YGYNO-978608; No.

of pages: 9; 4C:
Gynecologic Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Epidemiology, diagnosis, and treatment of gestational trophoblastic

disease: A Society of Gynecologic Oncology evidenced-based review
and recommendation☆
N.S. Horowitz a,⁎, R.N. Eskander b, M.R. Adelman c, W. Burke d
a
Brigham & Women's Hospital/Dana Farber Cancer Institute, Boston, MA, USA
b
University of California, San Diego, Moores Cancer Center, La Jolla, CA, USA
c
University of Utah, Salt Lake City, UT, USA
d
Stony Brook Medicine, Long Island, NY, USA

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.2. Molar pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.3. Human chorionic gonadotropin (hCG). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.4. GTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.5. Low-Risk GTN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.6. High-risk GTN. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.7. Ultra high-risk disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.8. Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.9. PSTT/ETT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.10. Survivorship issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.11. Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction
Gestational trophoblastic disease (GTD) is a group of interrelated
tumors that arise from abnormal fertilization events and include both
benign conditions (complete hydatidiform mole (CM) and partial
hydatidiform mole (PM), placental site nodule), potentially malignant
conditions (atypical placental site nodule APSN), as well as malignant
conditions (invasive mole (IM), choriocarcinoma (CA), placental-site
trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor
(ETT)). These malignancies are collectively referred to as gestational
trophoblastic neoplasia (GTN). While the majority of GTN occurs after
a molar pregnancy (50%), they can arise after any gestational event
with 25% arising after miscarriage or tubal pregnancy and 25% after
term or preterm pregnancies [1]. Unlike most malignancies, GTN
can be cured even in the presence of metastatic disease. With the
exception of PSTT and ETT, GTD arises from cytotrophoblasts and
syncytiotrophoblasts, and produce abundant amounts of human chori-
onic gonadotropin (hCG), which serves as an excellent tumor marker
for diagnosis, monitoring of response, and follow-up to detect recur-
rence. Given the rarity of this disease, management and treatment
recommendations are commonly informed by data from small, retro-
spective single institution or collaborative studies, small prospective
studies, meta-analyses, and expert opinion [2]. The purpose of this doc-
ument is to provide a comprehensive reference for the epidemiology,
management and outcomes of GTD/GTN. We carried out a systematic
review of English language studies, identified through a search of
MEDLINE/Pubmed, Cochrane Library, and Google Scholar from incep-
tion until June 2021. Using the terms gestational trophoblastic disease,

☆ This practice statement has been endorsed by the American College of Obstetricians and Gynecologists (ACOG).
⁎ Corresponding author at: Brigham & Women's Hospital/Dana Farber Cancer Institute, 75 Francis Street, Dept. of OB/GYN, Division of Gynecologic Oncology, Boston, MA 02115, USA.
E-mail address: nhorowitz@partners.org (N.S. Horowitz).

https://doi.org/10.1016/j.ygyno.2021.10.003
0090-8258/© 2021 Published by Elsevier Inc.

Please cite this article as: N.S. Horowitz, R.N. Eskander, M.R. Adelman, et al., Epidemiology, diagnosis, and treatment of gestational trophoblastic
disease: A Society of Gynecologi..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2021.10.003
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al.
gestational trophoblastic neoplasia, molar pregnancy, human chorionic
gonadotropin, chemotherapy, we generated the references for this re-
view and accompanying recommendations.
1.1. Epidemiology
Wide variations in the incidence of hydatidiform mole exist
throughout the world with rates ranging from 1 to 2 per 1000 pregnan-
cies in North America, Europe, and other developed nations, to 2–3
times higher in some Asian countries, Brazil, and India [3]. Extremes of
reproductive age and prior molar pregnancy have emerged as major
risk factors for the development of molar pregnancy. Age < 15 years,
and > 45 years are most strongly associated with the development of
molar pregnancy, with the risk being 5–10 times greater for those
over 45 [4,5]. The risk of a second molar pregnancy after a first increases
to approximately 1–2% (up from 0.1%) and after two molar pregnancies,
the risk of a third molar pregnancy is 15–20% [5–7]. This risk is much
higher after a complete mole and interestingly, subsequent moles
tend to be the same histology as the first [8].
Choriocarcinoma is the most common histologic GTN after a normal
pregnancy. Because of its rapid growth and high propensity for metasta-
tic disease, it is considered the most aggressive form of GTN. The inci-
dence of choriocarcinoma is approximately 3 per 100,000 deliveries in
Europe and North America, compared to approximately 23 per
100,000 in Southeast Asia [3,9]. This risk increases with increasing
maternal age [10].
PSTT and ETT are incredibly rare entities and most are diagnosed
remotely after non-molarpregnancies. The incidence of PSTT is approx-
imately 1 per 100,000 deliveries, and the incidence of ETT is approxi-
mately 0.1 per 100,000 deliveries [3,11].
1.2. Molar pregnancy
There are two histologically distinct subtypes of hydatidiform moles,
complete (CM) and partial (PM). The majority of CM result from fertil-
ization of an ovum lacking maternal nuclear DNA, with subsequent du-
plication of the haploid genome from a single sperm (80%) or dispermic
fertilization (20%). The resulting karyotypes are diploid, either 46 XX or
46 XY, and are completely paternally derived [12,13]. PM are almost al-
ways triploid, resulting from dispermic fertilization of an ovum
retaining its maternal DNA [12,13]. Although rare, if a woman has 2 or
3 consecutive moles familial recurrent hydatidiform mole syndrome
(FRHM)) should be suspected [14]. CM related to FRHM are diploid
and genetically biparental rather than androgenic and result from spo-
radic mutations in NLRP7 (70% of cases), KHDC3L (5–10%% of cases),
or from gene(s) unidentified to date. [14–16]. If FRHM is confirmed,
egg donation from an unaffected individual is a way to enable a success-
ful non-molar pregnancy [17].
Hydatidiform moles are characterized by unregulated trophoblastic
proliferation, resulting in increased production of hCG. Elevated hCG
levels above 100,000 IU/L are commonly observed with CM, but these
levels are rare in PM given the less prominent trophoblastic hyperplasia
[4,18]. Ultrasonographic findings of a vesicular pattern, indicating
hydropic villi, and theca lutein cysts are strongly suggestive of the diag-
nosis of CM [19]. Ultrasonographic features suggestive of a PM include
focal cystic changes in the placenta, presence of a nonviable fetus, and
an elevated ratio of the transverse to anteroposterior dimension of the
gestational sac [20].
The use of sensitive hCG assays and early ultrasound have shifted de-
tection of molar pregnancy into the first trimester and therefore the
classic presenting symptoms (excessive uterine size, anemia, pre-
eclampsia, hyperemesis, hyperthyroidism, and respiratory failure) are
rarely encountered [21–24]. This shift to earlier detection and evacua-
tion has necessitated the use of additional diagnostics such as flow cy-
tometry to determine ploidy, and immunohistochemistry staining for
the cyclin dependent kinase inhibitor, p57 [17]. As a paternally
2
Gynecologic Oncology xxx (xxxx) xxx
imprinted and maternally expressed gene, p57 can differentiate
between CM (p57 negative) and either a PM (p57 positive) or non-
molar hydropic abortions [25]. These additional diagnostics are
performed on tissue obtained at evacuation, not separate biopsies.
The initial treatment of hydatidiform moles in women who wish to
preserve fertility is suction dilation and curettage (D&C), preferably per-
formed with the largest cannula that is easily introduced and with
uterotonic agents administered as necessary [26,27]. Ultrasound guid-
ance may be used at the discretion of the surgeon but may increase
the rate of complete evacuation. Uterine evacuation by medication
only methods is discouraged due to high failure rates, risk of hemor-
rhage, and increased development of GTN requiring chemotherapy
[28]. RhD factor is expressed on trophoblastic tissue, therefore RhD im-
munoglobulin should be administered at the time of uterine evacuation
in Rh negative women [3]. Given the earlier gestational age of diagnosis,
complications during or after evacuation are uncommon, but surgeons
should be prepared to manage excessive bleeding and pulmonary com-
promise. For those who have completed childbearing and have a pre-
sumed molar pregnancy, hysterectomy provides an alternative
method of management. In one study, compared to uterine evacuation,
hysterectomy has a significant advantage in preventing post-molar GTN
with an approximately 80% reduction in risk [29]. Although hysterec-
tomy eliminates any locally invasive disease, some women will have oc-
cult metastases at the time of diagnosis and therefore hCG monitoring is
still warranted after hysterectomy [29].
Post-evacuation surveillance with hCG is critical in identifying the de-
velopment of post-molar GTN. Ideally, an assay that can detect all forms
of hCG (beta-hCG, core hCG, C-terminal hCG, nicked-free beta, beta-core,
and hyperglycosylated) equally well should be used and are often re-
ferred to as “total hCG assays” [30,31]. hCG is routinely monitored
weekly until normalization or diagnosis of GTN, however, appropriate
duration of hCG surveillance varies considerably by histologic subtype
and the institution performing the surveillance. Current guidelines for
the duration of surveillance from various organizations and trophoblastic
reference centers are noted in Table 1 [32–35]. A recent meta-analysis by
Albright et al. [35] confirmed that the overall incidence of post-molar
GTN is approximately 20% for CM and 4% for PM. For those patients
who normalize their hCG <56 days after evacuation, the risk of develop-
ing GTN is 0.03% following CM and 0.02% after PM. For those that normal-
ize ≥56 days the rate is still low, 0.3% and 0.03% respectively. This data is
very reassuring and supports the recommendation that once hCG nor-
malization is achieved follow up should continue until 3 months after
CM and 1 month after PM, while maintaining patient safety [35,36].
Despite earlier diagnosis, the incidence of post-molar GTN has
remained constant over time [37]. Risk factors for developing
post-molar GTN include hCG at diagnosis >100,000 IU/L, excessive uter-
ine size, theca lutein cysts, and age > 40 years. Women aged 40–49 with
initial hCG levels exceeding 175,000 mIU/mL represent an especially at
risk group, with 85% developing post-evacuation GTN [38]. In women
older than 50 years, the risk of post-evacuation GTN may be as high as
60%, regardless of presenting hCG level [39], though population based
Table 1
Current guidelines for hCG follow up after molar pregnancy.
1. ACOG monthly hCG x 6 months for both complete and partial mole (4).
2. National Comprehensive Cancer Network (NCCN) - 3 consecutive normal hCG
levels followed by 2 hCG assays in 3-month intervals (32)
3. FIGO - hCG monitoring every 1–2 weeks until normal followed by a single
confirmatory normal hCG in a month for partial moles and monthly hCG for
6 months for complete moles (26)
4. United Kingdom (UK) - monthly hCG for six months for both CM starting from
the date of evacuation if normalization took ≤56 days or from the date of nor-
malization if this took >56 days. For PM only one confirmatory normal hCG is
needed 1 month after the first normal (34)
5. New England Trophoblastic Disease Center (NETDC) - After normalization of
weekly hCG for partial mole one confirmatory hCG a month after normalization
and 3 monthly hCG for complete moles (36).
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al.
studies place this risk for older women around 30% [10]. For these
women, or for those in whom reliable hCG follow up cannot be ob-
tained, hysterectomy should be considered [39–41]. Although use of
prophylactic chemotherapy at the time of hysterectomy for molar preg-
nancy has been shown to decrease the risk of developing GTN, for those
that do develop GTN despite prophylactic chemotherapy, there is often
a delayed diagnosis, increase drug resistance, exposure to toxicity, and
worse outcome [42,43]. Therefore it is not recommended in this setting.
Development of a new gestation prior to the completion of post-
molar surveillance poses a diagnostic dilemma, and as such reliable con-
traception during this period is strongly advised. Importantly, recent
data suggests that the use of hormonal contraception during post-
molar follow-up does not increase the risk of developing or the severity
of GTN and does not postpone normalization of hCG [44–46].
1.3. Human chorionic gonadotropin (hCG)
Human chorionic gonadotropin (hCG) is part of the glycoprotein
hormone family along with luteinizing hormone (LH), follicle-
stimulating hormone (FSH), and thyroid-stimulating hormone (TSH).
These hormones are heterodimers, sharing a common alpha subunit
and different, but with varying degrees of homology, betasubunits.
The intact heterodimeric form of hCG is produced almost exclusively
by cytotrophoblast and syncytiotrophoblast of the placenta, GTN,
germ cell, and other somatic tumors, such as bladder or lung, with tro-
phoblastic elements [47]. In addition to the intact heterodimer, there
is another isoform, hyperglycosolated hCG (hCG\\H) which contains
more sugar residues than regular hCG, is predominately produced by
cytotrophoblasts, and promotes trophoblastic growth and invasion
[48]. In addition, multiple variants are produced by enzymatic degrada-
tion in the tissue and circulation. The most common variants include
free beta subunit, free alpha subunit, nicked hCG, nicked hCG beta,
and hCG beta subunit core fragment [47].
All common commercially available hCG assays are sandwich-type
immunoassays that measure the beta-subunit, the intact hCG, and
almost all the major variants described above. These sandwich assays
are highly sensitive and can detect serum hCG levels as low as
1–2 IU/L and in urine as low as 10–50 IU/L [47]. Fortunately, hCG is an
exquisitely sensitive tumor marker thus allowing for easy diagnosis,
monitoring response to treatment, and identifying recurrence of GTN.
This is most successful if the same assay is used consistently throughout
the course of care as there can be great variation between assays.
False negative and false positive results for hCG can occur
at the extremes of value. Markedly elevated hCG, usually when
hCG > 1000,000 IU/L can produce a phenomenon known as the “hook
effect”, in which the fixed, solid phase antibodies and the labeled, solu-
ble antibodies are saturated preventing sandwich formation and a neg-
ative result. If hook effect is suspected, the true value can be obtained
with serial dilutions of the sample before analysis [49,50]. Additionally,
false negative results can occur if the tumor secretes a form of hCG not
detected or under-detected by a particular assay. When there is a persis-
tently low but positive hCG level, defined as an hCG < 1000 IU/L with no
more than a two-fold variation over at least a 3-month period and in the
absence of tumor on imaging, one must consider false positive results,
phantom hCG, or other sources of hCG such as the pituitary [51]. Phan-
tom hCG results from heterophile antibodies that interfere with the im-
munoassay. This can be confirmed if hCG elevation is noted only in
serum and not in urine, by using two separate commercial assays in
which the results vary greatly or are negative in repeat assay, or by per-
sistent elevated hCG despite serial dilution of the serum. The pituitary
gland produces a small amount of hCG which becomes more pro-
nounced around menopause or in women in whom multi-agent, high
dose chemotherapy has temporarily stopped ovarian function. Pituitary
hCG can be distinguished from real trophoblastic hCG by placing the pa-
tient on higher dose oral contraceptive or GnRH agonist which will sup-
press pituitary hCG production [51].
3
Gynecologic Oncology xxx (xxxx) xxx
Table 2
FIGO /WHO criteria for diagnosis of post-molar GTN (26).
1. Plateauing of hCG +/− 10% for 4 consecutive values over 3 weeks (i.e., days 1, 7,
14, 21)
2. A rise in hCG levels of ≥10% for 3 values over 2-week period (i.e., days 1, 7, 14)
3. Histologic diagnosis of choriocarcinoma or clinical and/or radiologic evidence of
metastases
1.4. GTN
Unlike other malignancies, GTN does not necessarily need histologic
confirmation, (although choriocarcinoma is occasionally seen on a D&C
or hysterectomy), and is the only malignancy diagnosed based on a
serum assay. In 2018, FIGO/WHO updated criteria for diagnosing post-
molar GTN (Table 2) [26]. Prior to 2018, hCG persistence for 6 months
after evacuation was a diagnostic criterion, however, recent data sug-
gests ≥80% of those with a persistently elevated but falling hCG 6 months
after evacuation, who are managed expectantly without initiation of che-
motherapy, ultimately achieve undetectable levels. For those that do not
achieve undetectable levels, there is no worsening of outcome [52,53].
For GTN diagnosed after a non-molar pregnancy, a single elevated hCG
with exclusion of any other explanation other than GTN is sufficient for
diagnosis. This is particularly true if there is unexplained metastatic
disease. Importantly, biopsies should be avoided as the highly vascular
nature of GTN can lead to significant bleeding complications.
Once criteria are met, patients must be evaluated for extent of dis-
ease and assigned a FIGO anatomic stage (Table 3) and WHO risk
score (Table 4) to determine the likelihood of disease progression
and/or resistance to treatment with single agent chemotherapy [54].
Evaluation should include a complete physical examination including
a pelvic examination and a chest radiograph as lung and vaginal metas-
tases are the most common site of disease. FIGO expressly recommends
chest radiograph rather than chest computed tomography (CT) for stag-
ing as micrometastases are detected on CT scans in approximately 40%
of patients with negative chest X-rays. These micrometastases do not af-
fect overall survival and can unnecessarily increase the use of multi-
agent chemotherapy [55]. If there is evidence of metastatic disease on
the initial evaluation, CT scan of abdomen and pelvis as well as MRI of
the brain are warranted. Other investigations should include routine
laboratory tests (complete blood count, hepatic, renal, thyroid tests,
chemistry, blood group, and hCG) and a pelvic ultrasound to exclude
intrauterine pregnancy, asses uterine size, and estimate intrauterine
tumor size and/or invasion. When calculating WHO score it is important
to use the hCG at time of GTN diagnosis, not hCG at time of mole evac-
uation, as this can lead to an inappropriately elevated WHO score. Addi-
tionally, WHO risk scores do not apply to PSTT or ETT. Treatment for
these histologies is based on the independent adverse prognostic factors
FIGO stage (III/IV) and the time from the antecedent pregnancy, with
≥48 months considered high-risk disease warranting chemotherapy
[56,57].
Women with stage I or stage II/III with a WHO prognostic score < 7
are considered to have low-risk disease and are treated with single
agent chemotherapy while those with stage IV disease or WHO score ≥ 7
have high-risk disease and receive multi-agent chemotherapy. A sepa-
rate category of ultra- high-risk, defined as WHO score > 12, identifies
women at high risk of early death and poor outcome who should be
Table 3
FIGO staging (54):
Stage I Disease confined to uterine corpus
Stage II GTN extends outside of uterus, but is limited to the genital structures
(adnexa, vagina, broad ligament)
Stage III GTN extends to the lungs, with or without known genital tract
involvement
Stage IV All other metastatic sites
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al. Gynecologic Oncology xxx (xxxx) xxx

Table 4
WHO Risk Score (54).

Scores

0 1 2 4

Age (yr) <40 ≥40 –

Antecedent pregnancy Mole Abortion Term
Interval months from index pregnancy <4 4–<7 7–<13 ≥13
Pretreatment serum hCG (International Unit/L) <103 103–<104 104–<105 >105
Largest tumor size (including uterus) 3–<5 cm ≥5 cm
Site of metastases Lung Kidney/spleen Gastrointestinal/liver Brain
Number of metastases – 1–4 5–8 >8
Previous failed chemotherapy – – Single drug 2 or more drugs

Format for reporting to FIGO Annual Report: In order to stage and allot a risk factor score, a patient's diagnosis is allocated to a stage as represented by a Roman numeral I, II, III, and IV. This
is then separated by a colon from the sum of all the actual risk factor scores expressed in Arabic numerals for example, stage II:4, stage IV:9. This stage and score will be allotted for each
patient.
Definition of Risk Categories:
Low Risk - Stage I or Stage II/III with a WHO prognostic score < 7.
High Risk - Stage IV disease or any stage and WHO score ≥ 7.
Ultra-high Risk - Any stage with WHO score > 12.

treated with low dose induction chemotherapy before initiating multi-
agent chemotherapy [58].
1.5. Low-Risk GTN
Low-risk GTN is primarily treated and cured with one of two single
agent drugs, methotrexate (MTX) or Dactinomycin (Act-D)
[2,26,59–65]. A variety of doses and infusion schedules for these drugs
have been utilized but multi-day MTX (either 8-day or 5-day) and
pulse Act-D seem to be the most efficacious (Table 5) [59]. Weekly
methotrexate has been used secondarily for ease of schedule and low
toxicity but it is not as effective as multi-day regimens [60]. New data
suggests that modifying the 8-day MTX regimen to avoid a weekend ad-
ministration (treatment on the 8th day rather than 7th) does not com-
promise oncologic outcome [61]. To date, there is not a clearly superior
regimen between these two drugs, with complete remission rates rang-
ing between 75 and 90% and rare grade 3 or 4 toxicities, for both agents
[59–65]. Treatment therefore is often determined by institutional pref-
erence. However, in 2016, a Cochrane Review including over 600 pa-
tients in 7 randomized controlled trials showed Act-D appeared to be
superior to MTX (RR 0.65, 95%CI 0.57–0.75) [59]. Alternative single
drug options for low-risk GTN include etoposide or fluorouracil
[66,67], though these are not typically used outside of Asia.
Women with low-risk GTN with scores 5 or 6 are a particularly chal-
lenging group with only approximately 30% responding to single agent
chemotherapy [68]. A recent multicenter retrospective study identified
predictors of single agent resistance. In the study approximately 60% of
patients achieved complete remission after first or second line single
Table 5
Single-agent regimens for low-risk gestational trophoblastic neoplasia (59–65).
Methotrexate Regimens Primary remission rates
Weekly IM 30–50 mg/m2 49–74%
Multi-day every 2 weeks
5-day IV or IM 0.3–0.5 mg/kg 87–93%
8-day IV or IM 1 mg/kg on days 1,3,5,7⁎ 74–90%
8-day IM 50 mg on days 1,3, 5, 7⁎ 70–80%
High dose IV⁎⁎ 69–90%
100 mg/m2 over 30 min
200 mg/m2 over 12 h
Dactinomycin Regimens⁎⁎⁎
Pulse 1.25 mg/m2 IV every 2 weeks
5- day 10–12 micrograms IV every 5 days
⁎ Leucovorin 15 mg PO on days 2, 4, 6,8.
⁎⁎ Leucovorin 15 mg PO every 12 h × 6 doses beginning 24 h after starting MTX.
⁎⁎⁎ Maximum dose 2 mg (2000 micrograms).
agent therapy. All women with metastatic choriocarcinoma needed
multi-agent chemotherapy. For those without metastases or choriocar-
cinoma, and hCG was >410,000 IU/L and for those patients with metas-
tases or choriocarcinoma and hCG >150,000 IU/L combination
chemotherapy was also necessary to obtain remission [69].
After complete remission is obtained, consolidation therapy, using
the last effective regimen should be delivered to prevent relapses.
Lybol and colleagues showed that 3 rather than 2 cycles of consolidation
decreased the risk of relapse (4 vs 8%) [70]. The chemotherapy cycle de-
livered at first hCG normalization is considered the first consolidation
cycle.
Survival for women with low-risk GTN is excellent with rates ap-
proaching 100%. To achieve this high rate of success, additional chemo-
therapy regimens or surgical intervention may be necessary. Patients
can have primary resistant disease (rising hCG after two cycles of treat-
ment or hCG plateau (<10% change) over three cycles) or may develop
acquired resistance (hCG plateau over two course or rising hCG over
2 weeks after an initial response) [2]. New areas of metastases would
also qualify as resistance/progression. Depending upon the hCG level
at the time of resistance or if toxicity prevents adequate dosing/sched-
ule, switching to the alternate single agent (ActD or MTX) or other sin-
gle agent chemotherapy such as Carboplatin should be considered
[71,72]. If there is an inadequate response to the initial single agent,if
there are new metastases, and/or if hCG plateaus at a high level
(>3000 IU/L), then multi-agent chemotherapy regimens should be em-
ployed [2]. Additionally, for those with resistant disease, hysterectomy
or resection of persistent metastatic disease could be considered, espe-
cially for those who no longer desire to preserve their fertility [41,73].
Second dilation and curettage has been investigated as an alterna-
tive to chemotherapy for low-risk GTN. In appropriately selected pa-
tients, approximately 40% of patients are cured, avoiding toxicity of
chemotherapy altogether [74]. Although the ideal candidate for attempt
at second curettage could not be easily defined, patients at extremes of
reproductive age and those with WHO score of 5 or 6 were less likely to
respond to second curettage. Similarly, for those women with stage I
low-risk GTN who are done with child bearing, hysterectomy, with or
without a single dose of Act-D at the time of surgery, offers an excellent
cure rate [41 73].
Monitoring hCG during treatment should occur on a weekly basis or
with day 1 of each cycle, both are acceptable. Although consolidation
chemotherapy starts with the first normal hCG, remission is defined as
three consecutive normal hCG. Posttreatment surveillance consists of
69–90% monthly hCG for one year. In a recent population-based cohort study,
77–94% 73% of recurrences occurred within 1 year of remission and the risk of
recurrence beyond this was <1% per year [75]. If new symptoms such
as vaginal bleeding develop after the year of surveillance, recurrence
needs to be considered and hCG evaluated.

4
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al. Gynecologic Oncology xxx (xxxx) xxx

1.6. High-risk GTN regimen, TE/TP (paclitaxel and etoposide alternating weekly with pacli-
taxel and cisplatin), with a 70% cure rate, in patients who were
The management of patients with high-risk metastatic or recurrent etoposide and platinum naïve, and reduced hematologic adverse events
GTN remains a clinically difficult scenario. In an effort to cure patients [82]. Alternate salvage treatment programs, with response rates of
with high-risk disease, and salvage those with persistent/recurrent 20–75% are listed in Table 6 80, 83. Uniformly these multi-agent regi-
GTN, several multi-agent chemotherapy regimens have been identified mens have significant hematologic toxicity. Administering granulocyte
(Table 6) [76–83]. However, given the low prevalence of the disease, it is colony stimulating factors (G-CSF) as primary prophylaxis can decrease
unclear which multi-agent regimen is most effective and least toxic, as morbidity, treatment delays and dose reductions [84]. Given the signif-
randomized controlled trials have not been conducted. icant chemosensitivity of GTN, the prognosis for women with stage II or
Developed at Charing Cross in 1979, EMA-CO has become the pre- III high-risk disease remains very good with approximately 70–80%
ferred regimen in the management of patients with high-risk disease achieving complete remission with primary therapy and another
[77]. In a report of 272 consecutive women with high-risk GTN, the cu- 10–15% cured with additional lines of chemotherapy or surgery [77,80].
mulative 5-year survival rate was 86.2%. This was more efficacious in
the chemotherapy naïve population. Seventy-eight percent achieved 1.7. Ultra high-risk disease
complete remission with EMA-CO, 17% developed drug resistance of
whom 70% were salvaged with other chemotherapy, while 11 patients For those patients with ultra high-risk disease (WHO score > 12),
(4%) experienced early deaths [78]. Many other groups have shown experts advocate using induction chemotherapy to reduce the risk of
similar responses to this multi-drug regimen [76,77]. As with low-risk life-threatening complications, predominantly hemorrhage from meta-
disease, chemotherapy for high-risk disease is continued for at least 3 static implants. The use of an induction regimen, with combination low
consolidation courses after the first hCG normalization [76,77]. dose etoposide and cisplatin (EP on days 1 and 2, weekly x 2–3 weeks),
Despite the established efficacy of the EMA-CO regimen, approxi- has been shown to significantly reduce the risk of early death, as re-
mately 30% of women will develop resistance, or experience relapse ported in the Charing Cross experience [58]. When patients present
after remission, necessitating salvage chemotherapy [80]. In these pa- with central nervous system metastatic lesions, in addition to low-
tients, alternate regimens containing etoposide and platinum, with or dose induction EP, the MTX dose in the EMA-CO or EMA-EP regimen
without surgical resection, can usually affect cure. In EMA-CO failures, should be increased to 1 g/m2. Intrathecal (IT) methotrexate
the most commonly employed regimen is EMA-EP (substituting (12.5 mg) can be considered and is typically administered during the
etoposide and cisplatin for cyclophosphamide and vincristine in the CO or EP portion of the multi-agent regimens. Survival rates of 80–85%
EMA-CO regimen), with cure rates ranging from 66 to 85% [79,81]. In have been reported with these regimens and IT MTX [85,86]. Further-
an effort to mitigate the significant hematologic toxicity encountered more, there may be utility to gamma-knife, stereotactic radiotherapy,
using EMA-EP, investigators have also examined a taxane containing and surgical resection to control CNS disease. Whole-brain radiation is
controversial given the long- term cognitive toxicities. For these ultra
high-risk patients, consolidation with 3–4 cycles of therapy should be
Table 6 considered.
Salvage chemotherapy regimens for high-risk, persistent/recurrent, or refractory GTN
(76–83, 87,89, 90).
Active areas of investigation include the utilization of high-dose che-
motherapy (HDC), with stem cell support and use of immune check-
1. EMA-CO - Etoposide with methotrexate, actinomycin D (EMA) and vincristine point inhibitors. Prior investigators have shown sustained complete
and cyclophosphamide (CO)
responses to high-dose chemotherapy with stem cell support in pa-
Day 1 Etoposide 100 mg/m2 IV bolus tients with disease refractory to multiagent regimens. In a review of
Actinomycin-D 500 μg IV push 32 patients treated with HDC at 2 referral centers, 41% (N = 13)
Methotrexate 100 mg/m2 IV push
remained disease free after HDC with or without additional treatment
200 mg/m2 IV over 12 h
Day 2⁎ Actinomycin-D 500 μg IV push [87]. All patients who survived had hCG values ≤12 IU/L before HDC.
Etoposide 100 mg/m2 IV bolus In an effort to capitalize on elevated programmed death ligand
Leucovorin 15 mg PO q 12 h 1 (PD-L1) expression levels identified in GTN specimens [88], use of sin-
Day 8 Vincristine 1.0 mg/m2 gle agent pembrolizumab has been explored. In a small cohort of 4 pre-
Cyclophosphamide 600 mg/m2
viously treated patients (2 with choriocarcinoma and 2 with placental
2. EMA-EP – Etoposide, methotrexate, actinomycin-D, and cisplatin site trophoblastic tumor), 3 experienced durable remissions with single
Day 1 Etoposide 100 mg/m2 IV bolus
agent pembrolizumab, highlighting the potential utility of immunother-
Actinomycin-D 500 μg IV push apy in these disease settings [89]. Furthermore, in a recent small phase II
Methotrexate 100 mg/m2 IV push study, avelumab was shown to cure 8 out of 15 women (53%) with low-
200 mg/m2 IV over 12 h risk GTN whose disease progressed after first line therapy with MTX or
Day 2⁎ Actinomycin-D 500 μg IV push
ActD with minimal and mild toxicity. Importantly, there was also one
Etoposide 100 mg/m2 IV bolus
Leucovorin 15 mg PO q 12 h documented pregnancy after avelumab treatment [90]. The DART trial
Day 8 Etoposide 150 mg/m2 IV bolus (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors;
Cisplatin 75 mg/m2 IV bolus NCT02834013) is currently examining the utility of dual agent immuno-
3. TE-TP – Paclitaxel + etoposide alternating Paclitaxel + cisplatin therapy in patients with recurrent GTN.
4. ACE – Actinomycin-D, cisplatin, etoposide
5. VIP – Etoposide, ifosphamide cisplatin 1.8. Surgery
6. BEP – Bleomycin, etoposide, cisplatin
7. ICE – Ifosphamide, carboplatin, etoposide
8 Gemcitabine
Despite therapeutic advances and approaches, the importance of
9. Capcetabine or 5 FU containing regimen such as FAEV – floxuridine, surgery in the management of GTN should not be over looked. Hysterec-
dactinomycin, etoposide, and vincristine tomy as well as resection of oligometastatic extra-uterine disease plays
10. Liposomal doxorubicin an important role in the management of those with isolated
11. High dose chemotherapy with stem cell support
chemoresistant disease or those with uterine confined disease who no
12. Immune check point inhibitors
longer desire to preserve fertility [91,92]. Furthermore, salvage hyster-
Methotrexate dose increased to 1 g/m2 if brain metastases.
ectomy, rather than use of multi-agent chemotherapy, should be con-
⁎ Some centers omit day 2 etoposide, Act-D.
sidered in patients with evidence of persistent uterine disease despite

5
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al.
single agent chemotherapy [41,73]. Surgery may also be necessary to
deal with disease-related hemorrhage complications when emboliza-
tion is not available or has failed.
1.9. PSTT/ETT
Given that PSTT and ETT arise from intermediate trophoblast, it is
not surprising that these histologies behave similarly to each other but
are different clinically from other GTN and therefore have unique man-
agement. [56,57]. Surgery is the mainstay of treatment for these dis-
eases and consists of hysterectomy with lymphadenctomy reserved
for those with grossly enlarged lymph nodes [93]. There are case reports
of local uterine resection with preservation of fertility [94]. Although
they are not chemotherapy resistant, compared to choriocarcinoma or
post-molar GTN, they are not as sensitive. First line treatment with
multi-agent regimens like EMA-CO or EMA-EP is often reserved for
those that present with advanced stage disease or have ≥48 months
from the antecedent pregnancy [56,57]. These risk factors are the
same for both PSTT and ETT. A relatively new entity, atypical placental
site nodule (APSN), has been associated with concurrent PSTT/ETT or
the development of PSTT/ETT within 16 months of diagnosis in approx-
imately 10–15% of cases. This is based on small numbers but suggests
patients with APSN should have a thorough clinical evaluation and con-
sider hysterectomy. Larger series and longer follow up is necessary
however in order to best counsel patients [95].
1.10. Survivorship issues
The majority of women with molar pregnancies or GTN will be cured
with treatment, and counseling regarding future pregnancies is critical.
History of GTN or use of single agent chemotherapy has not been asso-
ciated with an increased risk of infertility and patients can expect nor-
mal reproductive function [96]. Use of multi-agent chemotherapy
however, was shown to induce early menopause (<45 years) in ap-
proximately 35% of women and this risk increased with increasing age
at the start of treatment [97]. In women who subsequently become
pregnant after molar pregnancy or treatment for GTN, there are good
data to reassure them that the rate of live births, and other pregnancy
outcomes such as spontaneous abortions and obstetrical complications,
are no different than the general population, regardless of whether or
not chemotherapy was administered [6]. The one difference is the risk
of a second molar pregnancy [98]. When patients subsequently
conceive, obtaining an early ultrasound in the first trimester to confirm
a non-molar pregnancy is recommended. Additionally, hCG should be
measured approximately 6–8 weeks after the completion of any gesta-
tional event (miscarriage, ectopic, term pregnancy) to ensure that it has
normalized and to exclude the development of choriocarcinoma.
Though the risk of non-molar GTN is incredibly small, an hCG evaluation
is a simple, inexpensive, and relatively non-invasive test to insure this
has not developed Examination of the placenta can be considered but
is not mandatory [2].
In an analysis of approximately 1900 patients and over 32,000
person-years of follow up, Savage and his colleagues showed that
MTX carried no substantial long- term risk of secondary malignancies.
Even after EMA-CO or other alkylating agent containing regimens, the
risk of secondary malignancies such as leukemia was minimally
increased and was associated with prolonged exposure [97].
1.11. Recommendations
Women with presumed hydatidiform mole should undergo evacua-
tion with suction curettage and ultrasound guidance if necessary.
Uterotonics should be administered after evacuation. Given the in-
creased risk of GTN, hysterectomy is an acceptable alternative in
women with risk factors for GTN, ≥40 years old or those who have
6
Gynecologic Oncology xxx (xxxx) xxx
completed child bearing. Medically induced evacuations of known
molar pregnancies should be avoided. (Level II-2).
Weekly hCG monitoring is recommended after evacuation of a com-
plete (CM) or partial mole (PM). Once hCG normalization is achieved,
hCG follow up should continue until 3 months after CM and 1 month
after PM. (Level I).
Patients who meet criteria for GTN (Table 1) must undergo staging
per FIGO and WHO Prognostic Scoring System. Staging should include
physical exam, serum hCG (from diagnosis of GTN not the initial hCG
value at the time of molar pregnancy diagnosis), pelvic ultrasound,
and chest x-ray. For those with vaginal metastases or pulmonary metas-
tases on chest x-ray, a CT of the chest, abdomen, pelvis and a brain MRI
should be obtained. (Level II-2).
Either single agent multi-day MTX or bolus Act-D is recommended
for treatment of low-risk GTN. Second curettage is an acceptable alter-
native for those wishing to avoid chemotherapy. (Level I and II-1).
For patients with low-risk GTN who develop resistance to or relapse
after single agent chemotherapy treatment with the alternative single
agent (if hCG ≤3000 IU/L) or with EMA-CO (if hCG >3000 IU/L) is rec-
ommended. (Level II-3).
Hysterectomy should be considered for those with stage I choriocar-
cinoma or invasive mole who no longer desire fertility preservation.
Hysterectomy should also be considered as management of complete
mole for women aged 40–49 with an initial hCG > 175,000 IU/L or
age ≥ 50 with any hCG value. Furthermore, for women with GTN, a
dose of single agent chemotherapy at the time of hysterectomy should
be administered to treat occult metastases. (Level II-2).
For patients with high-risk GTN, EMA-CO is the recommended first
line treatment while those with ultra high-risk GTN should receive in-
duction low dose EP followed by either EMA-CO or EMA-EP. (Level I
and II-1).
For those patients with brain metastases, the MTX dose should be in-
creased to 1 g /m2. Other treatments to consider include neurosurgical
consultation, radiation, and intrathecal MTX. (Level II-2).
G-CSF primary prophylaxis should be used in etoposide and plati-
num containing regimens and as needed to maintain treatment sched-
ule and dose intensity of other regimens. (Level II-2).
For those whose disease is resistant to or relapses after multi-agent
chemotherapy consider consultation or referral to a high volume tro-
phoblastic disease center. Management for these women should include
surgery, when appropriate, and salvage chemotherapy including
immune checkpoint inhibitors or high dose chemotherapy with stem
cell transplant, in selected patients. (Level II-3).
Three cycles of consolidation chemotherapy, consisting of the last
effective regimen, should be given after normalization of the hCG
(Level II-2).
Surveillance for low and high-risk GTN should consist of monthly
hCG x 12 months after completion of consolidation chemotherapy. Fur-
thermore, for patients with ultra high-risk disease hCG x 24 months
after completion of chemotherapy is recommended. (Level II-3).
For patients with presumed stage I PSTT and ETT hysterectomy with
removal of suspicious lymph nodes, and cytoreduction for those with
metastatic disease, should be performed. Furthermore, chemotherapy
with EMA-EP should be administered to those diagnosed with advanced
stage disease or diagnosis ≥48 months from antecedent pregnancy.
(Level II-3).
For those with persistent low level hCG (< 200 IU/L), non-
gestational tumors, false positive hCG, and pituitary hCG should be ex-
cluded by measuring hCG on a different assay and in the urine, by
obtaining a CT of chest, abdomen, pelvis and a brain MRI with pituitary
views, checking menopausal hormones, and trialing high dose oral con-
traceptive pills or GnRH agonist. (Level II-3).
For women with a history of GTD, a first trimester ultrasound should
be performed and a hCG should be assessed 6–8 weeks after conclusion
of any pregnancy event. Examination of the placenta can be considered
but is not mandatory. (Level II-3).
N.S. Horowitz, R.N. Eskander, M.R. Adelman et al.
Author contributions
Dr. Neil Horowitz developed the practice statement outline, contrib-
uted to the practice statement, reviewed and edited the final draft.
Drs. Ramez Eskander and Marisa Adelman contributed to the prac-
tice statement and reviewed the final draft.
Dr. William Burke reviewed the outline, practice statement draft and
oversaw the practice statement development.
Declaration of Competing Interest
Dr. Burke reports other from Titan Medical, outside the submitted
work.
Dr. Adelman reports personal fees from AbbVie, outside the submit-
ted work.
Dr. Horowitz reports personal fees from Up to Date, outside the
submitted work.
Dr. Eskander reports other from AstraZeneca, other from Clovis
Oncology, other from Eisai, outside the submitted work.
Acknowledgements
Dr. Horowitz's research is supported by the Donald P. Goldstein,
M.D. Trophoblastic Tumor Registry Endowment and The Dyett Family
Trophoblastic Disease Research and Registry Endowment. These
endowments had no direct role in the generation of the data or the
manuscript.
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