1. State of the Art: Gestational Trophoblastic Lesions Treatment beyond single agents Barry Hancock (Sheffield, UK) International Gynecologic Society Meeting 2006

5. Which group of patients?  Risk (WHO score, Dutch classification)  Prognosis (Hammond)  Stage (Song, FIGO)  Choriocarcinoma risk (Japan)  Criteria for treatment

6. Two scenarios  Single agent resistance  ‘High’ risk disease

7. Single agent resistance  Alternative single agent  Combination chemotherapy (EMA-CO, MAC, EA etc)

8. Single agent resistance  For ‘low’ risk non-metastatic disease single agent chemotherapy is 60-90% successful  Second line multi-agent therapy is virtually always (>95%) successful in dealing with single agent resistance

9. Benefits Is intensive chemotherapy necessary for all high risk patients?  Higher CR  Less salvage treatment  Shorter treatment period Risks  Over treatment  Higher financial costs  More toxicity

10. What is the evidence base?  One randomized controlled trial  Lots of small-moderate sized series  One retrospective comparative study

11. Primary treatment for high risk GTN MAC (MTX, dactinomycin, chlorambucil or cyclophosphamide) EMA-CO (etoposide, MTX, dactinomycin, cyclophosphamide, vincristine) EMA/MEA CHAMOCA (cyclophosphamide, hydroxyurea, dactinomycin, MTX, vincristine, doxorubicin) CHAMOMA (+ melphalan) FME (FU, MTX, etoposide) Previously single agent MTX!

12. Primary remission rates in high risk GTN MAC 63-80% CHAMOCA 82% MAC vs CHAMOMA 73% vs 65% EMA-CO >80% EMA/MEA/FME 75-80%

13. Salvage treatment in high risk GTN EMA-EP (EMA - etoposide, cisplatin) BEP (bleomycin, etoposide, cisplatin) CEC (cyclophosphamide, etoposide, cisplatin) MISC (high dose chemotherapy, carboplatin/paclitaxel, paclitaxel/etoposide and paclitaxel/cisplatin doublet)

14. Salvage treatment 20-60% success

15. Surgery

16. Toxicity EP-EMA CHAMOCA EMA-CO MAC EMA/MEA/FME

17. Toxicity  Multi-treated patients  Potential mortality whatever is chosen

18. Acute toxicity Alopecia+++++ Neutropenia++++ Anemia+++ Nausea/vomiting++ Stomatitis++ Neutropenic sepsis++ Thrombocytopenia+

19. Long-term toxicity  Increased second malignancy  Premature menopause  Unknown!

20. Staff Nurse Ellen Zitek in BBCs ‘Casualty’ Treated for ‘cancer’ after a molar pregnancy

22. FIGO SCORING0124 Age< 40  40 -- Antecedent pregnancy MoleAbortionTerm- Interval months from index pregnancy < 44 - < 77 - < 13  13 Pre-treatment serum hCG (IU/L) < 10 3 10 3 - < 10 4 10 4 - < 10 5  10 5 Largest tumour size (including uterus) cm < 33 - < 5  5 - Site of metastasesLungSpleen, kidney Gastro- intestinal Liver, brain Number of metastases-1-45-8> 8 Previous failed chemotherapy --Single drug2 or more drugs

23. Chemotherapy for High Risk GTN (Sheffield UK) Day 1 MTX 100mg/m 2 iv Folinic acid rescue Day 8, 9, 10Dactinomycin 500µg iv Etoposide 100mg/m 2 iv et seq 7 days M/AE

24. Sheffield Trophoblast Centre, UK 1986-2005 Registration 8211 459 (6%) Persistent GTN Low risk High risk 54 (12%) MAE 79 8 405 (88%) MTX Resistant AEA

25. Methotrexate resistant GTN CR 78 (99%) EA 79Refractory 1 1 † Median follow-up 8 years Late deaths 0 2nd malignancy 0 Further pregnancy >60%

26. High risk GTN MEA 54 CR 42 (78%) Refractory 12 2 other TAH 55 CEC 2 4 1 +7+7 49 (91%) alive and well Median follow-up 8.5 years Late deaths 0 Further pregnancy >60% 2nd malignancy 0 14†

27. Cure rates in GTN 1st line Salvage Low risk (70-90%) 75%99% High risk (10-30%) 75%95% Overall 98% cure

28. Conclusion  The majority of patients are curable whatever the ‘risk’ or ‘stage’  It doesn’t seem to matter which regimen you choose as long as it works and you are familiar with it!  ‘Specialist’ center skills may be more important than the actual therapy  But - occasional patients still die despite multiple chemotherapy and surgical interventions

32. Methotrexate in high risk GTN (Sheffield, UK 1973-86) AVC - dactinomycin, vincristine, cyclophosphmide Median follow-up 24y 22 MTX 12 4 Other Resistance AVC 6 (27%) CR 20 Alive and well 3 + 11 2 † Late deaths 0 2nd malignancies 0