in the name of god dr. f behnamfar md. diagnosis and treatment of gestational trophoblastic disease
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In The Name of In The Name of GodGod
Dr. F Behnamfar MDDr. F Behnamfar MD
Diagnosis and treatment of gestational trophoblastic disease
Gestational Trophoblastic Gestational Trophoblastic NeoplasiaNeoplasia
A spectrum of interrelated conditions A spectrum of interrelated conditions originating from placenta:originating from placenta:
Complete and partial molesComplete and partial moles Invasive moleInvasive mole Gestational choriocarcinomaGestational choriocarcinoma Placental Site Throphoblastic TumorPlacental Site Throphoblastic Tumor
Hydatiform MolesHydatiform Moles
1 in 1500 pregnancy1 in 1500 pregnancy 1 in 600 therapeutic abortions 20% will develop malignant sequelae
requiring chemotherapy Most will have non-metastatic molar
proliferation or invasive moles gestational choriocarcinomas and
metastatic disease can develop
Complete Hydatiform MolesComplete Hydatiform Moles
Some diagnosed as missed abortions (early ultrasound without symptoms)
most patients have a clinical or ultrasonographic diagnosis of hydatidiform mole
Uterine enlargement beyond the expected gestational age in up to 50% may present with vaginal bleeding or
expulsion of molar vesicles
Complete Hydatiform MolesComplete Hydatiform Moles complications of molar pregnancy, including
pregnancy induced hypertension, hyperthyroidism, anemia, and hyperemesis gravidarum, are more frequently seen among patients with complete moles
15–25% of patients will have theca lutein cysts with ovarian enlargement of more than 6 cm
Diagnoses
usually during the first trimester of pregnancy most common symptom: abnormal bleeding uterine enlargement greater than expected for
gestational age absent fetal heart tones cystic enlargement of the ovaries hyperemesis gravidarum Abnormally high level of hCG for gestational age
Gestationalchoriocarcinoma
occurs in approximately 1 in 20,000–40,000 pregnancies
50% after term pregnancies 25% after molar pregnancies remainder after other gestational events
Placental site trophoblastic tumors can develop after any type of pregnancy
Molar PregnancyMolar Pregnancy
Usually diagnosed during first trimesterUsually diagnosed during first trimester Most common symptom abnormal Most common symptom abnormal
bleedingbleeding Ultrasonography has replaced all other Ultrasonography has replaced all other
diagnostic proceduresdiagnostic procedures Findings may be subtle in cases of early Findings may be subtle in cases of early
complete or partial molecomplete or partial mole Suction curettage is the best type of Suction curettage is the best type of
uterine evacuationuterine evacuation
Follow upFollow up
Serial hCG values, as long as decreasing Serial hCG values, as long as decreasing no role for chemotherapyno role for chemotherapy
AUB more than 6weeks after any kind of AUB more than 6weeks after any kind of pregnancy should be evaluated with hCGpregnancy should be evaluated with hCG
Diagnoses of Malignant SequeleDiagnoses of Malignant Sequele
Increasing hCG levels (Increase of three Increasing hCG levels (Increase of three values > 10% over 2 weeks ) or plateau values > 10% over 2 weeks ) or plateau (four values ± 10% over 3 weeks ) (four values ± 10% over 3 weeks )
Histologic diagnoses of Choriocarcinoma Histologic diagnoses of Choriocarcinoma or invasive mole from uterine currettageor invasive mole from uterine currettage
Clinical or radiographic evidence of Clinical or radiographic evidence of metastasesmetastases
Gestational Trophoblastic Gestational Trophoblastic NeoplasiaNeoplasia
Staging Staging Nonmetastatic (I)Nonmetastatic (I) Metastatic(II-IV)Metastatic(II-IV)
FIGO ScoringFIGO Scoring Low risk (Total score<7)Low risk (Total score<7) High risk (Total score>7and =7)High risk (Total score>7and =7)
Clinical classification of NCI Clinical classification of NCI
Poor-prognosis metastaticgestational trophoblastic
disease(NCI)
Any risk factor: Long duration (z4 months since last pregnancy) Pretherapy hCG level z40,000 mIU/ml Brain or liver metastases Antecedent term pregnancy Prior chemotherapy
FIGO scoring systemFIGO scoring system
Age(years) Age(years) Antecedent pregnancy Antecedent pregnancy Interval from index pregnancy (months) Interval from index pregnancy (months) Pretreatment human chorionic gonadotropin level Pretreatment human chorionic gonadotropin level Largest tumor size including uterus (cm) Largest tumor size including uterus (cm) Site of metastases Site of metastases Number of metastases identified Number of metastases identified Previous failed chemotherapyPrevious failed chemotherapy
FIGO Scoring SystemFIGO Scoring System
Treatment of low risk GTNTreatment of low risk GTN
Variety of agent :MTX,Actinomycin Variety of agent :MTX,Actinomycin D ,Etoposide,5FU and CisplatinumD ,Etoposide,5FU and Cisplatinum
Early hysterectomy shortens the duration and Early hysterectomy shortens the duration and amount of chemotherapy to produce remissionamount of chemotherapy to produce remission
Alternative single agent if plateu or increasing Alternative single agent if plateu or increasing hCGhCG
Multiagent regimen if alternative single agent Multiagent regimen if alternative single agent failesfailes
100% curable100% curable
MethotrexateMethotrexate
Li et al,1956,First treatment of metastatic Li et al,1956,First treatment of metastatic GTNGTN
1964,Bagshawe,administration of folinic 1964,Bagshawe,administration of folinic acid, reducing toxicity acid, reducing toxicity
1976, Bagshawe, mutch better response 1976, Bagshawe, mutch better response to single agent MTX for nonmetastaticto single agent MTX for nonmetastatic
Other drugs tested, more toxic Other drugs tested, more toxic
ChemotherapyChemotherapy
Single agent MTX therapy Single agent MTX therapy
Nonmetastatic Nonmetastatic
Low risk metastaticLow risk metastatic Multi agent regimens Multi agent regimens
resistance to MTX resistance to MTX initially high risk tumors initially high risk tumors
MTX single agent protocolsMTX single agent protocols
MTX alone, 5days,0.4mg/kg/dayMTX alone, 5days,0.4mg/kg/day MTX alone,one inj. weekly,30 -50mg/m2MTX alone,one inj. weekly,30 -50mg/m2 MTX with folinic acid ,MTX 1mg/kg/day MTX with folinic acid ,MTX 1mg/kg/day
folinic acid 0.1mg/kg/day,every other folinic acid 0.1mg/kg/day,every other day,8days regimenday,8days regimen
MTX with folinic acid ,MTX100mg/m2 IV MTX with folinic acid ,MTX100mg/m2 IV bolus,followed by 200mg/m2/12h and bolus,followed by 200mg/m2/12h and folinic acid folinic acid
Strategies for further coursesStrategies for further courses
Regular administration every 7-14 daysRegular administration every 7-14 days
Single systematic course, further courses Single systematic course, further courses depending on HCG decrease(if plateau or depending on HCG decrease(if plateau or reelevatdreelevatd
Change of chemotherapeutic agentChange of chemotherapeutic agent
Stable hCG for three consecutive weeksStable hCG for three consecutive weeks
Re-elevated hCGRe-elevated hCG
Not falling at least one log within 18 days Not falling at least one log within 18 days of first treatmentof first treatment
Remission and RelapseRemission and Relapse
Remission :hCG level within normal range Remission :hCG level within normal range for at least three consecutive weeks for at least three consecutive weeks
Relapse :Rising hCG after remissionRelapse :Rising hCG after remission
MTX ToxicityMTX Toxicity
HepatotoxicityHepatotoxicity GI disturbancesGI disturbances GranulocytopeniaGranulocytopenia ThrombocytopeniThrombocytopeni MucositisMucositis
Demographic praperties of low risk GTN Demographic praperties of low risk GTN case case
vali. Ase Hospital TUMSvali. Ase Hospital TUMS
Age Min max Mean
Gravid 1 11 3.2
Abortion 0 4 0.4
Staging of low risk GTN case Staging of low risk GTN case vali. Ase Hospital TUMSvali. Ase Hospital TUMS
88
1.510.5
0
10
20
30
40
50
60
70
80
90
I II III
FIGO Score of low risk GTN case FIGO Score of low risk GTN case vali. Ase Hospital TUMSvali. Ase Hospital TUMS
13.5
43.9
31.8
4.5 3 1.50
5
10
15
20
25
30
35
40
45
zero I III III IV V&VI
Toxicity of MTX in low risk GTN case Toxicity of MTX in low risk GTN case vali. Ase Hospital TUMSvali. Ase Hospital TUMS
17.2
7.8
2
024681012141618
Nausea vomitting
Hepatoxicity
Hematoxicity
Failure Frequency of low risk GTN case Failure Frequency of low risk GTN case vali. Ase Hospital TUMSvali. Ase Hospital TUMS
72
1117
001020304050607080
complete remission
toxicityresistant
relapse
ResultsResults
Failure frequency :18 (28%)Failure frequency :18 (28%) Initial resistance 11 (17%)Initial resistance 11 (17%) Relapse 0Relapse 0 Toxicity 7 (11%)Toxicity 7 (11%)
MethodsMethods
Retrospective study,1996-2006 Valie-Asr Retrospective study,1996-2006 Valie-Asr Low risk GTN(metastatic and Low risk GTN(metastatic and
nonmetastatic) nonmetastatic) Single agent weekly pulse MTX Single agent weekly pulse MTX
30-50mg/kg30-50mg/kg Questionare from files and telephoning to Questionare from files and telephoning to
patientspatients
ResultsResults
66 low risk GTN cases(58 nonmetastatic 66 low risk GTN cases(58 nonmetastatic and 8 metastatic)and 8 metastatic)
97% following molar pregnancy and 3% 97% following molar pregnancy and 3% following abortionfollowing abortion
ToxicityToxicity
%7.8 Hepatotoxicity%7.8 Hepatotoxicity %17.2 GI disturbances%17.2 GI disturbances %2 Granulocytopenia%2 Granulocytopenia No MucositisNo Mucositis
Second Line of treatmentSecond Line of treatment
Pulse Actinomicin(1.25mg/m2)BiweeklyPulse Actinomicin(1.25mg/m2)Biweekly
18 cases 18 cases
%100 Response%100 Response
Time to Negative Beta hCGTime to Negative Beta hCG
First line 7.18+_3.5 weeksFirst line 7.18+_3.5 weeks
Second line 21+-weeksSecond line 21+-weeks
BhCG LevelBhCG Level
Resistant Group :16937 mIu/mlResistant Group :16937 mIu/ml
Response Group :8056 mIu/mlResponse Group :8056 mIu/ml
Pulse MTX,72% remission rate with low Pulse MTX,72% remission rate with low toxicitytoxicity
Actinomycin as second line,%100 cure of Actinomycin as second line,%100 cure of MTX resistant and toxic groupMTX resistant and toxic group
Prolonged regression of HCG in resistantProlonged regression of HCG in resistant
groupgroup Higher HCG level in resistant groupHigher HCG level in resistant group
DiscussionDiscussion
New England Center of Boston(1984)New England Center of Boston(1984)
(Only nonmetastatic)(Only nonmetastatic) 8 days regimen (MTX-FA)8 days regimen (MTX-FA) 88% remission rate88% remission rate 1.2 cycles in average1.2 cycles in average 14% Hepatotoxicity14% Hepatotoxicity 6% granulocytopenia6% granulocytopenia
DiscussionDiscussion
Jaice S. Kwon et al (2001)Jaice S. Kwon et al (2001) Weekly IV Methotrexate 100mg/m2 with Weekly IV Methotrexate 100mg/m2 with
folinic acid (nonmetastatics)folinic acid (nonmetastatics) 45.5% respnse rate (Folinic acid may be 45.5% respnse rate (Folinic acid may be
detrimental)detrimental) Low toxicity ( no change of treatment )Low toxicity ( no change of treatment ) Only significant prognostic factor Only significant prognostic factor
pretreatment hCG levelpretreatment hCG level
DiscussionDiscussion
Gleeson 1993,Hoffman1996,Homsely Gleeson 1993,Hoffman1996,Homsely 1988(GOG)1988(GOG)
Weekly pulse MTXWeekly pulse MTX
73-89% complete response73-89% complete response
30% GI disturbance ,20% lucopenia30% GI disturbance ,20% lucopenia
AdvantagesAdvantages
Outpatient administrationOutpatient administration Patient conveniencePatient convenience Minimal systemic toxocityMinimal systemic toxocity Low cost Low cost Comparable efficacy to other first-line Comparable efficacy to other first-line
treatmentstreatments
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