www.AJOG.

org Reviews

ONCOLOGY
Gestational trophoblastic disease II: classification and
management of gestational trophoblastic neoplasia
John R. Lurain, MD

G estational trophoblastic neopla-

sia (GTN) includes invasive
mole, choriocarcinoma, placental site
Gestational trophoblastic neoplasia (GTN) includes invasive mole, choriocarcinoma, pla-
cental site trophoblastic tumor, and epithelioid trophoblastic tumor. The overall cure rate
trophoblastic tumor (PSTT), and epi- in treating these tumors is currently ⬎90%. Thorough evaluation and staging allow se-
thelioid trophoblastic tumor (ETT). lection of appropriate therapy that maximizes chances for cure while minimizing toxicity.
The epidemiology, pathology, clinical Nonmetastatic (stage I) and low-risk metastatic (stages II and III, score ⬍7) GTN can be
presentation, and diagnosis of these treated with single-agent chemotherapy resulting in a survival rate approaching 100%.
tumors were discussed in part I of this High-risk GTN (stages II-IV, score ⱖ7) requires initial multiagent chemotherapy with or
review. The overall cure rate in treating without adjuvant radiation and surgery to achieve a survival rate of 80-90%.
these tumors is currently ⬎90%. This
Key words: chemotherapy, choriocarcinoma, gestational trophoblastic disease,
success is the result of the inherent sen-
gestational trophoblastic neoplasia
sitivity of trophoblastic neoplasms to
chemotherapy, the effective use of the
tumor marker human chorionic go-
nadotropin (hCG) for diagnosing dis- because it does not often induce remis-
ease and monitoring therapy, the refer- sion or influence treatment and it may
ral of patients to or consultation with result in uterine perforation and
Classification/staging
clinicians who have special expertise in hemorrhage.5-8
When the diagnosis of GTN is suspected
management of these diseases, the In 2002, the International Federation of
or established, a metastatic workup and
identification of prognostic factors Gynecology and Obstetrics (FIGO) de-
an evaluation for risk factors is under-
that predicts treatment response and fined criteria for the diagnosis of postmo-
taken.1-4 Along with a complete history
enhances individualization of therapy, lar disease and adopted a combined ana-
and physical examination, the following
and the use of combined modality tomic staging and modified World Health
laboratory tests should be obtained:
treatment with chemotherapy, radia- Organization (WHO) risk-factor scoring
complete blood cell count including
tion, and surgery in the highest risk pa- system for GTN.9 The components needed
platelets, coagulation studies, serum
tients. PSTT and its related ETT re- to diagnose postmolar GTN include at
chemistries including renal and liver
main therapeutic challenges, since they function panels, blood type and anti- least 1 of the following: (1) hCG plateau for
are more frequently chemotherapy re- body screen, and quantitative serum 4 consecutive values over 3 weeks; (2) hCG
sistant and do not have the same hCG hCG level. Recommended radiologic rise of ⱖ10% for 3 values over 2 weeks; (3)
marker relationship as invasive mole studies include chest x-ray with com- hCG persistence 6 months after molar
and choriocarcinoma. puted tomography (CT) scan of the chest evacuation; (4) histopathologic diagnosis
if the chest x-ray is negative, CT scans of of choriocarcinoma; or (5) presence of
the abdomen and pelvis, and CT scan or metastatic disease. The FIGO stage (Table
From the John I. Brewer Trophoblastic 1) is designated by a Roman numeral fol-
magnetic resonance imaging of the brain
Disease Center, Northwestern University lowed by the modified WHO score (Table
Feinberg School of Medicine, Chicago, IL. (Figure). If the physical examination and
chest x-ray are normal in the absence of 2) designated by an Arabic numeral, sepa-
Received June 17, 2010; accepted June 30,
symptoms, other sites of metastasis are rated by a colon. PSTTs and ETTs are clas-
2010.
uncommon. Measurement of hCG in ce- sified separately.
Reprints: John R. Lurain, MD, John I. Brewer
Trophoblastic Disease Center, Northwestern rebrospinal fluid may be helpful in de- Treatment is based on classification
University Feinberg School of Medicine, 250 E. tecting brain involvement. Pelvic ultra- into risk groups defined by the stage and
Superior St., Suite 05-2168, Chicago, IL sound or magnetic resonance imaging scoring system.10 Patients with non-
60611. [email protected]. metastatic (stage I) and low-risk meta-
may also be useful in detecting extensive
0002-9378/free uterine disease for which hysterectomy static (stages II and III, score ⬍7) GTN
© 2011 Mosby, Inc. All rights reserved.
may be of benefit. Repeat curettage after can be treated with single-agent chemo-
doi: 10.1016/j.ajog.2010.06.072
hydatidiform mole evacuation is gener- therapy, with resulting survival rates ap-
For Editors’ Commentary, ally not recommended unless there is ex- proaching 100%. Patients classified as
see Table of Contents cessive uterine bleeding and evidence of having high-risk metastatic disease
intracavitary molar tissue exists on scan, (stage IV and stages II-III, score ⱖ7)

JANUARY 2011 American Journal of Obstetrics & Gynecology 11

Reviews Oncology www.AJOG.org

Treatment
FIGURE
Low-risk disease
Radiologic studies of gestational trophoblastic neoplasia Patients with nonmetastatic (stage I) and
low-risk metastatic (stages II and III,
A B
score ⬍7) GTN should be treated with
single-agent methotrexate or actinomy-
cin D chemotherapy.11,12 Several differ-
ent outpatient chemotherapy protocols
have been used, which in mostly nonran-
domized, retrospective studies have
yielded fairly comparable overall results
(Table 3). The variability in primary re-
mission rates reflects differences in drug
D dosages, schedules, and routes of admin-
istration, as well as patient selection cri-
teria. In general, the weekly intramuscu-
lar (IM) or intermittent intravenous
(IV) infusion methotrexate and the bi-
weekly single-dose actinomycin D pro-
tocols are less effective than one of the
C 5-day methotrexate or actinomycin D
protocols and the 8-day methotrexate-
folinic acid regimen. Also, older patient
age, higher hCG levels, nonmolar ante-
cedent pregnancy, histopathologic diag-
nosis of choriocarcinoma, presence of
metastatic disease, and higher FIGO
score are each associated with an in-
creased risk of initial chemotherapy re-
A, Chest x-ray of classic appearance of pulmonary metastases from gestational trophoblastic neoplasia sistance. Despite these differences in
(GTN). B, Lung computed tomography (CT) showing micropulmonary metastases in GTN. Metastases are primary remission rates with initial che-
seen on chest CT scan in 30-40% of patients with normal chest x-rays. C, Pelvic CT scan of 21-year-old motherapy, almost all patients are even-
woman with uterine hemorrhage and human chorionic gonadotropin of 140,000 mIU/mL 8 weeks post- tually cured with most being able to pre-
partum. Enlarged uterus contains necrotic tumor; curettage showed choriocarcinoma. D, Brain CT scan serve fertility.
showing left frontal lobe tumor of 35-year-old woman with gestational choriocarcinoma. Methotrexate 0.4 mg/kg (maximum
Lurain. Gestational trophoblastic disease II. Am J Obstet Gynecol 2011. 25 mg) IM or IV push daily for 5 days
every other week seems to be the most
effective treatment protocol.13-15 In
1995, we reviewed nearly 30 years’ expe-
should be treated in a more aggressive FIGO staging system is essential for de-
rience in treating nonmetastatic GTN at
manner with multiagent chemotherapy termining initial therapy for patients
the Brewer Trophoblastic Disease Center
⫾ adjuvant radiation or surgery to with GTN to assure the best possible out-
to determine effectiveness of therapy,
achieve cure rates of 80-90%. Use of the comes with the least morbidity. evaluate toxicity, and assess factors asso-
ciated with chemotherapy resistance. Of
the 253 patients initially treated with sin-
TABLE 1 gle-agent methotrexate 0.4 mg/kg (max-
Staging for gestational trophoblastic neoplasia imum 25 mg) IV push daily for 5 days
Stage Description
every 2 weeks, 226 (89.3%) achieved pri-
mary remission, 22 (8.7%) were placed
I Disease confined to uterus
.............................................................................................................................................................................................................................................. into remission with subsequent single-
II Disease extends outside uterus but is limited to genital structures (adnexa, agent actinomycin D, and only 5 (2.0%)
vagina, broad ligament) required multiagent chemotherapy or
..............................................................................................................................................................................................................................................
III Disease extends to lungs with or without genital tract involvement hysterectomy for cure, with all 253 pa-
..............................................................................................................................................................................................................................................
IV Disease involves other metastatic sites tients achieving permanent remission.
..............................................................................................................................................................................................................................................
Lurain. Gestational trophoblastic disease II. Am J Obstet Gynecol 2011.
Significant toxicity to methotrexate ne-
cessitating a change to another chemo-

12 American Journal of Obstetrics & Gynecology JANUARY 2011

www.AJOG.org Oncology Reviews

therapeutic agent occurred in only 12

patients (4.7%); no life-threatening tox- TABLE 2
icity occurred. The most common toxic- Scoring system for gestational trophoblastic neoplasia
ity was stomatitis: there was no alopecia Risk factor Score
and nausea was not a common side ef-
fect. Factors found to be associated with 0 1 2 4
..............................................................................................................................................................................................................................................

resistance to initial methotrexate che- Age, y ⱕ39 ⬎39 ⫺ ⫺

..............................................................................................................................................................................................................................................
motherapy were: high pretreatment Antecedent pregnancy Mole Abortion Term
..............................................................................................................................................................................................................................................
hCG level, nonmolar antecedent preg- Pregnancy event to treatment interval, mo ⬍4 4-6 7-12 ⬎12
nancy, and clinicopathologic diagnosis ..............................................................................................................................................................................................................................................

of choriocarcinoma. Our results of about Pretreatment hCG, mIU/mL ⬍10 3

10 -10 3 4
10 -10 4 5
⬎10 5
..............................................................................................................................................................................................................................................

90% complete response and 100% survival Largest tumor mass, including uterus, cm ⬍3 3-4 ⱖ5 ⫺
..............................................................................................................................................................................................................................................
confirmed earlier reports from our center Site of metastases ⫺ Spleen, kidney GI tract Brain, liver
..............................................................................................................................................................................................................................................
and others that single-agent methotrexate No. of metastases ⫺ 1-4 5-8 ⬎8
in a 5-day outpatient course every 2 weeks ..............................................................................................................................................................................................................................................

is a highly effective and well-tolerated Previous failed chemotherapy ⫺ ⫺ Single drug ⱖ2 drugs
..............................................................................................................................................................................................................................................
treatment.15 GI, gastrointestinal; hCG, human chorionic gonadotropin.
Total score for patient is obtained by adding individual scores for each prognostic factor: low risk ⬍7; high risk ⱖ7.
An alternative methotrexate regimen Lurain. Gestational trophoblastic disease II. Am J Obstet Gynecol 2011.
consists of slightly higher doses of meth-
otrexate (1.0-1.5 mg/kg) IM every other
day alternating with folinic acid used as secondary therapy in the pres- (49-53%) than for pulsed actinomycin D
(0.1-0.15 mg/kg) IM over 8 days with at ence of methotrexate resistance or as pri- (69-90%). Two retrospective case stud-
least a 1-week interval between courses. mary therapy for patients with hepatic or ies compared 5-day IM methotrexate
This methotrexate-folinic acid protocol renal compromise or effusions contrain- with the 8-day methotrexate-folinic acid
is reported to have decreased toxicity dicating the use of methotrexate.29-34 protocol for treatment of low-risk
(especially stomatitis), but is more ex- Several studies have compared differ- or nonmetastatic postmolar GTN.19,38
pensive and inconvenient, and is associ- ent methotrexate and actinomycin D There was no difference in remission
ated with a more frequent need for a regimens for treatment of low-risk, rates in the study by Wong et al19 (76%)
change in chemotherapy to achieve re- mostly nonmetastatic GTN. Three ran- whereas in the study by Smith et al38 the
mission.16-22 High-dose methotrexate domized clinical trials compared weekly remission rates were 92% for patients
infusion (100 mg/m2 IV push followed IM methotrexate to biweekly actinomy- with methotrexate alone vs 72% for pa-
by 200 mg/m2 IV 12-hour infusion with cin D.35-37 In each trial, the primary tients treated with methotrexate-folinic
folinic acid rescue), with the interval be- complete response rates were signifi- acid. Gleeson et al39 reported primary re-
tween doses reliant on posttreatment cantly lower for weekly IM methotrexate mission rates of 69% and 75% in patients
hCG trends, is another modified metho-
trexate dosage schedule used for treat-
ment of low-risk GTN. This treatment TABLE 3
protocol also results in more frequent Chemotherapy for low-risk gestational trophoblastic neoplasia
need for second-line therapy and is ex-
pensive.22-25 Methotrexate administered Primary remission
Chemotherapy regimen rate, %
in single weekly IM doses of 30-50
mg/m2, although having the advantages 1. MTX 0.4 mg/kg (maximum 25 mg)/d IV or IM for 5 d; repeat 87–93
every 14 d
of convenience, decreased cost, and ..............................................................................................................................................................................................................................................
2
lower toxicity, has the lowest complete 2. MTX 30-50 mg/m IM weekly 49–74
..............................................................................................................................................................................................................................................
response rate of any regimen and is not 3. MTX 1 mg/kg IM d 1, 3, 5, 7; folinic acid 0.1 mg/kg IM d 2, 4, 6, 74–90
appropriate therapy for metastatic dis- 8; repeat every 15-18 d, or as needed
..............................................................................................................................................................................................................................................
ease or choriocarcinoma.26-28 2
4. MTX 100 mg/m IVP, then 200 mg/m in 500 mL D5W over 12 h; 2
69–90
Actinomycin D (10-12 mg/kg IV daily folinic acid 15 mg IM or PO q 12 h for 4 doses beginning 24 h
for 5 days every other week or as a single after start of MTX; repeat every 18 d, or as needed
..............................................................................................................................................................................................................................................
1.25 mg/m2 IV dose every 2 weeks) is an 5. Act-D 10-13 ␮g/kg IV qd for 5 d; repeat every 14 d 77–94
..............................................................................................................................................................................................................................................
acceptable alternative to methotrexate. 6. Act-D 1.25 mg/m IV every 2 wk 2
69–90
Actinomycin D has a more toxic side ef- ..............................................................................................................................................................................................................................................
7. Alternating MTX/Act-D regimens 1 and 5 100
fect profile (nausea, alopecia) than ..............................................................................................................................................................................................................................................

methotrexate and produces local tissue ACT-D, actinomycin D; D5W, dextrose 5% in water; IM, intramuscular; IV, intravenous; IVP, intravenous push; MTX, metho-
trexate; PO, by mouth; qd, daily.
injury if IV extravasation occurs. There- Lurain. Gestational trophoblastic disease II. Am J Obstet Gynecol 2011.
fore, actinomycin D has most often been

JANUARY 2011 American Journal of Obstetrics & Gynecology 13

Reviews Oncology www.AJOG.org

with nonmetastatic postmolar GTN static GTN were pretherapy hCG level develop resistance to the initial chemo-
treated with weekly IM methotrexate or ⬎100,000 mIU/mL, age ⬎35 years, therapeutic agent, but ⬎90% will be
methotrexate-folinic acid, respectively. FIGO score ⬎4, and large vaginal cured by the use of sequential single-
Lertkhachonsuk et al40 randomly as- metastases.43-45 agent chemotherapy. Eventually, ap-
signed patients with nonmetastatic GTN Regardless of the treatment protocol proximately 10% of patients will require
to treatment with either methotrexate- used, chemotherapy is continued until multiagent chemotherapy with or with-
folinic acid or 5-day actinomycin. Com- hCG values have returned to normal and out surgery to achieve remission.
plete remission was achieved in 74% of at least 1 course has been administered
the women in the methotrexate-folinic after the first normal hCG level. Chemo- High-risk metastatic disease
acid arm vs 100% of the women in the therapy is changed to an alternative sin- Patients with high-risk metastatic GTN
actinomycin D arm. Kohorn41 com- gle-agent if the hCG level plateaus above (FIGO stage IV and stages II-III score
pared 5-day actinomycin to pulse acti- normal during treatment or if toxicity ⱖ7) should be treated initially with mul-
nomycin for treatment of patients with precludes an adequate dose or frequency tiagent chemotherapy with or without
nonmetastatic postmolar GTN. The pri- of treatment. If there is a significant ele- adjuvant surgery or radiation therapy.12
mary remission rate was 88% for the vation in hCG level, development of Over time, the multiagent chemotherapy
5-day course vs 78% for the pulsed regi- metastases, or resistance to sequential regimen of choice for high-risk disease
men. Abrao et al42 retrospectively ana- single-agent chemotherapy, multiagent has changed. Throughout the 1970s and
lyzed patients with low-risk, mostly non- chemotherapy should be initiated. Hys- 1980s, methotrexate, actinomycin D,
metastatic GTN treated with 5-day terectomy for low-risk GTN may be per- and cyclophosphamide or chlorambucil
regimens of methotrexate and actino- formed as adjuvant treatment coincident (MAC) was the preferred first-line ther-
mycin D or a combination of methotrex- with the initiation of chemotherapy to apy, yielding cure rates of 63-71%.47 In
ate and actinomycin D. Complete remis- shorten the duration of treatment if fer- the early 1980s, the combination regi-
sion rates were not significantly different tility preservation is not desired. Hyster- men of cyclophosphamide, hydroxyu-
at 69%, 61%, and 79%, respectively; ectomy may also become necessary to rea, actinomycin D, methotrexate with
however, the adverse side effect rate was eradicate persistent, chemotherapy-re- folinic acid, vincristine, and doxorubicin
much greater with combination therapy sistant disease in the uterus or to remedy (CHAMOCA) was reported to have an
(62%) than with single-agent metho- uterine hemorrhage from tumor. Hys- improved primary remission rate of
trexate (29%) or actinomycin D (19%). terectomy is the treatment of choice for 82%48; however, in a randomized trial of
Patients categorized as having low-risk PSTT and ETT. CHAMOCA vs MAC, both the primary
metastatic GTN (FIGO stages II and III, This past year, we updated our results remission rate (65% vs 73%) and the ul-
score ⬍7) can usually be treated success- of treatment of low-risk GTN (FIGO timate cure rate (70% vs 95%) were in-
fully with initial single-agent chemo- stage I and stages II-III; score ⬍7) at the ferior for CHAMOCA compared with
therapy using one of the 5-day dosage Brewer Trophoblastic Disease Center MAC, and CHAMOCA was more tox-
schedules of methotrexate or actinomy- over the past 28 years. From 1979 ic.49 In the 1980s, etoposide was discov-
cin D, as for nonmetastatic disease (Ta- through 2006, we treated 359 patients ered to be a very effective agent for treat-
ble 3). The weekly methotrexate or with low-risk GTN. The complete re- ment of GTN, and the addition of
biweekly actinomycin D single-dose sponse rate to the initial single-agent etoposide to multiagent chemotherapy
protocols currently in use for nonmeta- chemotherapeutic drug was 79%: 78% in the regimen of etoposide, high-dose
static postmolar disease should not be (276/352) for methotrexate and 86% methotrexate with folinic acid, actino-
used for treatment of metastatic disease. (6/7) for actinomycin D, with 92% of pa- mycin D, cyclophosphamide, and vin-
The combined experience of 3 special- tients having a complete response to cristine (EMA-CO) resulted in im-
ized trophoblastic disease centers in the sequential single-agent chemotherapy. proved remission and survival rates
United States with single-agent metho- The remaining 8% of patients were all (Table 4).50
trexate or actinomycin D treatment of placed into remission with the use of Over the last 15 years, several groups
low-risk metastatic GTN yielded excel- multiagent chemotherapy and/or sur- have confirmed the efficacy of the
lent outcomes. Primary remission was gery. Resistance to the initial chemo- EMA-CO regimen as primary therapy
achieved in 48-67% of patients with the therapeutic agent was associated with for high-risk GTN, reporting complete
first single-agent chemotherapy regi- presence of metastatic disease, clinico- response rates of 71-78% and long-term
men. From 1-14% of patients needed pathologic diagnosis of choriocarci- survival rates of 85-94%.51-58 In our 2 re-
multiagent chemotherapy after failed noma, and increasing FIGO score.46 ported series, the complete response
sequential single-agent chemotherapy In summary, cure rates for both non- rates were 71% and 67%, and the overall
with or without surgery to achieve re- metastatic and low-risk metastatic GTN survival rates were 91% and 93%, respec-
mission, but eventually all patients were should approach 100% with the use of tively.55,56 The only patients who died
cured. Risk factors for drug resistance to initial single-agent methotrexate or acti- had FIGO stage IV disease with scores
initial single-agent chemotherapy in this nomycin D chemotherapy. Approxi- ⬎12. No treatment-related deaths or
group of patients with low-risk meta- mately 20% of low-risk patients will life-threatening toxicity occurred. Neu-

14 American Journal of Obstetrics & Gynecology JANUARY 2011

www.AJOG.org Oncology Reviews

tropenia necessitating a 1-week delay

of treatment, anemia requiring blood TABLE 4
transfusion, and grades 3-4 neutropenia Chemotherapy for high-risk gestational trophoblastic neoplasia
without thrombocytopenia were associ- Day Drug Dosing
ated with only 14%, 5.8%, and 1.9% of 1 Etoposide 100 mg/m2 IV over 30 min
treatment cycles, respectively. The Actinomycin D 0.5 mg IVP
EMA-CO protocol, or some variation of MTX 100 mg/m2 IVP, then 200 mg/m2 in 500 mL D5W over 12 h
..............................................................................................................................................................................................................................................
it, is currently the initial treatment of 2 Etoposide 100 mg/m IV over 30 min 2

choice for high-risk metastatic GTN be- Actinomycin D 0.5 mg IVP

cause of low toxicity allowing adherence Folinic acid 15 mg IM or PO every 12 h for 4 doses starting 24 h after start
to treatment schedules, high complete of MTX
..............................................................................................................................................................................................................................................
2
response rates, and overall high resultant 8 Cyclophosphamide 600 mg/m IV
survival. Chemotherapy for high-risk Vincristine 1.0 mg/m2 IVP
..............................................................................................................................................................................................................................................
disease is continued for at least 2-3 IM, intramuscular; IV, intravenous; IVP, intravenous push; MTX, methotrexate.
Repeat cycle on days 15, 16, and 22 (every 2 wk).
courses after the first normal hCG.12
Lurain. Gestational trophoblastic disease II. Am J Obstet Gynecol 2011.
When central nervous system metas-
tases are present, whole brain irradiation
(3000 cGy in 200-cGy fractions), or sur- had uterine wedge resection for resistant plete clinical responses to bleomycin,
gical excision with stereotactic irradia- choriocarcinoma survived.70 etoposide, and cisplatin; etoposide, ifos-
tion in selected patients, is usually given Despite the use of multimodel pri- famide, and cisplatin; and ifosfamide,
simultaneously with the initiation of sys- mary therapy in high-risk GTN, approx- carboplatin, and etoposide, and 10 (63%)
temic chemotherapy. During radiother- imately 30% of patients will have an were cured. Of the 10 patients who failed
apy, the methotrexate infusion dose in incomplete response to first-line chemo- primary therapy with EMA-CO, 9 (90%)
the EMA-CO protocol is increased to 1 therapy or relapse from remission.76-79 had complete clinical responses to
g/m2 and 30 mg of folinic acid is given Most of these patients will have multiple EMA-EP or bleomycin, etoposide, cispla-
every 12 hours for 3 days starting 32 metastases to sites other than the lung tin, but only 6 (60%) subsequently
hours after the infusion begins. An alter- and vagina, and many will have had in- achieved a lasting remission.76
native to brain irradiation is the use of adequate chemotherapy. Salvage che- In summary, cure rates for high-risk
intrathecal as well as high-dose IV meth- motherapy with drug regimens employ- GTN of 80-90% are now achievable with
otrexate. Reported cure rates with brain ing etoposide and a platinum agent often intensive multimodality therapy with
metastases are 50-80%, depending on combined with surgical excision of per- EMA-CO chemotherapy, along with ad-
patient symptoms as well as number, size, sistent tumor will result in cure of most juvant radiotherapy or surgery when in-
and location of the brain lesions.59-63 of these high-risk patients. The EMA-EP dicated. Approximately 30% of high-risk
Adjuvant surgical procedures, espe- regimen, substituting etoposide and cis- patients will fail first-line therapy or re-
cially hysterectomy and pulmonary re- platin for cyclophosphamide and vin- lapse from remission. Salvage therapy
section for chemotherapy-resistant dis- cristine in the EMA-CO protocol, is con- with platinum-containing drug combi-
ease as well as procedures to control sidered the most appropriate therapy nations, often in conjunction with surgi-
hemorrhage, are important components for patients who have responded to cal resection of sites of persistent tumor,
in the management of high-risk GTN. EMA-CO but have plateauing low hCG will result in cure of most of these high-
Approximately half of high-risk patients levels or who have developed re-elevation risk patients with resistant disease. Even
will require some form of surgical proce- of hCG levels after a complete response to those patients with metastatic disease to
dure during the course of treatment to EMA-CO.80,81 In patients who have clearly the brain, liver, and gastrointestinal tract
effect cure.64-75 In a series of 50 patients developed resistance to methotrexate- now have a 75%, 73%, and 50% survival
with high-risk GTN treated with containing protocols, drug combinations rate, respectively.46
EMA-CO as primary or secondary ther- containing etoposide and platinum with
apy at the Brewer Center from 1986 bleomycin, ifosfamide, or paclitaxel have PSTTs and ETTs
through 2005, 24 (48%) underwent 28 been found to be effective.12,76,82 Hysterectomy with lymph node dissec-
adjuvant surgical procedures, and 21 In 2005, we reported on 26 patients tion is the recommended treatment for
(87.5%) were cured. Fifteen (88%) of 17 with persistent or relapsed high-risk PSTT and ETT, because of the relative
patients who underwent hysterectomy; 4 GTN who received secondary platinum- resistance of these tumors to chemother-
(80%) of 5 patients who had resistant based salvage chemotherapy at the apy and their propensity for lymphatic
foci of choriocarcinoma in the lung re- Brewer Center. The overall survival was spread. Chemotherapy should be used in
sected; all 4 patients who had suturing of 61.5% (16/26). Of the 16 patients who patients with metastatic disease and in
the uterus, uterine artery embolization, failed primary therapy with methotrex- patients with nonmetastatic disease who
small bowel resection, and salpingec- ate/actinomycin D-based chemotherapy have adverse prognostic factors, such as
tomy for bleeding; and the 1 patient who without etoposide, 10 (63%) had com- interval from last known pregnancy to

JANUARY 2011 American Journal of Obstetrics & Gynecology 15

Reviews Oncology www.AJOG.org

diagnosis ⬎2 years, deep myometrial in- of 6-12 months; other testing such as x- of etoposide-containing drug combina-
vasion, tumor necrosis, and mitotic rays or scans are rarely indicated. Con- tions for treatment of GTN in the 1980s, an
count ⬎6/10 high power fields. Al- traception should be maintained during increased risk of secondary malignancies,
though the optimal chemotherapy regi- treatment and for 1 year after comple- including acute myelogenous leukemia,
men for PSTT and ETT remains to be tion of chemotherapy, preferably using colon cancer, melanoma, and breast can-
defined, the current clinical impression oral contraceptives. Because of the 1-2% cer, was identified.91 f
is that a platinum-containing regimen, risk of a second gestational trophoblastic
such as EMA-EP or a paclitaxel/cispla- disease event in subsequent pregnancies, REFERENCES
tin–paclitaxel/etoposide doublet, is the pelvic ultrasound is recommended in the 1. Lurain JR. Treatment of gestational tropho-
treatment of choice. The survival rate is first trimester of a subsequent pregnancy blastic tumors. Curr Treat Options Oncol 2002;
approximately 100% for nonmetastatic to confirm a normal gestation, the prod- 3:113-24.
disease and 50-60% for metastatic ucts of contraception or placentas from 2. Ngan S, Seckl MJ. Gestational trophoblastic
neoplasia management: an update. Curr Opin
disease.83-85 future pregnancies should be carefully
Oncol 2007;19:486-91.
examined histopathologically, and a se- 3. Soper JT. Gestational trophoblastic disease.
Reasons for treatment failure rum quantitative hCG level should be Obstet Gynecol 2006;108:176-87.
We recently reviewed our experience in determined 6 weeks after any pregnancy. 4. Berkowitz RS, Goldstein DP. Current man-
treating patients with GTN whose care Successful treatment of GTN with agement of gestational trophoblastic disease.
Gynecol Oncol 2009;112:654-62.
was transferred to the Brewer Center af- chemotherapy has resulted in a large
5. Schlaerth JB, Morrow CP, Rodriguez M. Di-
ter failing treatment elsewhere to deter- number of women who maintain their agnostic and therapeutic curettage in gesta-
mine causes of treatment failure and to reproductive potential despite exposure tional trophoblastic disease. Am J Obstet Gy-
compare our results of treating these pa- to drugs that have ovarian toxicity and necol 1990;162:1465-70.
tients from 1979 through 2006 with teratogenic potential. Most women re- 6. Pezeshki M, Hancock BW, Silcocks P, et al.
The role of repeat uterine evacuation in the
those previously reported from 1962 sume normal ovarian function after che-
management of persistent gestational tropho-
through 1978. The most common rea- motherapy and exhibit no increase in in- blastic disease. Gynecol Oncol 2004;95:423-9.
sons for unsuccessful GTN treatment be- fertility. Many successful pregnancies 7. van Trommel NE, Massuger LF, Verheijen
fore transfer to the Brewer Center were: have been reported, without an increase RH, et al. The curative effect of a second curet-
(1) use of single-agent chemotherapy for in abortions, stillbirths, congenital tage in persistent trophoblastic disease: a ret-
rospective cohort study. Gynecol Oncol 2005;
patients with high-risk disease; and (2) anomalies, prematurity, or major obstet-
99:6-13.
inappropriate use of weekly IM metho- ric complications. There is no evidence 8. Garner EI, Feltmate CM, Goldstein DP,
trexate chemotherapy for treatment of for reactivation of disease because of Berkowitz RS. The curative effect of a second
patients with metastatic disease, FIGO subsequent pregnancies, although pa- curettage in persistent trophoblastic disease: a
scores ⱖ7, and/or nonpostmolar chorio- tients who have had 1 trophoblastic dis- retrospective cohort study. Gynecol Oncol
carcinoma. Successful secondary GTN 2005;99:3-5.
ease episode are at greater risk for the de-
9. Ngan HYS, Bender H, Benedet JL, et al.
treatment in this patient group im- velopment of a second episode in a Gestational trophoblastic neoplasia, FIGO stag-
proved from 59% during 1962 through subsequent pregnancy, unrelated to ing and classification. Int J Gynecol Obstet
1978 to 93% during 1979 through 2006, whether they had previously received 2003;83:175-7.
seemingly as a result of more experi- chemotherapy. Patients are advised to 10. Lurain JR, Casanova LA, Miller DS, Rade-
enced clinicians administering more ef- maker AW. Prognostic factors in gestational
delay conception for 1 year after cessa-
trophoblastic tumors: a proposed new scoring
fective chemotherapy treatment proto- tion of chemotherapy to allow for unin- system based on multivariate analysis. Am J
cols.86 Request for advice from or terrupted hCG follow-up and to permit Obstet Gynecol 1991;164:611-6.
referral for treatment to clinicians with the elimination of mature ova that may 11. Lurain JR. Pharmacotherapy of gestational
expertise in management of gestational have been damaged by exposure to cyto- trophoblastic disease. Expert Opin Pharmaco-
ther 2003;4:1-13.
trophoblastic disease is recommended toxic drugs.88-90
12. Alazzam M, Tidy J, Hancock BW, Osborne
for a patient who fails single-agent ther- Because many anticancer drugs are R. First line chemotherapy in low risk gestational
apy for low-risk disease and for any pa- known carcinogens, there is concern that trophoblastic neoplasia. Cochrane Database
tient with high-risk disease.87 the chemotherapy used to induce long- Syst Rev 2009;1:CD007102.
term remissions or cures of one cancer 13. Hammond CB, Hertz R, Ross GT, et al. Pri-
Follow-up after treatment for GTN mary chemotherapy for nonmetastatic gesta-
may induce second malignancies. Until
tional trophoblastic neoplasms. Am J Obstet
After hCG regression to normal and recently, there were no reports of increased Gynecol 1967;98:71-8.
completion of chemotherapy, serum susceptibility to the development of other 14. Hammond CB, Borchert LG, Tyrey L, et al.
quantitative hCG levels should be ob- malignancies after successful chemother- Treatment of metastatic trophoblastic disease:
tained at 1-month intervals for 12 apy for GTN, probably because of the rel- good and poor prognosis. Am J Obstet Gy-
necol 1973;115:451-7.
months. The risk of relapse is about 3% atively short exposure of these patients to
15. Lurain JR, Elfstrand EP. Single-agent meth-
in the first year after completing therapy, intermittent schedules of methotrexate otrexate chemotherapy for the treatment of
but is exceedingly low after that. Physical and actinomycin D and the infrequent use nonmetastatic gestational trophoblastic tu-
examinations are performed at intervals of alkylating agents. After the introduction mors. Am J Obstet Gynecol 1995;172:574-9.

16 American Journal of Obstetrics & Gynecology JANUARY 2011

www.AJOG.org Oncology Reviews
16. Bagshawe KD, Dent J, Newlands ES, et al. tic disease associated with dose scheduling or 46. Hoekstra AV, Lurain JR, Rademaker AW, et
The role of low-dose methotrexate and folinic chemotherapy resistance? Gynecol Oncol al. Gestational trophoblastic neoplasia: treat-
acid in gestational trophoblastic tumors. Br J 2002;85:36-9. ment outcomes. Obstet Gynecol 2008;112:
Obstet Gynecol 1989;96:795-802. 32. Twiggs LB. Pulse actinomycin D scheduling 251-8.
17. Garrett AP, Garner EO, Goldstein DP, et al. in nonmetastatic gestational trophoblastic neo- 47. Lurain JR, Brewer JI. Treatment of high-risk
Methotrexate infusion and folinic acid as pri- plasia: cost-effective chemotherapy. Gynecol gestational trophoblastic disease with metho-
mary therapy for nonmetastatic and low-risk Oncol 1982;16:190-5. trexate, actinomycin D and cyclophosphamide
metastatic gestational trophoblastic tumors. J 33. Schlaerth JB, Morrow CP, Nalick RH, et al. chemotherapy. Obstet Gynecol 1985;65:
Reprod Med 2002;47:355-62. Single-dose actinomycin D in the treatment of 830-4.
18. Berkowitz RS, Goldstein DS, Bernstein MR. postmolar trophoblastic disease. Gynecol On- 48. Begent RHJ, Bagshawe KD. The manage-
Ten years’ experience with methotrexate and col 1984;19:53-6. ment of high-risk choriocarcinoma. Semin On-
folinic acid as primary therapy for gestational 34. Petrilli ES, Twiggs LB, Blessing JA, et al. col 1982;9:198-203.
trophoblastic disease. Gynecol Oncol 1986;23: Single-dose actinomycin D treatment for non- 49. Curry SL, Blessing JA, DiSaia PJ, et al. A
111-8. metastatic gestational trophoblastic disease. prospective randomized comparison of metho-
19. Wong LC, Choo YC, Ma HK. Methotrexate Cancer 1987;60:2173-6. trexate, actinomycin D and chlorambucil (MAC)
with citrovorum factor rescue in gestational tro- 35. Gilani MM, Yarandi F, Eftekhar Z, et al. versus modified Bagshawe regimen in “poor
phoblastic disease. Am J Obstet Gynecol Comparison of pulse methotrexate and pulse prognosis” gestational trophoblastic disease.
1985;152:59-62. actinomycin D in the treatment of low-risk ges- Obstet Gynecol 1989;73:357-62.
20. McNeish IA, Strickland S, Holden L, et al. tational trophoblastic neoplasia. Aust N Z J Ob- 50. Newlands ES, Bagshawe KD, Begent RJH,
Low-risk persistent gestational trophoblastic stet Gynecol 2005;45:161-4. et al. Results with EMA/CO (etoposide, metho-
disease: outcome following initial treatment with 36. Yarandi F, Eftekhar Z, Shojaei H, et al. Pulse trexate, actinomycin D, cyclophosphamide, vin-
low-dose methotrexate and folinic acid, 1992- methotrexate versus pulse actinomycin D in the cristine) regimen in high-risk gestational tropho-
2000. J Clin Oncol 2002;20:1838-44. treatment of low-risk gestational trophoblastic blastic tumors (1979-1989). Br J Obstet
21. Khan F, Everand J, Ahmed S, et al. Low-risk neoplasia. Int J Gynecol Obstet 2008;103:33-7. Gynecol 1991;98:550-7.
persistent trophoblastic disease treated with 37. Osborne R, Filiaci M, Schink J, et al. A ran- 51. Bolis G, Bonazzi C, Landoni F, et al.
low-dose methotrexate: efficacy and long term EMA/CO regimen in high-risk gestational tro-
domized phase III trial comparing weekly par-
effects. Br J Cancer 2003;89:2197-201. phoblastic tumor (GTT). Gynecol Oncol 1988;
enteral methotrexate and “pulsed” actinomycin
22. Growden WB, Wolfberg AJ, Goldstein DP, 31:439-44.
as primary management for low-risk gestational
et al. Evaluating methotrexate treatment in pa- 52. Bower M, Newlands ES, Holden L, et al.
trophoblastic neoplasia: a gynecologic oncol-
tients with low-risk postmolar gestational tro- EMA/CO for high-risk gestational trophoblastic
ogy group study. Gynecol Oncol 2008;108:52.
phoblastic neoplasia. Gynecol Oncol 2009;112: disease: results from a cohort of 272 patients.
38. Smith EB, Weed JC Jr, Tyrey L, et al. Treat-
353-7. J Clin Oncol 1997;15:2636-43.
ment of nonmetastatic gestational trophoblas-
23. Berkowitz RS, Goldstein DP, Bernstein MR. 53. Kim SJ, Bae SN, Kim JH, et al. Risk factors
tic disease: results of methotrexate alone ver-
Methotrexate infusion with folinic acid in primary for the prediction of treatment failure in gesta-
sus methotrexate-folinic acid. Am J Obstet
therapy of nonmetastatic trophoblastic tumors. tional trophoblastic tumors treated with
Gynecol 1982;144:88-92.
Gynecol Oncol 1990;36:56-9. EMA/CO regimen. Gynecol Oncol 1998;71:
39. Gleeson NC, Finan MA, Fiorica JV, et al.
24. Elit L, Covens A, Osborne R, et al. High- 247-53.
Nonmetastatic gestational trophoblastic dis-
dose methotrexate for gestational trophoblastic 54. Matsui H, Suzuka K, Iitsuka Y, et al. Com-
ease: weekly methotrexate compared with
disease. Gynecol Oncol 1994;54:282-7. bination therapy with methotrexate, etoposide
25. Wong LC, Ngan HYS, Cheng DKL, et al. 8-day methotrexate-folinic acid. Eur J Gynecol and actinomycin D for high-risk gestational tro-
Methotrexate infusion in low-risk gestational Oncol 1993;14:461-5. phoblastic tumors. Gynecol Oncol 2000;78:
trophoblastic disease. Am J Obstet Gynecol 40. Lertkhachonsuk AA, Israngura N, Wilailak 28-31.
2000;183:1579-82. S, et al. Actinomycin D versus methotrexate- 55. Escobar PF, Lurain JR, Singh DK, et al.
26. Homesley HD, Blessing JA, Rettenmaier M, folinic acid as the treatment of stage I, low-risk Treatment of high-risk gestational trophoblastic
et al. Weekly intramuscular methotrexate for gestational trophoblastic neoplasia: a random- neoplasia with etoposide, methotrexate, acti-
nonmetastatic gestational trophoblastic dis- ized controlled trial. Int J Gynecol Cancer nomycin D, cyclophosphamide, and vincristine
ease. Obstet Gynecol 1988;72:413-8. 2009;19:985-8. chemotherapy. Gynecol Oncol 2003;91:552-7.
27. Homesley HD, Blessing JA, Schlaerth J, et 41. Kohorn EI. Decision making for chemother- 56. Lurain JR, Singh DK, Schink JC. Primary
al. Rapid escalation of weekly intramuscular apy administration in patients with low-risk ges- treatment of metastatic high-risk gestational
methotrexate for nonmetastatic gestational tro- tational trophoblastic neoplasia. Int J Gynecol trophoblastic neoplasia with EMA-CO chemo-
phoblastic disease: a gynecologic oncology Cancer 1996;6:279-85. therapy. J Reprod Med 2006;51:767-72.
group study. Gynecol Oncol 1990;39:305-8. 42. Abrao RA, de Andrade JM, Tiezzi DG, et al. 57. Turan T, Karacay O, Tulunay G, et al. Re-
28. Hoffman MS, Fiorica JV, Gleeson NC, et al. Treatment for low-risk gestational trophoblastic sults with EMA/CO (etoposide, methotrexate,
A single institution experience with weekly intra- disease: comparison of single-agent metho- actinomycin D, cyclophosphamide, vincristine)
muscular methotrexate for nonmetastatic ges- trexate, dactinomycin and combination regi- chemotherapy in gestational trophoblastic neo-
tational trophoblastic disease. Gynecol Oncol mens. Gynecol Oncol 2008;108:149-53. plasia. Int J Gynecol Cancer 2006;16:1432-8.
1996;60:292-4. 43. DuBeshter B, Berkowitz RS, Goldstein DP. 58. Lu WG, Ye F, Shen YM, et al. EMA-CO che-
29. Osathanondh R, Goldstein DP, Pastorfide Management of low-risk gestational tropho- motherapy for high-risk gestational trophoblas-
GB. Actinomycin D as the primary agent for blastic tumors. J Reprod Med 1991;36:36-9. tic neoplasia: a clinical analysis of 54 patients.
gestational trophoblastic disease. Cancer 44. Soper JT, Clarke-Pearson DL, Berchuck A, Int J Gynecol Cancer 2008;18:357-62.
1975;36:863-6. et al. Five-day methotrexate for women with 59. Evans AC Jr, Soper JT, Clarke-Pearson DL,
30. Petrilli ES, Morrow CP. Actinomycin D tox- metastatic gestational trophoblastic disease. et al. Gestational trophoblastic disease meta-
icity in the treatment of trophoblastic disease: a Gynecol Oncol 1994;54:76-9. static to the central nervous system. Gynecol
comparison of the 5-day course to single-dose 45. Roberts JP, Lurain JR. Treatment of low- Oncol 1995;59:226-30.
administration. Gynecol Oncol 1980;9:18-22. risk metastatic gestational trophoblastic tumors 60. Small W Jr, Lurain JR, Shetty RM, et al.
31. Kohorn EI. Is lack of response to single- with single-agent chemotherapy. Am J Obstet Gestational trophoblastic disease metastatic to
agent chemotherapy in gestational trophoblas- Gynecol 1996;174:1917-24. the brain. Radiology 1996;200:277-80.

JANUARY 2011 American Journal of Obstetrics & Gynecology 17

Reviews Oncology www.AJOG.org

61. Rustin GJ, Newlands ES, Begent RH, et al. tional trophoblastic tumors. Radiology 2002; tional trophoblastic neoplasia (GTN) with
Weekly alternating etoposide, methotrexate and 222:640-4. paclitaxel/cisplatin alternating with paclitaxel/
actinomycin D/vincristine and cyclophosphamide 73. Fleming EL, Garrett LA, Growden WB, et al. etoposide (TP/TE). Ann Oncol 2008;19:
chemotherapy for treatment of CNS metastases The changing role of thoracotomy in gestational 1578-83.
of choriocarcinoma. J Clin Oncol 1989;7:900-4. trophoblastic neoplasia at the New England 83. Papadopoulos AJ, Foskett M, Seckl MJ, et
62. Bakri Y, Berkowitz RS, Goldstein DP, et al. Trophoblastic Disease Center. J Reprod Med al. Twenty-five years clinical experience with
Brain metastases in gestational trophoblastic 2008;53:493-8. placental site trophoblastic tumors. J Reprod
tumor. J Reprod Med 1994;39:179-84. 74. Alazzam M, Hancock BW, Tidy J. Role of Med 2002;47:460-4.
63. Newlands ES, Holden L, Seckl MJ, et al. hysterectomy in managing persistent gesta- 84. Hassadia A, Gillespie A, Tidy J, et al. Pla-
Management of brain metastases in patients tional trophoblastic disease. J Reprod Med cental site trophoblastic tumor: clinical features
with high-risk gestational trophoblastic tumors. 2008;53:519-24. and management. Gynecol Oncol 2005;99:
J Reprod Med 2002;47:465-71. 75. Doumplis D, Al-Khatib K, Sieunarine K, et al. 603-7.
64. Mutch DG, Soper JT, Babcock CJ, et al. A review of the management by hysterectomy 85. Schmid P, Nagai Y, Agarwal R, et al. Prog-
Recurrent gestational trophoblastic disease. of 25 cases of gestational trophoblastic tumors nostic markers and long-term outcome of pla-
Cancer 1990;66:978-82. from March 1993 to January 2006. Br J Obstet cental-site trophoblastic tumors: a retrospec-
65. Pisal N, North C, Tidy J, et al. Role of hys- Gynecol 2007;114:1168-71. tive observational study. Lancet 2009;374:
terectomy in the management of gestational 76. Lurain JR, Nejad B. Secondary chemother- 48-55.
trophoblastic disease. Gynecol Oncol 2002;87: apy for high-risk gestational trophoblastic neo- 86. Kohorn EI. Regional centers for trophoblas-
190-2. plasia. Gynecol Oncol 2005;97:618-23. tic disease. Am J Obstet Gynecol 2007;196:
66. Newlands ES, Bower M, Holden L, et al. 77. Yang J, Xiang Y, Wan X, et al. Recurrent 95-6.
Management of resistant gestational tropho- gestational trophoblastic tumor: management 87. Lurain JR, Hoekstra AV, Schink JC. Results
blastic tumors. J Reprod Med 1998;43:111-8. and risk factors for recurrence. Gynecol Oncol of treatment of patients with gestational tropho-
67. Tomada Y, Arii Y, Kaseki S, et al. Surgical 2006;103:587-90. blastic neoplasia referred to the Brewer Tropho-
indications for resection of pulmonary metasta- 78. Ngan HY, Tam KF, Lam KW, et al. Relapsed blastic Disease Center after failure of treatment
ses of choriocarcinoma. Cancer 1980;46: gestational trophoblastic neoplasia: a 20-year elsewhere (1979-2006). J Reprod Med
2723-30. experience. J Reprod Med 2006;51:829-34. 2008;53:535-40.
68. Xu L-T, Sun C-F, Wang Y-E, et al. Resection 79. Powles Y, Savage PM, Stebbing J, et al. A 88. Woolas RP, Bower M, Newlands ES, et al.
of pulmonary metastatic choriocarcinoma in 43 comparison of patients with relapsed and Influence of chemotherapy for gestational tro-
drug-resistant patients. Ann Thorac Surg chemo-refractory gestational trophoblastic phoblastic disease on subsequent pregnancy
1985;39:257-9. neoplasia. Br J Cancer 2007;96:732-7. outcome. Br J Obstet Gynecol 1998;105:
69. Saito K, Harado K, Nakayama H, et al. Role 80. Mao Y, Wan X, Lv W, Xie X. Relapsed or 1032-5.
of thoracotomy in pulmonary metastases from refractory gestational trophoblastic neoplasia 89. Matsui H, Iitsuka Y, Suzuka K, et al. Early
gestational choriocarcinoma. J Thorac Cardio- treated with etoposide and cisplatin/etoposide, pregnancy outcomes after chemotherapy for
vasc Surg 1983;85:815-20. methotrexate, and actinomycin D (EP-EMA) gestational trophoblastic tumor. J Reprod Med
70. Lurain JR, Singh DK, Schink JC. The role of regimen. Int J Gynecol Obstet 2007;98:44-7. 2004;49:531-4.
surgery in the management of high-risk gesta- 81. Newlands ES, Mulholland PJ, Holden L, et 90. Garrett LA, Garner EI, Feltmate CM, et al.
tional trophoblastic neoplasia. J Reprod Med al. Etoposide and cisplatin/etoposide, metho- Subsequent pregnancy outcomes in patients
2006;51:773-6. trexate and actinomycin D (EMA) for patients with molar pregnancy and persistent gesta-
71. Vogelzang RL, Nemcek AA, Skrtic Z, et al. with high-risk gestational trophoblastic tumors tional trophoblastic neoplasia. J Reprod Med
Uterine arteriovenous malformations: primary refractory to EMA/cyclophosphamide and vin- 2008;53:481-6.
treatment with therapeutic embolization. J Vasc cristine and patients presenting with metastatic 91. Rustin GJS, Newlands ES, Lutz J-M, et al.
Interv Radiol 1991;2:517-22. placental site trophoblastic tumors. J Clin Oncol Combination but not single agent methotrexate
72. Lim AK, Agarwal R, Seckl MJ, et al. Embo- 2000;18:854-9. chemotherapy for gestational trophoblastic tu-
lization of bleeding residual uterine vascular 82. Wang J, Short D, Sebire NJ, et al. Salvage mors (GTT) increases the incidence of second
malformations in patient with treated gesta- chemotherapy of relapsed or high-risk gesta- tumors. J Clin Oncol 1996;14:2769-73.

18 American Journal of Obstetrics & Gynecology JANUARY 2011