Br J Cancer

http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/47http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/42http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/41http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/28http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/36http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/29http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/45http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/38http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/43http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/35http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/40http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/32http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/33http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/26http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/44http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/47http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/27http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/24http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/25http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/37http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/46http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/34http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/31http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/30http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia/abstract/39


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http://www.uptodate.com/contents/initial-management-of-high-risk-gestational-trophoblastic-neoplasia?topicKey=ONC%2F96232&elapsedTimeMs=0&sou… 9/13

2009; 100:979.

48. Golfier F, Labrousse C, Frappart L, et al. [Evaluation of treatment relating to gestational trophoblastic

tumor registered to the French Trophoblastic Disease Reference Center (TDRC) in Lyon from 1999 to

2005]. Gynecol Obstet Fertil 2007; 35:205.

49. McNeish IA, Strickland S, Holden L, et al. Low-risk persistent gestational trophoblastic disease: outcome

after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002;

20:1838.

50. Lurain JR. Gestational trophoblastic disease II: classification and management of gestational trophoblastic

neoplasia. Am J Obstet Gynecol 2011; 204:11.

51. Lurain JR, Schink JC. Importance of salvage therapy in the management of high-risk gestational

trophoblastic neoplasia. J Reprod Med 2012; 57:219.

52. Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease. Lancet 2010; 376:717.

53. Ahamed E, Short D, North B, et al. Survival of women with gestational trophoblastic neoplasia and liver

metastases: is it improving? J Reprod Med 2012; 57:262.

54. Committee on Practice Bulletins-Gynecology, American College of Obstetricians and Gynecologists.

ACOG Practice Bulletin #53. Diagnosis and treatment of gestational trophoblastic disease. Obstet

Gynecol 2004; 103:1365.

55. Society of Gynecologic Oncologists Clinical Practice Guidelines. Practice guidelines: gestationaltrophoblastic disease. Oncology (Williston Park) 1998; 12:455.

56. Lim AK, Agarwal R, Seckl MJ, et al. Embolization of bleeding residual uterine vascular malformations in

patients with treated gestational trophoblastic tumors. Radiology 2002; 222:640.

57. Yang JJ, Xiang Y, Wan XR, Yang XY. Diagnosis and management of uterine arteriovenous fistulas with

massive vaginal bleeding. Int J Gynaecol Obstet 2005; 89:114.

58. McGrath S, Harding V, Lim AK, et al. Embolization of uterine arteriovenous malformations in patients with

gestational trophoblastic tumors: a review of patients at Charing Cross Hospital, 2000-2009. J Reprod Med

2012; 57:319.

59. Goldstein DP, Zanten-Przybysz IV, Bernstein MR, Berkowitz RS. Revised FIGO staging system for

gestational trophoblastic tumors. Recommendations regarding therapy. J Reprod Med 1998; 43:37.

Topic 96232 Version 1.0

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GRAPHICS

FIGO Staging of Gestational Trophoblastic Neoplasia (GTN) and

modified WHO Prognostic Scoring System as adapted by FIGO

Stage

I

Disease confined to the

uterus

Stage

II

GTN extends outside of

the uterus, but is limited

to the genital structures

Stage

III

GTN extends to the lungs,

with

or

without genital tract

involvement

StageIV

All other metastatic sites

The stage should be followed

by the sum of the risk factors

(eg, III:5)

Risk factorScore

0 1 2 4

Age (years) 12

Pretreatment

serum hCG

(mIU/mL)

10

Largest tumor

(including

uterus)

8

Prior failed

chemotherapy

– – Single

drug

≥2

drugs

FIGO: International Federation of Gynecology and Obstetrics; WHO: World Health Organization;

hCG: human chorionic gonadotropin.

* Interval (in months) between end of antecedent pregnancy and start of chemotherapy.

Original figure modified for this publication. Berkowitz RS, Goldstein DP. Current management of

gestational trophoblastic diseases. Gynecol Oncol 2009; 112:654. Table used with the permission of

Elsevier Inc. All rights reserved.

Graphic 98185 Version 2.0

3 3

4

4

5

5


11/13



Results of chemotherapy in 90 patients with high-risk stage II and

III gestational trophoblastic neoplasia (GTN) (New England

Trophoblastic Disease Center, July 1965 to December 2013)

Stage Treatment Number of

patients Remissions (%)

II 16 16 (100)

Primary 11 11 (68.9)

Second-line 5 5 (31.1)

III 74 71 (95.9)

Primary 59 59 (79.7)


Total 90 87 (96.7)

Primary 70 70 (77.8)




12/13



Results of chemotherapy in 39 patients with stage IV gestational

trophoblastic neoplasia (New England Trophoblastic Disease Center,

July 1965 to December 2013)

Time period Total number of

patients Remissions (%)

1965 to 1975 20 6 (30)

1976 to 2013 19 16 (84)



13/13


Disclosures: Ross S Ber kow itz, MD Nothing to disclose. Donald Peter Goldstein, MD Nothing todis c los e. Neil S Horowitz, MD Nothing to disclose. Barbara Goff, MD Nothing to disclose. Don S

Dizon, MD, FACP Employee of UpToDate, Inc. Sandy J Falk, MD, FACOG Employee of UpToDate, Inc.

Cont ribut or dis c los ures are rev iew ed f or c onf lic t s of int eres t by t he edit orial group. When f ound, t hes e

are addres s ed by v et t ing t hrough a mult i-lev el rev iew proc es s , and t hrough requirement s f or

ref erenc es t o be prov ided t o s upport t he c ont ent . Appropriat ely ref erenc ed c ont ent is required of allaut hors and mus t c onf orm t o UpToDat e s t andards of ev idenc e.

Conflict of intere st policy

Disclosures
http://www.uptodate.com/home/conflict-interest-policy

Initial Management of High-risk Gestational Trophoblastic Neoplasia

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