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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