10/02/2014

Agenda
Gestational trophoblastic disease:
history
Gestational trophoblastic disease
• Mola hydatidosa • Hippocrates was the first to describe in 400 BC,
‘dropsy of the uterus’ (~ waterzucht, oedeem)
• Gestational trophoblastic neoplasia
• Registration • Marchand, 1895, link with pregnancy
Pentalfa januari 2014

Frederic Amant MD PhD
Gynaecologische oncologie, UZ Leuven

Gestational Trophoblastic Diseases Incidence

Gestational trophoblastic disease WHO Classification Lurain et al 2010

• Highly heterogeneous
• Heterogeneous group of diseases originating WHO Classification • Complete mole 1:1000
• Moles, partial, complete, invasive
from trophoblastic epithelium of the placenta Hydatiform mole Pre Invasive
• 15-20% chance for malignant evolution
•Complete mole
Choriocarcinoma,
Partial mole
PSTT, ETT
• b-hCG is a very reliable tumormarker Invasive mole Malignant • Partial mole 3:1000
Choriocarcinoma Malignant
• <5% chance for malignant evolution
Placental site trophoblastic tumor (PSTT) Malignant
Epitheliod trophoblastic tumor Malignant
Exaggerated placental site Benign
Placental site nodule Benign
Unclassified trophoblastic lesions Benign 5

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Gestational Trophoblastic Diseases: Molar pregnancy: previously reportes Mola hydatidosa: current diagnosis
Distinction between GTD & GTN features
• Mole: abnormal pregnancy due to abnormal fecondation
• Symptoms: vaginal blood
– Molar pregnancy is not a trophoblastic tumor • Vaginal blood loss loss during first trimester
– Complete mole = Diploid egg (2 sets of paternal chromosomes), 
– Partial mole = Triploid egg (2 sets of paternal chromosomes)
• hyperemesis gravidarum • Diagnosis:
• positive dyscongruence o Ultrasound
• hyperthyroidism o Pathology
• pre-eclampsia
• Gestational trophoblastic tumors: • anemia
– Occur mostly after molar pregancy
– Develop after any kind of pregnancy

Suction curettage for partial mole Treatment of hydatidiform mole

Seckl et al 2010 Lancet
Mola and co-twin
• Oxytocin infusion, cervical dilatation, suction curettage
with sonographic control
• Rhogam° for rhesus negative patients (rhesus D factor • Incidence 1: 20 000 - 100 000 pregnancies
expression on trophoblast) • High risk pregnancy ( vaginal blood loss, pre-
• No Mifegyne° (mifepriston, antiprogestin) or Cytotec°
(misoprostol, prostaglandin) in order to decrease the risk eclampsia, fetal death)
for uterine contractions and subsequent risk trophoblastic
embolisation
• Hysterectomy only in case of life threatening bleeding (or
for women with completed family)
• 2nd curettage only if hCG < 5000
Sebire 2002 Lancet

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Twin pregnancy of a complete hydatidiform mole
and healthy co-twin.
(A) Ultrasonography and (B) MRI
Complete mola and healthy co-twin: high risk for
fetal loss though live births are possible Follow up β-hCG after surgical
(Seckl, Lancet 2010)
(Wee 2005 Prenat Diagn)
evacuation
• Weekly until 2 normal values
• Normal hCG < 8 weeks: monthly hCG during 6
months
• Normal hCG > 8 weeks: monthly hCG continuous
until 6 months

hCG regressie curve Conception after molar pregnancy
Normalisation hCG ≤ 8 weeks
 Conception allowed 6 mts after suction
curettage
Normalisation hCG > 8 weeks
 Conception allowed 6 mts after normalisation of
hCG
Delattre et al 2013 seminariewerk
Schlaerth et al 1981 Obstet Gynecol
Recurrence after molar pregnancy
• Risk for a 2nd molar pregnancy
1-2%
• Risk for a 3rd molar pregnancy
15-20%
6-10 weeks after each future pregnancy hCG
needs to be measured

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Agenda
Recurrent molar pregnancy: domain structure of NLRP7 and Gestational Trophoblastic Diseases:
identified mutations in 17 families
(Seckl, Lancet 2010; Fisher Lancet 2011)
• Molar pregnancy may progress to
trophoblastic tumor (GTN)
• Mola hydatidosa
R693Q
R693W
R693P After ANY type of pregnancy
P716A

L398R P651S
R721W
C761Y N913S
• Gestational trophoblastic neoplasia Complete Mole  10‐20 % GTD
• Registration Partial Mole  <1 % GTD
E113GfsX7 E570X P716LfsX21
R432X
T61TfsX7 Y318CfsX7 L6776PfsX6 Spontaneous Abortion 1 / 6000 GTD
PYD NACHT Leucine‐rich region Term delivery 1 / 40000 GTD
www.mole‐chorio.com
www.ctrt.org.uk/gestationnal/pre.html

Indications for chemotherapy for gestational Gestational choriocarcinoma with International Federation of Gynecology and Obstetrics (2000) scoring system
for gestational trophoblastic neoplasia, by prognostic factor
trophoblastic disease in the UK (Seckl, Lancet 2010) massive invasion of myometrium 0 1 2 4
• Plateaued or rising hCG concentration after evacuation Age (years) <40 ≥40 .. ..
– A plateaued hCG concentration is defined as four or more equivalent values Antecedent pregnancy Mole Abortion Term ..
of hCG for at least 3 weeks (days 1, 7, 14, and 21), and rising as two Interval from antecedent pregnancy <4 4‐6 7‐12 >12
consecutive increases in hCG concentration of 10% or more for at least 2 to chemotherapy (months)
weeks (days 1, 7 and 14) hCG concentration (IU/L) <10³ 10³‐<104 104‐105 >105
• Heavy vaginal bleeding or evidence of gastrointestinal or intraperitoneal Number of metastases 0 1‐4 5‐8 >8
haemorrhage Site of metastases Lung Spleen,  Gastrointestinal Brain, liver
• Histological evidence of choriocarcinoma kidney tract
• Evidence of metastases in brain, liver, or gastrointestinal tract, or radiological Largest of tumour mass diameter (cm) .. 3‐5 >5 ..
opacities larger than 2 cm on chest Rx Previous chemotherapy .. .. Monotherapy Combined therapy
• Serum hCG concentration of 20 000IU/L or more, 4 weeks or more after hCG=human chorionic gonadotropin. *Patient’s score is total of individual scores for the eight prognostic factors.  Low 
risk of resistance to monochemotherapy 0‐6, high risk 7 or more. Placental‐site trophoblastic tumour should not be
evacuation, because of risk of uterine perforation scored but needs to be staged. Stage I disease is confined to the uterus; stage II disease extends to the genital tract; 
stage III disease is spread to lungs with or without extension to the genital tract; and stage IV occupies all other
metastatic sites including liver, kidney, spleen and brain.

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Treatment depends on WHO risk score Chemotherapy – low risk Side-effects of Methotrexate
• Low risk (WHO score 0-6) (95% of patients MTX Bagshaw schedule Methotrexate 1mg/kg                                               d1,3,5,7
• No or moderate alopecia, tiredness, bone
q2w Folinic acid 0.05mg/kg                                              d2,4,6,8
with hydatidiform mole): Mtx monotherapy till marrow suppression, mucositis gastro-intestinal
normalisation β-hCG, followed by 2 MTX‐Actinomycin Methotrexate 25mg                                                      d1‐4 tract (oral, nausea, vomiting , diarrhea)
consolidation cycles q11d Actinomycin 0.5mg                                                        d1‐4
Folinic acid 7.5mg • Uncommon: hepato- and nefrotoxicity,
• High risk (WHO score ≥ 7) or resistence to Actinomycin mono Actinomycin‐D 0.3mg/m²                                             d1‐5      pulmonary toxicity
1st line therapy: combination chemotherapy q12d
• Cave! Incompatible with NSAID’s or high dose
Vit C (interference with renal excretion of MTX)

EMA-CO chemotherapy regimen for patients at high risk of TP-TE schedule for relapsed gestational trophoblastic neoplasia
Chemotherapy– high risk monochemotherapy resistance
Schedule
Day 1 (TP)
Schedule

Dexamethasone 20 mg orally (12 h before paclitaxel)

Day 1 (EMA)
Dexamethasone 20 mg orally (6 h before paclitaxel)
Etoposide 100 mg/m² by intravenous infusion for 30 min
Cimetidine 30 mg in 100 mL normal saline intravenous for 30 min
EMACO Etoposide, MTX                                                                       d1 Dactinomycin 0∙5 mg intravenous bolus Chlorphenamine 10 mg intravenous bolus
q2w Actinomycin, Cyclophosphamide, Vincristin d8 Methotrexate 300 mg/m² by intravenous infusion for 12 h Paclitaxel 135 mg/m² in 250 mL normal saline intravenous for 3 h
Day 2 (EMA)* Mannitol 10% in 500 mL intravenous for 1 h
Etoposide 100 mg/m² by intravenous infusion for 30 min Cisplatin 60 mg/m² in 1 L normal saline intravenous for 3 h
MTX‐Etoposide MTX  1000mg/m²                                                                    d1 Dactinomycin 0∙5 mg intravenous bolus Post‐hydration 1 L normal saline, 20mmol potassium chloride, and 1 g magnesium sulphate intravenous for 2 h
high dose Etoposide 100mg/m²                                                           d1,2 Folinic acid rescue† 15 mg intramuscular or orally every 12 h for four doses Day 15 (TE)
q1w Day 8 (CO) Dexamethasone 20 mg oral (12 h before paclitaxel)

Vincristine 1 mg/m² intravenous bolus (maximum 2 mg) Dexamethasone 20 mg oral (6 h before paclitaxel)

Cimetidine 30 mg in 100 mL normal saline intravenous for 30 min
Cyclophosphamide 600 mg/m² intravenous infusion for 30 min
Chlorphenamine 10 mg intravenous bolus
EMA=etoposide, methotrexate, and dactinomycin. CO=cyclophosphamide and vincristine. EMA alternates with CO 
every week. *Reduction of the EMA by omission of the day 2 dose of etoposide and dactinomycin is only Paclitaxel 135 mg/m² in 250 mL normal saline intravenous for 3 h.
exceptionally needed to avoid extended intervals between courses caused by myelosuppression. This problem is  Etoposide 150 mg/m² in 1 L normal saline intravenous for 1 h
usually overcome with filgrastim and increased frequency (four doses daily) and duration (up to 4 days) of folinic TP=paclitaxel‐cisplatin. TE=paclitaxel‐etoposide.
acid rescue. †Rescue begun 24 h after start of methotrexate infusion.

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Sampling protocol for hCG concentration in all patients Agenda

Late sequelae from chemotherapy after initial chemotherapy (monotherapy or combination)
UK version, Seckl, Lancet 2010
• No effect on fertility (Seckl Lancet 2010) Urine Blood
• No increased incidence of congenital Year 1 • Mola hydatidosa
malformations (Woolas BJOG 1998, Rustin BMJ 1984) 1-6 weeks Every week Every week
• Gestational trophoblastic neoplasia
2-6 months Every 2 weeks Every 2 weeks
• Slight increased risk in incidence of second 7-12 months Every 2 weeks ‘’
• Registration
tumors (n=1377: 37 second tumours vs 24 that Year 2 Every 4 weeks ‘’
Year 3 Every 8 weeks ‘’
where expected (p 0,011) (Rustin JCO 1996)
Year 4 Every 3 months ‘’
Year 5 Every 4 months ‘’
After year 5 Every 6 months ‘’

Gestational Trophoblastic Diseases: Gestational Trophoblastic Diseases:

GTD centralisation/reference
Rationale for centralisation
Rationale for centralisation
1. England: Bagshawe 1973 Evolution of Fatal cases of GTN (Dutch)
• Charing Cross, Sheffield & Dundee
2. The Netherlands: 1977 Rarity + Heterogeneity + Complexity
3. France, Lyon: 1999
4. Switzerland, Geneva: 2008 =
5. Others: Hungary, US, Quebec, Asia Inaccuracy in diagnosis + follow-up + management
• International Societies
─ ISSTD : International Society for the Study of Trophoblastic
Disease
─ EOTTD : European Organisation for Treatment of Trophoblastic  Centralisation reduces mortality
Disease (http://www.eottd.com)

Lybol, BJOG 2012

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Gestational Trophoblastic Diseases: Gestational Trophoblastic Diseases: GTD : Rationale for centralisation
Rationale for centralisation Rationale for centralisation Treatment of GTN
Overcome the most common pitfalls
• 11.000.000 residents Treatment optimization
• 1505 gynaecologists • GTD
– 517 Walloon province • Avoid mis-diagnosis – Early recognition & treatment of GTN
– 264 Brussels • Avoid harmful uterine evacuations
• Improved follow-Up, identification of GTN
– Avoid over-treatment
– 724 Flanders
• 141 hospitals • GTN • 10-20% of heavy chemo are useless
• 120-250 GTD patients/year • Adequate Work-up – Avoid under-treatment
• Appropiate FIGO stade/score • 2/3 of deceased patients received inadequate
• GTN: 12-25 cases/year • GYNAECO  ‐ 1 case / 4‐5 y
• PATHO ‐ 1 case /4 y • Multidisciplinary approach for individualized initial treatment
• MED ONCOL ‐ 1 case /10 y treatment J Lurain 1987

Belgian GTD Register http://www.mole‐chorio‐bgog.eu/nl/ Take home message

• GTN has an overall cure rate of 98% with fertility

Example of feedback retention due to improvements of follow up
to gynaecologist protocols and treatment
• Effective treatments, hCG as a biomarker and
registration are pivotal for this succes

www.mole‐chorio‐bgog.eu

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Jotunheimen, Norway , 2013