Key words
guideline - trophoblastic disease - trophoblastic neoplasia - molar pregnancy - choriocarcinoma
I Guideline Information
Guidelines program of the DGGG, OEGGG and SGGG
For information on the guidelines program, please refer to the end of the guideline.
Citation format
Gestational and Non-gestational Trophoblastic Neoplasia. Guideline of the DGGG, OEGGG
and SGGG (S2k-Level, AWMF Registry No. 032/049, April 2022). Geburtsh Frauenheilk
2023; 83: 267–288
Guideline documents
The complete long version in German and a slide version of this guideline together
with a list of the conflicts of interest of all of the authors are available on the
homepage of the AWMF
(http://www.awmf.org/leitlinien/detail/ll/032-049.html).
Guideline authors
See [Tables 1] to [4].
Table 1 Lead author and/or coordinating guideline author.
|
Author
|
AWMF professional society
|
|
Prof. Dr. C. Tempfer, Bochum
|
Gynecological Oncology Working Group [Arbeitsgemeinschaft für Gynäkologische Onkologie]
(AGO e. V.) of the German Society for Gynecology and Obstetrics [Deutsche Gesellschaft
für
Gynäkologie und Geburtshilfe] (DGGG) and the German Cancer Society [Deutsche Krebsgesellschaft
e. V.] (DKG)
|
|
Prof. Dr. L.-C. Horn, Leipzig
|
German Pathology Society [Deutsche Gesellschaft für Pathologie e. V.] (DGP)
|
The following professional societies/working groups/organizations/associations stated
that they wished to contribute to the guideline text and participate in the consensus
conference and
nominated representatives to attend the consensus conference ([Table 2]).
Table 2 Representativity of the guideline authors: particiption of target user groups.
|
DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association
|
|
Gynecological Oncology Working Group of the DGGG and DKG [Arbeitsgemeinschaft für
gynäkologische Onkologie der DGGG und der DKG] (AGO) – Uterus Organ Commission [Organkommission
Uterus]
|
|
Professional Association of Gynecologists [Berufsverband der Frauenärzte e. V.] (BVF)
|
|
German Society for Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie
und Geburtshilfe e. V.] (DGGG)
|
|
German Society of Clinical Chemistry and Laboratory Medicine [Deutsche Gesellschaft
für Klinische Chemie und Laboratoriumsmedizin e. V.] (DGKL)
|
|
German Society of Nuclear Medicine [Deutsche Gesellschaft für Nuklearmedizin e. V.]
(DGN)
|
|
German Pathology Society [Deutsche Gesellschaft für Pathologie e. V.] (DGP)
|
|
German Cancer Society [Deutsche Krebsgesellschaft] (DKG)
|
|
Austrian Society for Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie
und Geburtshilfe e. V.] (OEGGG)
|
|
Swiss Society for Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie
und Geburtshilfe] (SGGG)
|
II Guideline Application
Table 3 Representativity of the guideline authors: participation of target patient groups.
|
AWMF/non-AWMF professional society/organization/association
|
|
Federal Association of Womenʼs Self-help After Cancer [Bundesverband Frauenselbsthilfe
nach Krebs e. V.]
|
Table 4 Contributing guideline authors.
|
Author
Mandate holder
|
DGGG working group (AG)/AWMF/non-AWMF professional society/organization/association
|
|
PD Dr. S. Ackermann, Darmstadt
|
Expert
|
|
Prof. Dr. R. Dittrich, Erlangen
|
German Society of Endocrinology [Deutsche Gesellschaft für Endokrinologie] (DGE)
|
|
Dr. J. Einenkel, Leipzig
|
Expert
|
|
Prof. Dr. med. A. Günthert, Luzern
|
Swiss Society for Gynecology and Obstetrics (SGGG)
|
|
Frau H. Haase
|
Federal Association of Womenʼs Self-help After Cancer
|
|
Prof. Dr. med. J. Kratzsch, Leipzig
|
German Society of Clinical Chemistry and Laboratory Medicine (DGKL)
|
|
PD Dr. M. Kreissl, Augsburg
|
German Society of Nuclear Medicine (DGN)
|
|
Prof. Dr. med. S. Polterauer, Wien
|
Austrian Society for Gynecology and Obstetrics (OEGGG)
|
|
Prof. Dr. Dr. A. D. Ebert, Berlin
|
Professional Association of Gynecologists (BVF)
|
|
Prof. Dr. E. Steiner, Rüsselsheim
|
Expert
|
|
Prof. Dr. F. Thiel, Göppingen
|
Expert
|
|
Prof. Dr. Michael Eichbaum, Wiesbaden
|
Expert
|
|
Prof. Dr. Tanja Fehm, Düsseldorf
|
Expert
|
|
Dr. Martin C. Koch, Ansbach
|
Expert
|
|
Dr. Paul Gaß, Erlangen
|
Expert and guidelines secretariat
|
Purpose and objectives
The purpose of this guideline is to provide information and advice to women about
the diagnosis, treatment and follow-up of trophoblastic disease. The focus is on the
differentiated
management of different forms of gestational and non-gestational trophoblastic disease.
In addition, the recommendations of the guideline aim to provide a basis for decision-making
during
interdisciplinary tumor conferences in cancer centers.
Targeted areas of patient care
Inpatient and outpatient care.
Target user groups/target audience
The guideline is aimed at all women with gestational and non-gestational trophoblastic
disease as well as the following medical professionals: gynecologists in private practice,
gynecologists working in hospitals, pathologists, specialists for nuclear medicine,
specialists for laboratory medicine, geneticists, nursing staff, radiologists and
oncologists specializing
in internal medicine.
Adoption and period of validity
The validity of this guideline was confirmed by the executive boards/heads of the
participating professional societies/working groups/organizations/associations as
well as by the board of
the DGGG and the DGGG guidelines commission in February 2022 and was thus approved
in its entirety. This guideline is valid from 1st April 2022 through to 30th March
2023. Because of the
contents of this guideline, this period of validity is only an estimate. The guideline
can be reviewed and updated at an earlier point in time if necessary. If the guideline
still reflects
the current state of knowledge, its period of validity can be extended.
III Methodology
Basic principles
The method used to prepare this guideline was determined by the class to which this
guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective
rules and
requirements for different classes of guidelines. Guidelines are differentiated into
lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined
as consisting of a
set of recommendations for action compiled by a non-representative group of experts.
In 2004, the S2 class was divided into two subclasses: a systematic evidence-based
subclass (S2e) and a
structural consensus-based subclass (S2k). The highest S3 class combines both approaches.
This guideline has been classified as S2k.
Grading of recommendations
The grading of evidence based on the systematic search, selection, evaluation and
synthesis of an evidence base which is then used to grade the recommendations is not
envisaged for S2k
guidelines. The various individual statements and recommendations are only differentiated
by syntax, not by symbols ([Table 5]).
Table 5 Grading of recommendations (based on Lomotan et al., Qual Saf Health Care 2010).
|
Description of binding character
|
Expression
|
|
Strong recommendation with highly binding character
|
must/must not
|
|
Regular recommendation with moderately binding character
|
should/should not
|
|
Open recommendation with limited binding character
|
may/may not
|
Statements
Expositions or explanations of specific facts, circumstances or problems without any
direct recommendations for action included in this guideline are referred to as “statements”.
It is not
possible to provide any information about the level of evidence for these statements.
Achieving consensus and level of consensus
At structured NIH-type consensus-based conferences (S2k/S3 level), authorized participants
attending the session vote on draft statements and recommendations. The process is
as follows. A
recommendation is presented, its contents are discussed, proposed changes are put
forward, and all proposed changes are voted on. If a consensus (> 75% of votes) is
not achieved, there is
another round of discussions, followed by a repeat vote. Finally, the extent of consensus
is determined, based on the number of participants ([Table 6]).
Table 6 Level of consensus based on extent of agreement.
|
Symbol
|
Level of consensus
|
Extent of agreement in percent
|
|
+++
|
Strong consensus
|
> 95% of participants agree
|
|
++
|
Consensus
|
> 75 – 95% of participants agree
|
|
+
|
Majority agreement
|
> 50 – 75% of participants agree
|
|
–
|
No consensus
|
< 51% of participants agree
|
Expert consensus
As the term already indicates, this refers to consensus decisions taken specifically
with regard to recommendations/statements issued without a prior systematic search
of the literature
(S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used
here is synonymous with terms used in other guidelines such as “good clinical practice”
(GCP) or “clinical
consensus point” (CCP). The strength of the recommendation is graded as previously
described in the chapter Grading of recommendations but without the use of symbols; it is only
expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”).
IV Guideline
1 Gestational trophoblastic disease (GTD)
Gestational trophoblastic disease (GTD) includes a cytogenetically and clinically
heterogeneous group of symptoms characterized by disordered differentiation and/or
proliferation of the
trophoblastic epithelium [1], [2]. The morphological classification is based on the World Health Organization (WHO)
classification [3]. GTD is differentiated into villous and non-villous GTD, depending on the presence
of absence of chorionic villi. Villous and non-villous
GTD includes both benign and malignant disease as well as lesions which progress from
benign to malignant, for example, persistent postmolar trophoblastic disease.
|
Consensus-based statement 1.S1
|
|
Expert consensus
|
Level of consensus +++
|
|
The morphological diagnosis and classification of GTD must be based on the most recent
version of the WHO classification.
|
In highly developed industrial nations, the prevalence of hydatidiform moles is reported
to be 1 per 591 pregnancies [4] and the prevalence of GTD is reported
to be 1 per 714 live births [5]. In a population-based Dutch study of 6343 cases with GTD collected over a period
of 20 years (1994 to 2013), the incidence
increased in the first 10 years, followed by stabilization of the incidence of disease.
Overall, the incidence of GTD over a period of 20 years was 1.67 cases/1000 births/year
[6]. An increased incidence of GTD was found in younger (10 – 19 years of age) and older
(40 – 54 years) women and was also correlated with ethnicity. Black
US-American women are over-represented in national registers, and the incidence in
Asian women is double that reported for women of Caucasian descent.
|
Consensus-based statement 1.S2
|
|
Expert consensus
|
Level of consensus +++
|
|
Postoperative staging of malignant GTD (e.g., choriocarcinoma, PSTT, ETT) must follow
the current TNM classification. FIGO staging is optional.
|
The indication for chemotherapy is based on the risk stratification of GTD and must
also be based on the most recent FIGO risk scoring system. This guideline used the
International
Federation of Gynecology and Obstetrics (FIGO) risk scoring system, shown in [Table 7]
[7].
Table 7 International Federation of Gynecology and Obstetrics (FIGO) risk score.
|
Score
|
0
|
1
|
2
|
4
|
|
Assessment: 0 – 4 points → low risk; 5 – 6 points → intermediate risk; ≥ 7 points → high risk
MP = molar pregnancy; TP = term pregnancy; CHXT = chemotherapy; hCG = human chorionic
gonadotropin; GI = gastrointestinal
|
|
Age (years)
|
< 40
|
≥ 40
|
|
|
|
Previous pregnancy
|
MP
|
miscarriage
|
TP
|
|
|
Interval between last pregnancy to initiation of CHXT (months)
|
< 4
|
4 – 6
|
7 – 12
|
> 12
|
|
hCG (IU/l)
|
< 103
|
103–104
|
104–105
|
> 105
|
|
Number of metastases
|
0
|
1 – 4
|
5 – 8
|
> 8
|
|
Site of metastasis
|
lung
|
spleen/kidney
|
GI tract
|
brain, liver
|
|
Largest tumor diameter (cm)
|
|
3 – 5
|
> 5
|
|
|
Previous CHXT
|
|
|
Monotherapy
|
Combination CHXT
|
|
Consensus-based recommendation 1.E1
|
|
Expert consensus
|
Level of consensus +++
|
|
The risk stratification of GTD must be based on the most recent FIGO risk scoring
system.
|
2 Determination of human chorionic gonadotropin (hCG)
In addition to histological confirmation of trophoblastic disease, determination of
serum hCG levels is the most important parameter affecting the choice and duration
of therapy and used to
assess the efficacy of therapy.
|
Consensus-based recommendation 1.E2
|
|
Expert consensus
|
Level of consensus +++
|
|
When determining hCG levels, it is important to use an assay that cross-reacts strongly
with the following six irregular forms of hCG which are specifically produced by GTD:
hyperglycosylated hCG, nicked hyperglycosylated hCG, nicked hyperglycosylated hCG
without the C-terminal peptide, free beta-hCG, nicked free beta-hCG and beta-core
fragment.
|
The reference range limit for hCG measurements is assay-specific and must not be confused
with the assayʼs detection limit (synonyms: sensitivity, lower limit of detection).
In cases of
persistently low hCG levels, before starting treatment it is important to clarify
whether the measured hCG values are above the reference range limit of the assay used
for premenopausal
non-pregnant women. It should also be noted that the reference range limit for postmenopausal
women is slightly higher than that for premenopausal women and is therefore unsuitable
for
premenopausal patients with GTD.
|
Consensus-based recommendation 1.E3
|
|
Expert consensus
|
Level of consensus ++
|
|
If there is a suspicion of false-positive hCG values, findings may be checked using
the following approaches:
-
Test the linearity of the hCG results by diluting the sample or by precipitation with
PEG;
-
Use blocking cannula;
-
Parallel determination of hCG in serum and urine;
-
Compare results with those obtained by a second laboratory which uses an appropriate
but different assay to determine hCG levels.
Monitoring of treatment based on hCG levels must always use the same assay method.
|
The hCG value is considered negative if the measured hCG value is either below the
detection limit of the assay used or within the reference range (normal value) of
the assay for healthy,
non-pregnant premenopausal women (if the patient is premenopausal) or for healthy
postmenopausal women (if the patient is postmenopausal). In exceptional cases, a properly
negative value may
also be slightly higher than the limit of the reference range.
3 Villous GTD
|
Consensus-based statement 1.S3
|
|
Expert consensus
|
Level of consensus +++
|
|
Villous GTD forms include partial moles, hydatidiform moles and invasive moles.
|
|
Consensus-based recommendation 1.E4
|
|
Expert consensus
|
Level of consensus +++
|
|
The term “partial hydatidiform mole” should not be used in the morphological diagnosis/report
on diagnostic findings to describe a partial mole.
|
|
Consensus-based statement 1.S4
|
|
Expert consensus
|
Level of consensus +++
|
|
The goal of treatment for partial moles/hydatidiform moles is complete evacuation
of the trophoblastic material from the uterine cavity.
|
|
Consensus-based recommendation 1.E5
|
|
Expert consensus
|
Level of consensus +
|
|
Suction curettage performed under sonographic control must be used to evacuate the
trophoblastic material from the uterine cavity.
|
|
Consensus-based recommendation 1.E6
|
|
Expert consensus
|
Level of consensus +++
|
|
Units of red cell concentrate must be on hand during curettage of a partial mole/hydatidiform
mole.
|
|
Consensus-based recommendation 1.E7
|
|
Expert consensus
|
Level of consensus +++
|
|
The risk of perforation and bleeding is higher because the uterus is relaxed.
Uterotonic agents may be used in cases with heavy bleeding.
A hysterectomy must only be carried out in cases with life-threatening hemorrhage.
|
|
Consensus-based statement 1.S5
|
|
Expert consensus
|
Level of consensus +++
|
|
No anti-D immunoglobulin is required in cases with partial mole/hydatidiform mole,
as there is no expression of the RhD antigen.
|
|
Consensus-based recommendation 1.E8
|
|
Expert consensus
|
Level of consensus +++
|
|
Because of the risk of developing persistent GTD (0.5 – 4%), regular weekly testing
of serum hCG must be done after a partial mole has been diagnosed until the results for
hCG are negative (i.e., negative hCG levels in at least two consecutive tests).
|
|
Consensus-based recommendation 1.E9
|
|
Expert consensus
|
Level of consensus +++
|
|
Because of the risk of developing persistent GTD (16 – 24%), weekly monitoring of
hCG must be carried out after a hydatidiform mole has been diagnosed.
After the hCG level is found to be negative (at least two consecutive negative hCG
tests), monthly monitoring of hCG must be carried out for at least 6 months after
curettage.
Patients must use hormonal contraceptives. Combined oral preparations may be used.
|
|
Consensus-based recommendation 1.E10
|
|
Expert consensus
|
Level of consensus +++
|
|
In cases of twin molar pregnancy or women older than 45 years or if it takes more
than 8 weeks until the hCG level is negative, monitoring of hCG every three months
should be
carried out for a further 30 months after the hCG level has been found to be negative.
|
3.1 Persistent trophoblastic disease
|
Consensus-based recommendation 1.E11
|
|
Expert consensus
|
Level of consensus +++
|
|
If hCG values are persistently high after curettage and diagnosis of a partial mole/hydatidiform
mole, re-curettage under sonographic control may be carried out to avoid the
necessity of chemotherapy, especially if hCG values are lower than 1000 IU/l. After
repeat diagnosis of a partial mole and re-curettage, weekly monitoring of hCG levels
must be
carried out until the hcG level is found to be negative (i.e., at least 2 consecutive
negative hCG tests).
|
|
Consensus-based recommendation 1.E12
|
|
Expert consensus
|
Level of consensus +++
|
|
Prophylactic chemotherapy must not be administered after curettage of a hydatidiform
mole if hCG levels are decreasing or negative.
|
|
Consensus-based statement 1.S6
|
|
Expert consensus
|
Level of consensus +
|
|
The following criteria must be present for a diagnosis of persistent villous GTD (persistent
postmolar trophoblastic disease):
-
Four or more consecutive hCG tests where results show that hCG levels have plateaued
(cf. chapter 2 for the definition of the term “plateau”), or
-
An increase in hCG levels (cf. chapter 2 for the definition of the term “increase”)
over 2 consecutive measurements (Day 0 and Day 7), or
-
persistent hCG levels over a period of 6 months.
|
|
Consensus-based recommendation 1.E13
|
|
Expert consensus
|
Level of consensus ++
|
|
If the criteria for a diagnosis of persistent villous GTD are present, in addition
to a gynecological examination with palpation to exclude or detect metastasis, the
following
imaging examinations must be carried out: CT of the thorax and abdomen, transvaginal
ultrasound, MRI of the brain.
FDG-PET/CT may be carried out if diagnostic imaging is suspicious for metastasis.
|
|
Consensus-based recommendation 1.E14
|
|
Expert consensus
|
Level of consensus +++
|
|
Chemotherapy must be administered (unless there is an option of carrying out re-curettage)
if persistent villous GTD is diagnosed.
|
3.2 Chemotherapy for low and intermediate risk GTD
|
Consensus-based recommendation 1.E15
|
|
Expert consensus
|
Level of consensus ++
|
|
The drug of choice for low-risk cases (FIGO score < 5; cf. [Table 7]) is methotrexate 50 mg administered by IM injection on days
1, 3, 5, 7 with folic acid 15 mg administered PO on days 2, 4, 6, 8 (cf. Table 15
in the long version). If the patient develops methotrexate resistance (increase or
plateauing of
hCG levels – for definitions, cf. chapter 1.5 in the long version), treatment must
be switched to actinomycin D therapy (1.25 mg/m2 every 2 weeks) or
polychemotherapy (EMA/CO regimen) (cf. Tables 15 and 16 in the long version).
|
|
Consensus-based recommendation 1.E16
|
|
Expert consensus
|
Level of consensus ++
|
|
The drug of choice for cases with intermediate risk (FIGO score 5 – 6; cf. [Table 7]) is methotrexate 50 mg administered by IM injection
on days 1, 3, 5, 7 every 2 weeks and folic acid 15 mg administered PO on days 2, 4,
6, 8 (cf. Table 15 in the long version). However, cases with a FIGO score of 5 – 6
and
simultaneous distant metastasis and/or hCG > 411000 IU/l and/or a diagnosis of choriocarcinoma
must be treated with polychemotherapy (EMA/CO regimen) (cf. Tables 15 und 16 in
the long version).
|
|
Consensus-based recommendation 1.E17
|
|
Expert consensus
|
Level of consensus +++
|
|
If patients are treated with mono-chemotherapy, they must receive 3 consolidation
cycles of mono-chemotherapy after hCG levels are no longer detectable (i.e., at least
three
consecutive weekly measurements of hCG, with hCG levels below the detection limit).
|
|
Consensus-based recommendation 1.E18
|
|
Expert consensus
|
Level of consensus +++
|
|
If hCG levels are no longer detectable after completion of chemotherapy (i.e., at
least three consecutive weekly measurements of hCG, with hCG levels below the detection
limit),
hCG levels must be monitored and measured once a month for one year.
|
3.3 Methotrexate resistance
|
Consensus-based recommendation 1.E19
|
|
Expert consensus
|
Level of consensus +
|
|
The following criteria must be present to diagnose methotrexate resistance:
-
Four or more consecutive hCG tests where results show that hCG levels have plateaued
(cf. chapter 2 for the definition of the term “plateau”), or
-
An increase in hCG levels (cf. chapter 2 for the definition of the term “increase”)
|
|
Consensus-based recommendation 1.E20
|
|
Expert consensus
|
Level of consensus ++
|
|
In patients with chemotherapy resistance, re-staging must be done to search for metastasis
and must include a gynecological examination with palpation, transvaginal ultrasound,
CT of the thorax and abdomen and MRI of the brain.
FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above
diagnostic imaging.
|
|
Consensus-based recommendation 1.E21
|
|
Expert consensus
|
Level of consensus ++
|
|
The treatment of choice for cases with MTX resistance is another mono-chemotherapy
with actinomycin D (1.25 mg/m2 repeated every 2 weeks). Polychemotherapy according
to the EMA-CO regimen may be administered in the event that one of the two mono-chemotherapy
regimens fails or if patients have a FIGO score > 7 at re-staging.
|
|
Consensus-based recommendation 1.E22
|
|
Expert consensus
|
Level of consensus ++
|
|
Polychemotherapy according to the EMA-CO regimen must be administered if both mono-chemotherapy
regimens (MTX and actinomycin D) fail (cf. Table 16 in the long version).
|
|
Consensus-based recommendation 1.E23
|
|
Expert consensus
|
Level of consensus ++
|
|
Platinum-based regimens (BEP/carboplatin + paclitaxel/TP-TE/EMA-EP) must be used if
EMA-CO chemotherapy fails, (cf. Table 16 in the long version).
|
3.4 Chemotherapy for high-risk GTD
|
Consensus-based recommendation 1.E24
|
|
Expert consensus
|
Level of consensus +++
|
|
High-risk cases (FIGO score ≥ 7; [Table 7]) must receive chemotherapy according to the EMA-CO regimen (cf. Table 16 in the
long version).
|
|
Consensus-based statement 1.S7
|
|
Expert consensus
|
Level of consensus +++
|
|
Induction chemotherapy with 1 to 3 cycles of etoposide 100 mg/m2 on days 1 and 2 and cisplatin 20 mg/m2 on days 1 and 2, q7, may reduce early (< 4 weeks
after initiation of therapy) hemorrhage-related mortality of high-risk patients with
a FIGO score > 12.
|
|
Consensus-based recommendation 1.E25
|
|
Expert consensus
|
Level of consensus ++
|
|
During polychemotherapy according to the EMA-CO regimen, hCG levels must be measured
out before the start of each cycle. If hCG levels plateau or increase, the patient
must be
switched to multi-agent therapy with EMA-EP or BEP (cf. Table 16 in the long version).
Alternative treatments are the TP-TE regimen or a carboplatin-paclitaxel regimen.
|
|
Consensus-based recommendation 1.E26
|
|
Expert consensus
|
Level of consensus +
|
|
Chemotherapy must be continued until hCG levels are found to be negative (at least
three consecutive weekly measurements of hCG, with hCG levels below the detection
limit).
Failure to complete chemotherapy increases the risk of therapy resistance.
Once negative hCG levels have been achieved, up to three additional EMA-CO chemotherapy
cycles should be administered for consolidation. Consolidation cycles are not recommended
for patients treated with the BEP regimen.
|
|
Consensus-based recommendation 1.E27
|
|
Expert consensus
|
Level of consensus +++
|
|
In patients with chemotherapy resistance, re-staging must be done to search for metastasis
and must include gynecological examination with palpation, transvaginal ultrasound,
CT
of the thorax and abdomen and MRI of the brain. FDG-PET/CT may be carried out if there
is a suspicion of metastasis based on the above diagnostic imaging.
|
|
Consensus-based recommendation 1.E28
|
|
Expert consensus
|
Level of consensus +
|
|
If hCG levels are no longer detectable after the completion of chemotherapy (i.e.,
at least three consecutive weekly measurements of hCG, with hCG levels below the detection
limit), hCG levels must be monitored and measured once a month for one year.
During this period patients must take oral hormonal contraceptives.
Combined oral preparations or progestogen preparations may be used.
|
3.5 Invasive moles
|
Consensus-based recommendation 1.E29
|
|
Expert consensus
|
Level of consensus +++
|
|
Staging is based on CT of the thorax, CT of the abdomen, MRI of the brain, transvaginal
ultrasound and gynecological examination with palpation.
FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above
diagnostic imaging.
|
|
Consensus-based recommendation 1.E30
|
|
Expert consensus
|
Level of consensus ++
|
|
Patients with invasive mole must be treated with chemotherapy. The drug of choice
for low-risk cases (FIGO score < 7; [Table 7]) is
methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 and folic acid 15 mg administered
PO on days 2, 4, 6 (cf. Table 15 in the long version). High-risk
cases (FIGO score ≥ 7; [Table 7]) must receive chemotherapy according to the EMA-CO regimen (cf. Table 16 in the long version).
Chemotherapy may not be necessary for low-risk patients who have undergone hysterectomy.
|
|
Consensus-based statement 1.S8
|
|
Expert consensus
|
Level of consensus +++
|
|
Monitoring of hCG levels during and after therapy is done according to the same standards
used for hydatidiform mole (cf. 1.6.2 in the long version).
|
4 Non-villous GTD
4.1 Placental site nodules (PSN)
|
Consensus-based statement 1.S9
|
|
Expert consensus
|
Level of consensus +++
|
|
Curettage, usually consisting of complete removal of the lesion, is the treatment
of choice for PSN.
|
|
Consensus-based recommendation 1.E31
|
|
Expert consensus
|
Level of consensus +++
|
|
PSN is a benign lesion. Follow-up based on measurement of hCG levels is not required.
|
4.2 Exaggerated placental site (EPS)
|
Consensus-based recommendation 1.E32
|
|
Expert consensus
|
Level of consensus +++
|
|
Isolated EPS without hydatidiform mole must not be treated with chemotherapy. Postoperative
monitoring of hCG levels must only be done if there are clinical indications such
as
persistent vaginal bleeding.
|
|
Consensus-based recommendation 1.E33
|
|
Expert consensus
|
Level of consensus +++
|
|
If EPS is diagnosed in combination with partial mole or hydatidiform mole, follow-up
must adhere to the same standards used for partial mole or hydatidiform mole.
|
4.3 Placental site trophoblastic tumor (PSTT)
|
Consensus-based recommendation 1.E34
|
|
Expert consensus
|
Level of consensus +++
|
|
A simple hysterectomy must be carried out if PSTT is diagnosed in the curettage material.
|
|
Consensus-based recommendation 1.E35
|
|
Expert consensus
|
Level of consensus +++
|
|
In addition to gynecological examination with palpation, the following diagnostic
imaging is necessary to detect or exclude metastasis: CT of the thorax and abdomen,
transvaginal ultrasound, MRI of the brain.
FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above
diagnostic imaging.
|
|
Consensus-based recommendation 1.E36
|
|
Expert consensus
|
Level of consensus +++
|
|
Chemotherapy is necessary to treat FIGO stages II to IV and should consist of either
the EMA-CO regimen (cf. Table 16 in the long version) or the EP/EMA regimen (cf. Table
16 in
the long version). The BEP regimen may be used if the EMA-CO and EP/EMA regimens are
unsuccessful.
|
|
Consensus-based recommendation 1.E37
|
|
Expert consensus
|
Level of consensus +++
|
|
It is important to differentiate PSTT from EPS. Before deciding on a hysterectomy,
the opinion of a second pathologist should be obtained for premenopausal patients
wanting to
have children.
|
|
Consensus-based recommendation 1.E38
|
|
Expert consensus
|
Level of consensus +++
|
|
If hCG levels are no longer detectable after the completion of chemotherapy (at least
three consecutive weekly measurements of hCG, with hCG levels below the detection
limit),
hCG levels must be monitored and measured once a month for one year.
|
4.4 Epithelioid trophoblastic tumor (ETT)
|
Consensus-based statement 1.S10
|
|
Expert consensus
|
Level of consensus +++
|
|
Hysterectomy is the treatment of choice for ETT. As with PSTT, polychemotherapy is
indicated if metastasis is present at the initial diagnosis of ETT.
|
|
Consensus-based recommendation 1.E39
|
|
Expert consensus
|
Level of consensus +++
|
|
If hCG levels are no longer detectable after the completion of chemotherapy (i.e.,
at least three consecutive weekly measurements of hCG, with hCG levels below the detection
limit), hCG levels must be monitored and measured once a month for one year.
|
4.5 Choriocarcinoma (CCA)
|
Consensus-based recommendation 1.E40
|
|
Expert consensus
|
Level of consensus ++
|
|
As with hydatidiform mole, suction curettage under sonographic control must be carried
out if there is a suspicion of choriocarcinoma.
|
|
Consensus-based recommendation 1.E41
|
|
Expert consensus
|
Level of consensus +++
|
|
Units of red cell concentrate must be on hand during curettage.
|
|
Consensus-based recommendation 1.E42
|
|
Expert consensus
|
Level of consensus +++
|
|
Staging after histological confirmation of choriocarcinoma is based on gynecological
examination with palpation, transvaginal ultrasound, CT of the thorax and abdomen
and MRI of
the brain.
FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above
diagnostic imaging.
|
|
Consensus-based recommendation 1.E43
|
|
Expert consensus
|
Level of consensus ++
|
|
Chemotherapy must be carried out after histological confirmation of choriocarcinoma. The drug of choice for low-risk cases with a FIGO score < 5 (cf. [Table 7]) is methotrexate 50 mg administered by IM injection on days 1, 3, 5, 7 and folic acid 15 mg administered
PO on days 2, 4, 6 (cf. Table
15 in the long version). If the patient develops methotrexate resistance (increase
or plateauing; see chapter 2 for the definition of hCG plateau), treatment should
be switched
to actinomycin D therapy or polychemotherapy (cf. Table 15 and 16 in the long version).
|
|
Consensus-based recommendation 1.E44
|
|
Expert consensus
|
Level of consensus ++
|
|
Chemotherapy must be carried out after histological confirmation of choriocarcinoma.
The treatment of choice for intermediate-risk cases (FIGO score 5 or 6; cf. [Table 7]) is polychemotherapy using the EMA-CO regimen (cf. Table 16 in the long version).
|
|
Consensus-based recommendation 1.E45
|
|
Expert consensus
|
Level of consensus +++
|
|
Treatment for high-risk patients (FIGO score ≥ 7; [Table 7]) must consist of chemotherapy using the EMA-CO regimen (cf. Table 16 in
the long version).
|
|
Consensus-based statement 1.S11
|
|
Expert consensus
|
Level of consensus +++
|
|
Induction chemotherapy consisting of 1 to 3 cycles of etoposide 100 mg/m2 on days 1 and 2, q7, and cisplatin 20 mg/m2 on days 1 and 2, q7, may reduce early
(< 4 weeks after initiation of therapy) hemorrhage-related mortality of high-risk
patients with a WHO score > 12 ([Table 7]).
|
|
Consensus-based recommendation 1.E46
|
|
Expert consensus
|
Level of consensus +++
|
|
Re-staging to search for metastasis must be done if the patient develops chemotherapy
resistance, with re-staging based on gynecological examination with palpation, transvaginal
ultrasound, CT of the thorax and abdomen and MRI of the brain.
FDG-PET/CT may be carried out if there is a suspicion of metastasis based on the above
diagnostic imaging.
|
|
Consensus-based recommendation 1.E47
|
|
Expert consensus
|
Level of consensus +++
|
|
Chemotherapy must be continued until hCG levels are negative (at least three consecutive
weekly measurements of hCG, with hCG levels below the detection limit). Failure to
complete chemotherapy increases the risk of therapy resistance. Once negative hCG
levels have been achieved, up to three additional EMA-CO chemotherapy cycles should
be
administered for consolidation. Consolidation cycles are not recommended for patients
treated with the EMA-EP or BEP regimen.
|
|
Consensus-based recommendation 1.E48
|
|
Expert consensus
|
Level of consensus +++
|
|
After the completion of therapy, hCG levels levels must be monitored and measured
once a month for one year.
|
4.6 Multiple pregnancy and GTD
Cases of multiple pregnancy with GTD and one healthy twin have been reported in the
literature. In a series of 77 cases with hydatidiform mole and one healthy twin, the
pregnancy was
terminated in 24 cases [8]. Of the 53 women who continued their pregnancy, 23 had a spontaneous miscarriage
and two developed severe preeclampsia with
subsequent termination of the pregnancy. Twenty-four of the remaining 28 women had
a live birth. Irrespective of the pregnancy outcome, 15/77 women had chemotherapy
for persistent
trophoblastic disease. Lin et al. reported on 72 cases with complete mole and a healthy
co-twin [9]. Ten pregnancies were terminated, 35/62 cases had a live
birth. The rate of postoperative or postpartum gestational trophoblastic neoplasia
(GTN) was 46%. In a review of the literature, Suksai et al. identified a total of
204 cases in the
literature of complete mole with a second fetus. The live birth rate was 78/204 (38%).
Low hCG levels were a predictor for live birth [10].
Zilberman et al. (14 studies; n = 244; complete hydatidiform mole + normal fetus)
calculated a maternal rate of complications of 80%, a live birth rate of 50% and a
rate of subsequent GTN
of 34% [11].
5 Immunotherapy
GTD shows a high expression of the transmembrane protein programmed cell death-ligand
1 (PD-L1), which binds to the T-cell inhibitory receptor (programmed death protein
1 [PD-1]). Treatment
with the immune checkpoint inhibitor pembrolizumab, a monoclonal antibody which binds
to the PD-1 receptor, was investigated in patients with chemotherapy-resistant GTD
[12]. A total of four patients with chemotherapy resistance after several lines of combination
chemotherapy were treated with pembrolizumab 2 mg/kg every 3 weeks.
After remission was achieved, patients received a further five consolidation cycles.
Therapy was well tolerated. Complete remission was observed in three of four patients
after the end of
therapy, and remission persisted for between five and 24 months after completion of
therapy. A recent review of seven patients with previously treated, chemotherapy-resistant
GTD found that
6/7 patients responded to immunotherapy with pembrolizumab. A complete response was
observed in five patients [13]. Other case studies have reported similar
successes in patients, some of whom had extensive prior treatment. A single-arm prospective
study investigated the use of the PD-L1 antibody avelumab in patients with low-risk
GTN after
previous mono-chemotherapy with MTX. Patients were given avelumab 10 mg/kg every two
weeks until hCG levels had normalized, followed by three consolidation cycles. 8/15
patients had a
complete response to therapy [14].
6 Pregnancy After GTD
Pregnancy after GTD is possible and is not associated with an unfavorable maternal,
fetal or neonatal prognosis. It should be noted that there is a risk of recurrence.
Gadducci et al.
specifically calculated the risk of recurrence of GTD as 0.7 to 2.6% after a previous
instance of GTD and as 10% after two GTDs [15]. The live birth rate of
women with a history of GTD is 75%. There is no increase in the rate of congenital
malformations (1.8%); however, there may a slightly higher risk of intrauterine fetal
death [16]. In a systematic review of 18 studies on fertility after GTD, Garcia et al. reported
that there was no evidence for a lower fertility after GTD, but there was
a higher risk of miscarriage for pregnancies occurring less than six months after
the completion of GTD therapy and a higher risk of intrauterine fetal death [17].
Once patients have completed chemotherapy for GTD, the issue of potential long-term
side effects on fertility must be considered. This issue is compounded by the possibility
of a second
malignancy caused by the treatment. The review by Gaducci et al. reported a higher
risk of myeloid leukemia, which increased depending on the cumulative dose of etoposide
[18]. The genotoxicity of MTX and EMA-CO is low. In an analysis of 12 women treated with
MTX and 34 women treated with EMA-CO, 12/12 (100%) and 32/34 (97%) women,
respectively, had regular menstrual cycles after completion of chemotherapy [19].
7 Evaluation of Specimens
|
Consensus-based recommendation 4.E49
|
|
Expert consensus
|
Level of consensus +++
|
|
The report on findings must include the type of GTD.
|
|
Consensus-based recommendation 4.E50
|
|
Expert consensus
|
Level of consensus +++
|
|
The morphological diagnostic workup must ensure that alle therapeutically and prognostically
relevant parameters are ascertained. Findings must be reported according to the valid
WHO classification of tumors, the current TNM staging system and the R classification
(UICC).
|
|
Consensus-based recommendation 4.E51
|
|
Expert consensus
|
Level of consensus +++
|
|
The findings report for a hysterectomy carried out for GTD must including the following
information:
-
Type of GTD according to the WHO classification
-
Presence/absence of lymph node or vascular invasion (L- and V-status)
-
Presence/absence of perineural invasion (Pn-status)
-
Staging (pTNM and FIGO)
-
Three-dimensional tumor size in cm3
-
Minimal distance to vaginal margin in cm, if relevant
-
R classification (UICC)
|
8 Information for Patients
|
Consensus-based recommendation 5.E52
|
|
Expert consensus
|
Level of consensus +++
|
|
When appropriate relevant sources (print or internet media) are used to inform patients,
the information should be compiled in accordance with defined quality criteria for
healthcare information. The information should be provided to patients to support
them to make self-determined decisions for or against medical measures by communicating
the risks
in a generally understandable form (e.g., information about the reduction of absolute
risk).
|
|
Consensus-based recommendation 5.E53
|
|
Expert consensus
|
Level of consensus +++
|
|
The patient must be offered the option of including her partner or family members
in talks or discussions.
|
|
Consensus-based recommendation 5.E54
|
|
Expert consensus
|
Level of consensus +++
|
|
The patientʼs individual preferences, requirements, worries and anxieties must be
identified during the talk with the doctor and taken into account. If the patient
requires
several discussions for this, she must be offered the opportunity to have more discussions.
|
|
Consensus-based recommendation 5.E55
|
|
Expert consensus
|
Level of consensus +++
|
|
The patient should be offered psychosocial and psycho-oncological support for psychological
and sexual problems and problems with her partner.
|
|
Consensus-based recommendation 5.E56
|
|
Expert consensus
|
Level of consensus +++
|
|
Medical-oncological rehabilitation is designed specifically to treat disorders which
arise subsequent to the disease and its treatment. All patients must be informed and
advised
about their statutory options to apply for and make use of rehabilitation measures.
|
