1. In The Name of God Dr. F Behnamfar MD

2. Diagnosis and treatment of gestational trophoblastic disease

3. Gestational Trophoblastic Neoplasia A spectrum of interrelated conditions originating from placenta:  Complete and partial moles  Invasive mole  Gestational choriocarcinoma  Placental Site Throphoblastic Tumor

4. Hydatiform Moles  1 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

5. Complete 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

6. Complete 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

7. 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

13. Gestational choriocarcinoma 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

14. Molar Pregnancy  Usually diagnosed during first trimester  Most common symptom abnormal bleeding  Ultrasonography has replaced all other diagnostic procedures  Findings may be subtle in cases of early complete or partial mole  Suction curettage is the best type of uterine evacuation

15. Follow up  Serial hCG values, as long as decreasing no role for chemotherapy  AUB more than 6weeks after any kind of pregnancy should be evaluated with hCG

16. Diagnoses of Malignant Sequele  Increasing hCG levels (Increase of three values > 10% over 2 weeks ) or plateau (four values ± 10% over 3 weeks )  Histologic diagnoses of Choriocarcinoma or invasive mole from uterine currettage  Clinical or radiographic evidence of metastases

17. Gestational Trophoblastic Neoplasia  Staging Nonmetastatic (I) Nonmetastatic (I) Metastatic(II-IV) Metastatic(II-IV)  FIGO 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

18. Poor-prognosis metastatic gestational 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

19. FIGO scoring system  Age(years)  Antecedent pregnancy  Interval from index pregnancy (months)  Pretreatment human chorionic gonadotropin level  Largest tumor size including uterus (cm)  Site of metastases  Number of metastases identified  Previous failed chemotherapy

20. FIGO Scoring System

21. Treatment of low risk GTN  Variety of agent :MTX,Actinomycin D,Etoposide,5FU and Cisplatinum  Early hysterectomy shortens the duration and amount of chemotherapy to produce remission  Alternative single agent if plateu or increasing hCG  Multiagent regimen if alternative single agent failes  100% curable

22. Methotrexate  Li et al,1956,First treatment of metastatic GTN  1964,Bagshawe,administration of folinic acid, reducing toxicity  1976, Bagshawe, mutch better response to single agent MTX for nonmetastatic  Other drugs tested, more toxic

23. Chemotherapy  Single agent MTX therapy Nonmetastatic Nonmetastatic Low risk metastatic Low risk metastatic  Multi agent regimens resistance to MTX initially high risk tumors

24. MTX single agent protocols  MTX alone, 5days,0.4mg/kg/day  MTX alone,one inj. weekly,30 -50mg/m2  MTX with folinic acid,MTX 1mg/kg/day folinic acid 0.1mg/kg/day,every other day,8days regimen  MTX with folinic acid,MTX100mg/m2 IV bolus,followed by 200mg/m2/12h and folinic acid

25. Strategies for further courses  Regular administration every 7-14 days  Single systematic course, further courses depending on HCG decrease(if plateau or reelevatd

26. Change of chemotherapeutic agent  Stable hCG for three consecutive weeks  Re-elevated hCG  Not falling at least one log within 18 days of first treatment

27. Remission and Relapse  Remission :hCG level within normal range for at least three consecutive weeks  Relapse :Rising hCG after remission

28. MTX Toxicity  Hepatotoxicity  GI disturbances  Granulocytopenia  Thrombocytopeni  Mucositis

29. Demographic praperties of low risk GTN case vali. Ase Hospital TUMS AgeMinmaxMean Gravid1113.2 Abortion040.4

30. Staging of low risk GTN case vali. Ase Hospital TUMS

31. FIGO Score of low risk GTN case vali. Ase Hospital TUMS

32. Toxicity of MTX in low risk GTN case vali. Ase Hospital TUMS

33. Failure Frequency of low risk GTN case vali. Ase Hospital TUMS

34. Results Failure frequency :18 (28%)  Initial resistance 11 (17%)  Relapse 0  Toxicity 7 (11%)

35. Methods  Retrospective study,1996-2006 Valie-Asr  Low risk GTN(metastatic and nonmetastatic)  Single agent weekly pulse MTX 30- 50mg/kg  Questionare from files and telephoning to patients

36. Results  66 low risk GTN cases(58 nonmetastatic and 8 metastatic)  97% following molar pregnancy and 3% following abortion

37. Toxicity  %7.8 Hepatotoxicity  %17.2 GI disturbances  %2 Granulocytopenia  No Mucositis

38. Second Line of treatment  Pulse Actinomicin(1.25mg/m2)Biweekly  18 cases  %100 Response

39. Time to Negative Beta hCG  First line 7.18+_3.5 weeks  Second line 21+-weeks

40. BhCG Level  Resistant Group :16937 mIu/ml  Response Group :8056 mIu/ml

41.  Pulse MTX,72% remission rate with low toxicity  Actinomycin as second line,%100 cure of MTX resistant and toxic group  Prolonged regression of HCG in resistant group group  Higher HCG level in resistant group

42. Discussion New England Center of Boston(1984) (Only nonmetastatic)  8 days regimen (MTX-FA)  88% remission rate  1.2 cycles in average  14% Hepatotoxicity  6% granulocytopenia

43. Discussion Jaice S. Kwon et al (2001)  Weekly IV Methotrexate 100mg/m2 with folinic acid (nonmetastatics)  45.5% respnse rate (Folinic acid may be detrimental)  Low toxicity ( no change of treatment )  Only significant prognostic factor pretreatment hCG level

44. Discussion Gleeson 1993,Hoffman1996,Homsely 1988(GOG) Weekly pulse MTX 73-89% complete response 30% GI disturbance,20% lucopenia

45. Advantages  Outpatient administration  Patient convenience  Minimal systemic toxocity  Low cost  Comparable efficacy to other first-line treatments

46. Thanks