1. Ali AYHAN, MD. Baskent University School of Medicine Department of Obstetrics & Gynecology Division of Gynecologic Oncology Fertility Preservation in Female Cancer Patients

4. Main Goal of Cancer Therapy High Cure (PFS, OAS) Low morbidity Quality of life -Cosmetic appearence -Sexual life -Mood -Fertility preservation

5. Main Requirement of Fertility Preservation Preserving of the uterus Preserving at least one ovary If indicated freezing oocyte,embryo or ovarian tissue

6. All Therapeutic Modalities in Cancer Treatment -Radiation -Radical surgery -Chemotherapy... are associated with infertility

7. Objectives of Fertility Preservation Approach Similar oncologic outcomes to standard therapy Favorable obstetric outcome Low morbidity and cost Benefits >>>>> Risks Preservation of fertility Maintanence of endocrine function Increase in probability of recurrence and death Additional surgery

8. Available Fertility Preservation Strategies Cryopreservation - Sperm -Oocyte ( Slow vs. Vitrification) -Embryo ( Slow vs. Vitrification) -Ovarian Tissue Preservation -Primordial Follicle in vitro maturation Medical -GnRH agonist Surgical -Less Radical (Organ sparing surgery) -Ovarian Transposition (GYN ca, colorectal Ca, spinal ca…) -Transplantation of Cryopreserved ovary (ortho & heterotopic transplantation) -Uterus Transplantation -Uterus&ovarian transplantation(exper)

9. Candidate Selection is Important Age <35-40 ? Yrs Overall health status Origin of tumour, Stage, Grade Chance of 5 years OAS Therapy related premature ovarian insufficiency (Cryopreservation) Informed consent from patient, parents, partner (USO- high dose Gn- secondary POI) Previous infertility problems Close follow up

10. Hematologic Malignancies Chemotherapy ± Radiotherapy GonadoToxicity Impaired Reproductive Function

12. Fertility Preservation in Hematologic Malignancies -Time vs. Disease Burden Ovarian Tissue Preservation -Oocyte CryoPreservation (Needs Ovarian stimulation) -Primordial Follicle + IVM - IVF

13. Gynecological Cancer rates <40y Breast Ca 7% Cervical Ca 40% EOC 3-17% Endometrial Ca 2-14% BOT 30%

14. Breast Cancer 25% prior to menapause 7% under age 40 60% are hormone sensitive 5 yrs OAS rates Local disease 98% Regional disease 84% Noyes et al., Reproductive BioMedicine Online (2011) 23, 323– 333

15. Breast Cancer E2 & it’s metabolites ↑ disease progression Animal study Estrogen rec neg - tm progression Convensional stimulation --XX Aromatase inh - Letrozol (oktay 2006) SERM – Tmxfen (oktay 2003) Letrozole + GnRH

16. Breast Cancer Stimulation & oocyte harvest Do not delay treatment (Baynosa 2009, Madrigrano 2007) Treatment modification – Short-term modified protocols (10 days delay) (GnRH agonist rather than hCG) E ↑↑↑ in ovulation induction only 10 days & low E2 levels No effect on OAS, DFS (Azim et al., 2008)

17. FSS in Ovarian Malignancies (EOC, BOT,MOGCT, Sex Cord Stromal) Adequate surgical staging Removal of affected ovary and tube Preservation of the uterus and ovarian tissues in one or both ovaries Finally evaluation of normal appearing contralateral ovary* and endometrium (D&C)** Noyes et al., Reproductive BioMedicine Online (2011) 23, 323– 333 * Syncronised tumor and occult metastases (about%2.5-3) * Endometrioid type of epithelial tumors

18. Indication for FSS in EOC 1. Stage Ia Grade 1 Stage Ia Grade 2 (limited) 2. Stage Ic, Grade 3, Clear cell + Chemotherapy

19. Main Problems in FSS in EOC A) In preserved ovary Occult metastasis Relapse in preserved ovary B) Relapse related death due to the preservation of ovary, uterus C) Is there a place of complementary surgery after childbearing

20. FSS Does Not Affect Survival in Early Stage EOC Survival after FSS in patients with early ovarian cancer Without chemo is about 94%

21. Oncologic & Obstetric Outcome – Inv.EOC PatientsPregnanciesBirthRecurrenceDeath Colombo et al56251632 Zanetta et al84332253 Duska et al62211 Morice et al34107 4 Schilder et al52172652 Park et al6222 116 Raspagliesi et al103300 Colombo et al247672 Total328119(%36)104(%87)42(%13)20(%6)

22. 15% of all EOC15% of all EOC (Park et al., 2009) Young ageYoung age Early stageEarly stage 95% serous – mucinous95% serous – mucinous Do not require add. CTDo not require add. CT Overall survival 95 %Overall survival 95 % FSS in Borderline Tumors of the Ovary

23. BSO (very rare) USO Cystectomy (?) Partial excision* *at least 5mm TF border Ovarian procedures in BOT

24. Effect of surgical staging on 539 patients with borderline ovarian tumors: A Turkish Gynecologic Oncology Group study

25. Obstetric & Oncologic Outcome - BOT PatientsPregnanciesLive BirthsRecurrenceDeath Zanetta et al18944N/A350 Lim-Tan et al358660 Morice et al44171090 Boran et al62131040 Fauvet et al1623018270 Donnez et al1612 30 Seracchiolo et al196610 Carnatte et al178890 Morris et al432516141 Gotlieb al39222130 TOTAL626185(%30)107(%58)111(%18)1(%0.2)

26. Germ Cell Ovarian Tumors Young women & Adolescent girls. Unilateral often All need adjuvant chemotherapy, except stage- I, low grade immature teratomas and stage-IA dysgerminomas Chemo(platin based) is marked gonadotoxic, fertility preservation should be considered( Oocyte, embryo) accordingly. High Dose Gonadotrophin induction is needed. Noyes et al., Reproductive BioMedicine Online (2011) 23, 323– 333

27. Obstetric & Oncologic Outcome - GCT PatientsPregnanciesLive BirthsRecurrenceDeath Gershenson et al4022 32 Kanazawa et al2111911 Low et al74191472 Gershenson et al713730104 Zanetta et al1384128163 Perrin et al458742 Tangir et al64473853 TOTAL453185(%41)148(%80)46(%10)17(%3.8)

28. Endometrial Cancer and EIN/AEH Most frequent Gyn.Ca 25% premenopausal 5% under 40 age Type I good prognosis (PCOS) Grade I, EPR + Cure rate %95

29. At young ageAt young age Well differantiated End. CaWell differantiated End. Ca Stage IA, Grade I-IIStage IA, Grade I-II Progesterone therapyProgesterone therapy Evaluation of end. with 3 mts intervalEvaluation of end. with 3 mts interval Fertility desireFertility desire Fertility Sparing Treatment in Endometrial Cancer

30. Pretreatment Evaluation History (infertility...) Physicial Examination TVUSG D&C MRI enhanced – abdominopelvic – endovaginal coil Ca-125 Staging (Laparascopy or Laparatomy) Controversial??

31. Before and After Treatment MRI Sensitivity %80 Specifity %100

32. Progesteron Therapy MPA 200-600 /mg/ day Megestrol Acetate 40-160 /mg/day Levonorgestrel IUD / Prog Response Rate A. Hyperplasia %83-94 End. Ca %57-75.6 Duration of Treatment Range 3-6 months Median 9 months Recurrens rate A.Hyperplasia % 13 End. Ca % 11-50

33. Türk Jinekolojik Onkoloji Grubunun Endometrium Kanseri Fertilite Korunması Çalışması

34. P. Dursun et al. / International Journal of Gynecology and Obstetrics 119 (2012) 270–273

35. OUTCOMES - PROGESTERON THERAPY in ENDOMETRIUM CANCER PatientsRegressionRelapseLive BithsProgesterone Randal and Kurman12916Megestrol or MPA Duska et al121015MPA Imai et al14833MPA Kaku et al12921MPA Wang et al9843Megestrol Niwa et al12 85MPA Lowe et al2208Megestrol Sardi et al4303MPA Yang et al6422Megestrol Farhi et al4312Progestin Gotlieb et al13 69Megestrol TOTAL10081(%81)28(%28)47(%47)

36. Cervical Carcinoma 10%-15% of diagnosed during the childbearing years 43% of all cases younger than 45 years of age Seli E, Tangir J. Fertility preservation options for female patients with malignancies. Curr Opin Obstet Gynecol 2005 Jun;17(3):299–308.

37. Selection Criteria-1 Fertility desire; Age < 40 years; No evidence of local/distant metastasis; Sq/Adeno (except neuroendocrin type) Experienced team Dursun P, LeBlanc E, Nogueira MC. Radical vaginal trachelectomy (Dargent's operation) : a critical review of the literature. Eur J Surg Oncol. 2007 Oct;33(8):933-41. Epub 2007 Jan 5.

38. Selection Criteria-2 Stage Ia1 +/- LVSI, Ia2, Ib1; Tumor size <2 cm; Invasion less than 1 cm Disease located primarily on the ectocervix

39. Conservative management of early stage cervical cancer: is there a role for less radical surgery? Schmeler KM, Frumovitz M, Ramirez PT. Gynecol Oncol. 2011 Mar;120(3):321-5.Schmeler KMFrumovitz MRamirez PTGynecol Oncol. Authors n Parametrial inv. (%) Kinney 199583 0.0 Covens 2002536 0.6 Stegeman 2007103 0.0 Wright 2008270 0.4 Frumovitz 2009125 0.0

40. Type of Intervention Conisation/LEEP Trachelectomy* Trachelectomy following neoadjuvant chemotherapy Ovarian Transposition Lymphadenectomy * vaginal/abdominal/endoscopic

41. IA1 LVSI (-) CONE Tumor free margin and post-cone negative ECC Positive margin or positive ECC RE-CONE

42. TFB 0.5-1 cm 1 cm 2 cm

43. Laparoscopic pelvic LND Sentinel Node (immediate F/S or final pathology) Pelvic lymphadenectomy

44. Abd.Trachelectomy in Baskent

46. Obstetric & Oncologic outcome - TRACHELECTOMY PatientsPregnanciesLive BirthsRecurrenceDeath Shepherd et al123552854 Dargent et al96553643 Burnett et al213200 Bernardini et al80221874 Plante et al72503621 Schlaerth et al104200 Schneider et al367410 Boss et al192200 Ungar et al303200 Mathevet et al95563440 TOTAL582257(%44)164(%64)23(%3.9)12(%0.2)

47. Fertility Sparing Approach in Baskent Experience FSS Number Cx Ca 19 OC 46 BOT 38 Sarcoma 13 Total 116

48. n%  End Ca615,3  Ovarian Ca*2051,3  Breast Ca512,8  GTN25,1  Cx Ca12,5  Opere Pecoma12,5  Vulvar Sarcoma37,5  Lymphoma12,5  Total39100,0 Delivery After Any Cancer 37 GYN 2 Non-GYN 38 C/S Mean birth w. 2850gr * BOT, GCT

49. Patient Concent Selected patients Expected high survival Similar oncologic outcome Limited retrospective studies Experienced team (oncofertility teams) Close follow up Conclusions Advances in Treatment modalities Prolonged Survival, QoL More Survivors and Fertility Desire

50. Thank you for your attention