Referat II

MANAGEMENT OF RECURRENT
GESTATIONAL TROPHOBLAST TUMORS
By:
Dr Nahrisyah Ulfa Safna

Supervisor:
Dr H Patiyus Agustiansyah, SpOG(K)-
Onk, MARS
Moderator:
Dr Hj Hartati, SpOG(K)-Obginsos, Mkes

Assesor: Opponent:
Dr H Azhari, SpOG(K)-Obginsos Dr Terry Mutia
Dr H Amir Fauzi, SpOG(K)-Urogin, PhD Dr R Ismail Hadyathma
Dr A Abadi, SpOG(K)-FER Dr Radinal YS Prayitno
Dr H Irawan Sastradinata, SH, SpOG(K)-
Onk, MARS
DR Dr Peby Maulina Lestari, SpOG(K)-KFM
 Outline

Introduction

Literature Review

Conclusion

Reference
INTRODUCTION
 Introduction
Gestational Trophoblastic Disease/ GTD
A group of rare diseases in which abnormal trophoblast cells grow in the uterus
after conception

Hydatidiform mole is the most common type of GTD

Gestational trophoblastic neoplasia (GTN) is a type of gestational

trophoblastic disease that is almost always malignant
 Introduction
Gestational Trophoblastic Disease/ GTD

Hippocrates 400 BC

Marchand discovered an association with pregnancy in 1895

Majority of GTN patients recover with chemotherapy due to chemosensitivity of

these tumors, a small proportion of patients with GTN will relapse after completion
of treatment due to chemoresistant disease
 Introduction
Gestational trophoblastic neoplasia/ GTN
Invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and
trophoblastic epitheloid tumor

single agent chemotherapy with and an overall survival rate

Low risk GTN approaching 100%

High risk GTN multiagen chemotherapy and achieves a survival rate of

around 90%

Correct diagnosis and proper follow-up are important to maximize outcomes in patients with
this disease
Epidemiology

Gestational trophoblast neoplasia is more common in Asia

The prevalence of choriocarcinoma ranges from 2 per

100,000 pregnancies in the United States to 202 per 100,000
pregnancies in China

The risk of additional complete and partial mole increases to

1% to 2%

Approximately 6% to 20% of complete mole and 0.5% to 1% of partial mole, the

disease persists and transforms to GTN, which usually requires chemotherapy
LITERATURE
REVIEW
Definition
Gestational Trophoblastic Disease/ GTD
A group of rare diseases in which abnormal trophoblast cells grow in the uterus after
fertilization

Gestational trophoblastic neoplasia (GTN)

Includes invasive mole, choriocarcinoma, placental site trophoblastic tumor (PSTT) and
trophoblastic epitheloid tumor.

About 25% of GTN tumors will be resistant or will recur after initial chemotherapy
called recurrent GTN or chemoresistence GTN.

The interval between previous pregnancy and chemotherapy> 12 months, the

interval from the first chemotherapy to achieving normalized β-hCG> 14 weeks
were known predictors of GTN recurrence.
Classification

Gestational Trophoblastic All forms and classifications of hydatidiform mole

Disease (complete and partial hydatidiform mole), invasive mole,

Invasive mole, choriocarcinoma, placental site trophoblastic

Neoplasia Trofoblas tumor, epitheloid trophoblastic tumor
Gestasional
Etiology

Placental trophoblast  origins of molar pregnancy and gestational trophoblast

neoplasia

Cytotrophoblasts and syncytiotrophoblasts cause hydatidiform moles and

choriocarcinomas and placental site trophoblastic tumors (PSTT) along with
epithelioid trophoblastic tumors (ETT) from intermediate trophoblasts
Etiology
Complete hydatidiform mole usually occurs when an ovum without a mother's
chromosome was fertilized by a single sperm which then duplicates DNA, resulting in a
46XX androgenetic karyotype, all chromosomes inherited from the father. Approximately
10% complete mole is 46XY, which results from fertilization by two sperm.

Partial hydatidiform mole, especially in the triploid type that arises

from the fertilization of a healthy egg by two sperm
Risk Factor

Age
The risk of GTD increases threefold in women over 50 ages who have a
pregnancy
Ethnic Assians
Asian ethnic women are almost twice as likely to develop GTD

Previous molar pregnancy

Family history of molar pregnancy

Diet Factor
Low carotene intake and animal fats
Patophysiology

Hydatidiform moles and The placental trophoblast tumor site

choriocarcinomas arise from the arises from the interstitial trophoblast
trophoblast villi

Deviated villi structures with trophoblast hyperplasia, tangled villi vessels, and
stromal cariorectic debris
Pathology
Mola Hidatidosa

Complete hydatidiform mole is characterized by diffuse hydropic swelling and trophoblast

hyperplasia (syncytio, cyto, and intermediate trophoblast) on the surface of the chorionic villi 6
Partial hydatidiform mole occurs when ovum with a 23X (2: 1) haploid set of chromosomes is
fertilized by two spermatozoa carrying one of the sex chromosomes
Pathology
Invasive Mola

Hydatidiform mole which is characterized by the presence of enlarged molar villi

that penetrate deep into the myometrium

It is very similar to choriocarcinoma, with the production of secondary metastases

of lesions, especially in the vagina and lungs, but, unlike choriocarcinoma,
invasive moles can spontaneously regress.

Most are diploid but some are aneuploidy

Pathology
Choriocarcinoma /CCA

Invasive malignant neoplasm of the trophoblastic epithelium of the placenta

Microscopically, the neoplasm is composed of a proliferation of avillous invasive

syncytiotrophoblasts and cytotrophoblasts surrounded by necrosis and hemorrhage. An
intermediate trophoblast multinucleated giant cell is present and has an enlarged nucleus
and abnormal mitosis

Trophoblast cells are essentially rapidly dividing and invasive, with direct invasion of the
myometrium and vascular invasion
Pathology
Placental site trophoblast tumor (PSTT)

Microscopically as trophoblast infiltration is limited to the endometrium and

myometrium where the placenta implants.

It consists of sheets of intermediate trophoblast cells, with lesions of low or high grade malignancy

PSTT is characterized by low beta-hCG levels due to neoplastic intermediate trophoblast cell
proliferation.
Diagnose

1. Four or more hCG values ​plateaued for at least 3

Cancer Committee of
weeks
the International
2. Increase in hCG of 10% or greater for 3 or more
Federation of
values ​for at least 2 weeks
Gynecologists and
3. Histological diagnosis of CCA
Obstetricians (FIGO)
4. hCG persisting 6 months after molar evacuation.

1. History and physical examination, baseline (pretreatment)

quantitative serum hCG levels, complete blood and platelet
counts, and liver and kidney function tests
The necessary checks 2. Results of all pathological specimens
3. Pelvic ultrasound, chest X-ray, MRI
4. Additional imaging such as 18F-fluorodeoxyglucose
positron emission tomography (FDG-PET)
Diagnosis

FIGO anatomical staging

Stage 1 Disease confined to the uterus

Stage 2 GTN extends outside the uterus, but is limited to genital
structures (adnexa, vagina, broad ligament)
Stage 3 GTN extends to the lungs with or without known genital tract
involvement
Stage 4 All other metastases
Diagnosis
Modified WHO Prognostic Scoring System is
adopted from FIGO in GTN
Skor 0 1 2 4
Age <40 >40 - -
Antecedent pregnancy mola abortion -
Month interval from the <4 4-6
pregnancy index
Serum hCG sebelum <103 103-104 104-105 >105
pengobatan
The largest tumor size <3 3-4 cm > 5cm -
Metastation location lungs Spleen, kidneys gastrointestinal Brain, liver
Number of metastases - 1-4 5-8 >8
Chemotherapy failed - - single-agent > 2 agent
before chemotherapy chemotherapy
Treatment
Low risk GTN management

Women with low-risk GTN are usually treated with single-agent

chemotherapy, methotrexate (with or without folinic acid) or
Dactinomycin. (table 3)

Tumour resistance to first-line chemotherapy has been reported in up to 45% of

women with low-risk GTN
Treatment
Low risk GTN management

Table 3. Single agent regimen for low risk GTN

Mtx Regimen
1. Mtx: 0.4-0.5 mg / kg IV or IM daily for 5 days
2. Mtx: 30-50 mg / m2 IM every week
3. Mtx / FA
• Mtx 1 mg / kg IM or IV on days 1, 3, 5, 7
• FA 10 mg PO days 2, 4, 6, 8
6. High doses of Mtx / FA
• Mtx 100 mg / m2 IV bolus
• Mtx 200 mg / m2 12 hours infusion
• FA 15 mg setiap 12 hours infusion
• FA 15 mg every 12 hours in 4 doses IM or PO started 24 hours after starting Mtx

Actinomycin D Mtx Regimen

1. actD 10-12 mg / kg IV daily for 5 days
2. actD 1.25 mg / m 2 IV every 2 wk
 TREATMENT
Low-Risk GTN
Higher primary cure rates reported with
the five- and eight-day methotrexate regimens (10% to 33%) than
with weekly low-dose methotrexate. Resistance in low-risk GTN is
more likely to develop when pre-treatment hCG levels are high

A study from Charing Cross hospital (London, UK) found that single-agent
chemotherapy (methotrexate) only cured 30% of low-risk women with hCG levels
greater than 100,000 mIU/mL and was futile in low-risk lesions where hCG levels
were greater than 400,000 mIU/mL
 TREATMENT
• single-agent pulsed dactinomycin (Covens
Low-Risk GTN 2006) (where first line therapy has been
methotrexate);
• five-day dactinomycin (McNeish 2002);
• Etoposide and dactinomycin (EA) (Dobson
When first-line 2000);
chemotherapy fails, • Methotrexate, dactinomycin,
secondary cyclophosphamide (MAC) (Goldstein
chemotherapy, with or 2012);
without surgery, is • Etoposide, methotrexate,
used to achieve dactinomycin/cyclophosphamide,
remission. vincristine (EMA/CO) (McNeish 2002).
Treatment
High risk management of GTN

Women with high-risk GTN (FIGO Stage IV and Stage II-III, score> 6) are at a higher risk of
first-line treatment failure and therefore require multi-agent combination chemotherapy (with
or without adjuvant radiation therapy and or surgery) to achieve a cure

EMA / CO is now the preferred combination chemotherapy regimen in high-

risk metastatic GTN with a remission rate of 80% to 90%. Tables 4 and 5
summarize the most commonly used multiagent protocols for patients with
high-risk GTN and low-risk GTN who are resistant to a single drug.
 TREATMENT
High-Risk GTN • EMA/EP (Lurain 2005; Lu 2008; Mao 2007;
Newlands 2000);
• BEP (bleomycin, etoposide, cisplatin) (Lurain
2005; Zhao 2009);
• VBP or PVB (cisplatin or carboplatin, vinblastine,
bleomycin)
Several salvage regimens • (Azab 1989; Rodriguez 2010)
have been reported in the • VIP or ICE (ifosfamide, etoposide, cisplatin)
literature. (Lurain 2005);
• EP (etoposide, cisplatin) (Soper 1995; Theodore
1989);
• TP/TE (paclitaxel, cisplatin/paclitaxel, etoposide)
whereby TP and TE are alternated weekly (Wang
2008);
• FAEV (floxuridine, dactinomycin, etoposide,
vincristine) every 21 days (Feng 2011; Wan 2007).
Treatment
Managemen GTN risiko tinggi

Table 4. EMA / CO and EMA / EP regimen protocols

Day Regiment Dose
EMA / CO protocol
1 Etoposide 100 mg / m 2 by infusion in 200 mL saline for 30 minutes 0.5 mg IVP

actD 100 mg / m 2 IVP

Mtx 200 mg / m 2 through the infusion for 12 hours
2 Etopside 100 mg / m2 by infusion in 200 mL of saline for 30 minutes

actD 0,5 mg IVP

Asam folinic 15 mg every 12 hours x 4 doses of IM or PO started 24 hours after starting Mtx

8 Cyclophosphamide 600 mg / m2 by infusion in a saline solution for 30 minutes

Vincristine 1 mg / m2 IVP
EMA / EP pad protocol
1 Etopside 100 mg / m 2 by infusion in 200 mL of saline for 30 minutes

actD 0,5 mg IVP

Mtx 100 mg / m 2 IVP200 mg / m 2 through the infusion for 12 hours

2 Etopside 100 mg / m2 by infusion in 200 mL of saline for 30 minutes

actD 0,5 mg IVP

Asam folinic 15 mg every 12 hours x 4 doses IM or PO
Cisplatin 60 mg / m 2 IV with prehydration
Etopside 100 mg / m 2 by infusion in 200 mL of saline for 30 minutes
Treatment
High risk management of GTN
Day Regiment Dose
Table 5. MAC regimen protocol 1 Mtx 1 mg/kg IM
actD 0.5 mg IVP
Cyclophosphamide 3 mg/kg IVB for 45–60 min
2 FA 0.1 mg/kg PO
actD 0.5 mg IVP
Cyclophosphamide 3 mg/kg IVB for 45–60 min
3 Mtx 1 mg/kg IM
actD 0.5 mg IVP
Cyclophosphamide 3 mg/kg IVB for 45–60 min
4 FA 0.1 mg/kg PO
actD 0.5 mg IVP
Cyclophosphamide 3 mg/kg IVB for 45–60 min
5 Mtx 1 mg/kg IM
actD 0.5 mg IVP
Cyclophosphamide 3 mg/kg IVB for 45–60 min
6 FA 0.1 mg/kg PO
7 Mtx 1 mg/kg IM
8 FA 0.1 mg/kg PO
Treatment
Management GTN

The cure rate for non-metastatic and low-risk metastatic GTN is close to
100% with use of the single agent Mtx and actD administered sequentially
and use of a multi-agent protocol when single agent resistance develops

In patients with high-risk GTN, optimal cure rates are achieved by

administering intermittent intensive chemotherapy at intervals of 2 to 3 weeks,
if toxicity is tolerated
Treatment
Recurrence GTN Management

A study by Kang, et al in 2020 revealed that the interval between previous

pregnancy and chemotherapy> 12 months, and the interval from first
chemotherapy to achieving normalized β-hCG> 14 weeks were both
predictors of GTN recurrence.

Kang et al
EMA / EP is an effective salvage regimen for EMA / CO resistant patients, resulting in
cure rates ranging from 66.6% to 84.9%.
Wang et al
TP / TE produces a cure rate comparable to EMA / EP, but with lower toxicity
Osborne et al
a new 3-drug doublet regimen consisting of paclitaxel, etoposide, and cisplatin (TP / TE)
leading to complete remission
Treatment
Recurrence GTN Management

Cure rates for high-risk GTN from 80% to 90% can now be achieved with
intensive multimodal therapy, with EMA / CO with adjuvant radiotherapy and /
or surgery if indicated.

The survival of relapsing GTN patients after EMA / CO administration

increased significantly from 87% to 98% when the patient was treated with 2
cycles of low-dose EP induction chemotherapy (etoposide 100 mg / m2 and
cisplatin 20 mg / m2) on days 1 and 2, repeated every x 2 weeks before
starting EMA / CO

This regimen is very successful because of its relatively low toxicity allowing
adherence to treatment schedules, and a high complete response rate,
Treatment
Follow up

After achieving undetectable levels of hCG for 3 consecutive weeks and

completing chemotherapy, serum quantitative hCG levels should be obtained
at 12 month intervals for patients with stage I to III GTN and 24 months for
patients with stage IV GTN before pregnancy is possible.

The overall risk of recurrence is about 3% to 9% in the first year after

completing therapy, but rarely after 12 months of normal hCG levels.
Treatment
Follow up

Follow-up in patients with stage I to stage III GTN should receive follow-up with:
1. Measurement of weekly to normal serum hCG levels for 3 consecutive
weeks
2. Measurement of monthly serum hCG values to normal levels for 12
consecutive months
3. Contraception that is effective during the entire hormonal follow-up interval
Treatment
Follow up

Follow-up in patients with stage IV GTN should receive follow-up with: 14

1. Determination of weekly to normal serum hCG levels for 3 consecutive weeks
2. Determination of monthly to normal serum hCG levels for 24 consecutive
months
3. These patients require prolonged gonadotropin follow-up because they are at
increased risk of late recurrence
Treatment
Follow up

If at each follow-up serum hCG levels decreased and

the curve followed a normal ß-hCG regression curve
pattern (Morrow et al) and there were no clinical signs
or symptoms of new growth of trophoblast tissue, then
the follow-up was carried out in the same pattern until
week 12 after evacuation of molar tissue and if at week
12 the level of ß-hCG <5 mIU / ml followed by the next
stage of follow-up

Figure 5. Morrow Curve

Treatment
Follow up

The diagnosis of new growth of trophoblast tissue by ß-

hCG examination is determined by the criteria
recommended by Mozisuki et al, namely:
1. ß-hCG levels> 1000 mIU / ml at week 4
2. ß-hCG levels> 100 mIU / ml at week 6
3. ß-hCG levels> 30 mIU / ml at week 8

Figure 4. Mozisuki curve

 Phantom hCG

The measurement of apparent but spurious human chorionic

gonadotropin (hCG) has been reported in the literature over the last
three decades, and has recently been referred to as “phantom hCG”.

hCG is produced in pregnancy, in tumor marker for GTD

GTD, and in men with testicular with 100% sensitivity
germ cell malignancies. and specificity
 hCG

 In normal pregnancy, hydatidiform mole, and choriocarcinoma

similar levels of hCG-related molecule immunoreactivity (hCG
plus free b-subunit and b-core fragment) are present in both
serum and urine samples
 In patients with nontrophoblastic cancers, primarily hCG-free β-
subunit is detected in serum and hCG b-core fragment in urine
samples
 The finding of hCG immunoreactivity in serum, with the absence
of hCG, free β-subunit, or β-core fragment immunoreactivity in
urine, is suggestive of phantom hCG.
 False-postivie serum hCG

occur in 1/1,000 to 1/10,000 tests

CAUSED BY:
1.measurement of pituitary hCG-like substance;
2.production of free hCG a-subunit;
3.interference by nonhCG substances, including hLH or hLH a-
Misleading results are
subunit, both species-specific and heterophilic anti-animal
usually seen with values
immunoglobulin antibodies, rheumatoid factor, anti-hCG
below 1,000 mIU/mL
antibodies, and nonspecific serum factors; and
4.assay issues such as carryover by positive displacement
pipettes and contaminants that affect label detection (radioactive
iodine or fluorophores).
 False-postivie serum hCG (con't)

Characteristics of false-positive hCG measurements

1. low-level positive result (generally < 1,000 mIU/mL and usually < 150
mIU/mL);
2. positive serum but negative urine;
3. serial dilutions of serum that are not parallel to the hCG standard and
yield higher or lower levels of hCG when multiplied by dilution factor;
4. positive hCG results that are not consistent with clinical or surgical
findings;
5. no substantial changes in levels that were measured in serial blood
samples, even after therapeutic procedures; and
6. negative results in a different type of quantitative hCG assay
 Persistent low hCG value (quiescent GTN)

In patients with a history of hydatidiform mole or GTD

confirm the diagnosis using a different laboratory and hCG test

1.If results are very different (more than twofold), then a false-positive hCG
result is likely.
2.If the patient is over 45 years old or post-oophorectomy, then pituitary hCG
should be considered as the likely cause, regardless of history, and can be
confirmed with 2 weeks or so of combination estrogen–progesterone therapy,
which suppresses hCG in patients with this diagnosis

The diagnosis of “quiescent disease” can

be confirmed by showing the absence of
hCG hyperglycosylation (<0.3 ng / mL).
 Contraceptive recommendations

- Contraception is recommended during the follow-up

period, from post evacuation of the molar to 6
months - 1 year
- Old recommendation -> IUD and combined
contraceptive pills need to be avoided
- Current recommendations -> the use of hormonal
contraceptives can be recommended by monitoring
the hCG value. The combined contraceptive pill did
not increase the incidence of GTD or change the
regression pattern of hCG values
CONCLUSION
 Conclusion

1. Gestational trophoblastic neoplasia (GTN) includes a group of malignant pregnancy-

related tumors arising from an abnormal placenta.
2. Includes invasive molar, choriocarcinoma, placental site trophoblastic tumor (PSTT) and
trophoblastic epitheloid tumor.
3. Low-risk GTN (International Federation of Gynecology and Obstetrics / FIGO) stage I-III:
score <7) is managed with single agent chemotherapy and the overall survival rate is
close to 100%.
4. High-risk GTN (FIGO stage II-III: score ≥ 7 and stage IV) requires multi-agent
chemotherapy and achieves a survival rate of approximately 90%.
 Conclusion (con't)

5. Although the majority of GTN patients recover with chemotherapy due to

chemosensitivity of these tumors, a small proportion of GTN patients will experience
relapse after finishing treatment due to chemoresistants.
6. Retrospective case series shows that EMA / EP, BEP, TP / TE, FAEV and other
combinations have been shown to be effective as salvage therapy for recurrent or
resistant GTN
7. Persistently detectable serum levels of low hCG in individuals without pregnancy or
without a history of trophoblastic disease or tumor mass, false positive hCG or phantom
hCG should be considered.
 Thankyou
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