Fertility Sparing Surgery (FSS) in Gynecologic Oncology Ali AYHAN, MD. Baskent University School of Medicine Department of Obstetrics & Gynecology Division of Gynecologic Oncology

The Main Purpose of Cancer Therapy High cure Low morbidity High level of quality of life (as a mood, sexuel life, cosmetic appearence, fertility preservation...)

All Therapeutic Modalities in Female Cancer Are associated with infertility (radiation, radical surgery, chemo...)

is performed by different centers Therefore Fertility saving surgery instead of radical in early stage selected gyn/cancer is performed by different centers

FSS Objectives Similiar oncologic outcomes to standard therapy Favorable obstetric outcome Benefits > risks Low morbidity and cost

Benefits-Risks of FSS Risks Benefits Increase in probability of recurrence and death Additional surgery Benefits Preservation of fertility Maintanence of endocrine function

The Main Requirement of FSS Preserving of the uterus Preserving at least one ovary

Fertility Saving Surgery Depends on Type and origions of tumor Stage, grade, histology Age, performance Fertility desire Previous infertility problems Close follow up

Indications for Fertility Saving Surgery All germ cell Sex cord stromal (early stage) Borderline ovarian tumor Invasive EOC Cervical Carcinoma Endometrial Carcinoma

Adequate surgical staging Removal of affected ovary and tube Fertility Saving Surgery in Ovarian Tumors (EOC, BOT,MOGCT, Sex Cord Stromal) Adequate surgical staging Removal of affected ovary and tube Preservation of uterus and contralateral ovary Finally evaluation of normal appearing contralateral ovary* and endometrium (D&C)** * For occult metastases * Endometrioid type of epithelial tumors

SO TODAY; PROBLEM IS SMALL FSS in EOC 25-30% of all EOC are early stage at the diagnosis 14% of EOC will occur under 40 years Of these 62% will be stage I and IIa Not all, many of these desire to preserve fertility SO TODAY; PROBLEM IS SMALL

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

Main Problems in FSS in EOC A) In preserved ovary 1) occult metastasis 2) Relapse in spared ovary B) Is there any relationship between relapse, death and preservation of ovary, uterus or other risk factors C) Is there a place of complementary surgery after childbearing

Occult Metastasis in Normal Appearing Ovaries Varies from 7-33% in old literature In new literature, this figures are lower than older (about 2.5%)

(ICON1 and ACTION Studies) Survival 925 patients with early stage disease were subjected to Radical Surgery +Chemo (ICON1 and ACTION Studies) 5 yrs DFS 76% 5 yrs OS 82% J Natl Cancer Inst, 2003:95:105-112

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

Recurrence, Death and Pregnancy After FSS in EOC Author Recurrences Ovary / Total Deaths Pregnancy Colombo n=152 11 /18 9 (5.9%) 53 (35%) Brown n=16 2 / 2 2 ? Schilders n=52 3 / 5 26 UK Study n=56 12% Colombo N et al IJGC 2005, Monk BJ, DiSaia PJ, IJGC 2005, Farthing A, BJOG 2006

Obstetric Outcome After Fertility Saving Surgery in EOC Author % Pregnancy Term Delivery Abort. Ectopic Anomaly Colombo 1994 100 (25/25) 16 4 2 Zanetta 1997 56 (20/36) 17 Duska 1999 33.3 (2/6) 1 Morice 2001 22.2 (4/18) 3 Schilder 2002 71 (17/24) 26 5 Total 56.5 (68/109) 64 14

Fertility –Sparing Surgery in Borderline Tumors of the Ovary: 15% of all EOC Young age Early stage 95% serous - mucinous Overall survival 95 %

Fertility Sparing Surgery in Borderline Ovarian Tumors Staging Leaving the uterus Some functional ovarian tissue in place Evaluation of endometrial cavity?

Ovarian procedures in BOT BSO (very rare) USO Cystectomy Partial excision Cortical ovarian biopsy for cryopreservation

After FSS Recurrence 7.7-31 % Disease related death 0 Donnez, 2003 Morriu, 2001 Cutlieb, 1998 Disease related death 0 Pregnancy rates 31.8, 38.5 and 63.3 % Donnez, 2003

Ovarian Tumors of Low Malignant Potential Study No. Pts. Stage No. Pregn. Lim-Tam 1988 35 IA-III 8 Gotlieb 1998 39 22 in 15 Morris 2000 43 25 in 12 Zanetta 2001 189 44 in 44 Morice 2001 44 17 in 14 Rao 2005 38 6 in 5 Boran 2005 62 10 in 10

FSS in MOGCTs 20-25 % of all ovarian neoplasm Only 3 % of these are malignant Young age Early stage Generally unilateral (Dysgerminoma 12%)

Fertility Sparing Surgery In early and selected advanced stage Full staging Removal of affected ovary Preserving the contraleral ovary Preserving of the uterus + Chemo In early and selected advanced stage

The survival in FSS is similar to radical surgery in MOGCTs Survival in MOGCTs The survival in FSS is similar to radical surgery in MOGCTs

Pregnancy after surgery in MOGCTs Number of patients Pregnancy rate 29/32 76 % 19/20 95 % (Surg +Chemo) 16/20 80 % (Surg +Chemo) 12/12 100 % (Only surgery) Low et al, Zanette et al Gerhenson et al

Obstetric Outcome in MOGCT Author % Pregnancy Term Delivery Abort. Ektopic Anomaly Gershenson 1988 100 (12/16) 22 Perrin 1999 ------ 8 -- Low 2000 95 (19/20) 16 Zanetta 2001 80 (16/20) 26 9 3 Tangir 2003 76 (25/33) 38 2 Toplam 87.75 (72/89) 110 11

After Fertility Sparing Surgery: Oncologic Outcome: After Fertility Sparing Surgery: EOC MOGCTs BOT Survival is similiar to radical surgery

FSS in LMS 25% of uterine sarcomas 1% of all uterine malignancies 0.29 of all myomectomies (6815 myoma) 25% premenopausal

FSS in LMS Local excision (at least 0.5-1cm tumor free border )

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

Pretreatment Evaluation History (infertility...) Physicial Examination TVUSG D&C Abdominopelvic/ endovajinal coil MRI Ca-125 Laparoscopic evaluation Response to Progesterone or Staging Laparotomy

MRI Sensitivity %80 Specifity %100 Before and After Treatment

Progestogenic Agents MPA 200-600 /mg/ day Megace 40-160 /mg/day IUD / Prog Response Rate Hyperplasia with Atypia %83-94 End. Ca %57-75.6 Duration of Treatment Range 3-6 months Median 9 months Recurrens Hyperplasia with Atypia % 13 End. Ca % 11-50

Response Rates to Progesterones in Endometrial Cancer Drug Time Regr. Recur. Pregnancy 7 MA 3 ay 4 2 14 MA/ MPA 1 yıl 9 1 3 12 MA / MPA 3-18 ay MPA 2-14 ay MA / Tam - 8 13 3.5 ay 6 67 16 15 *26 %55 IVF 31 Kım 1997, Randal-Kurman 1997, Kaku 2001, Wang 2002, Gotlieb 2003 *Jadoul-Donnez 2003 Fertil Steril 2005;84; 1564

FSS in Endometrial Cancer At young age Well differantiated End. Ca Stage IA, Grade I-II Progestin therapy Evaluation of end with 3 months interval Fertility desire

*Tumor <2 cm, Deep Stromal Inv. <1 cm FSS in Cervical Cancer %27.9 patients < 40 age (SEER) Cx Ca most prevalant in 35-39 years of age Adenocarcinoma is a problem Squam/ Adeno (except neuroendocrine type) IA-IB1* *Tumor <2 cm, Deep Stromal Inv. <1 cm

FSS in Cervical Cancer Cone Only Preinvazive Ia1 LVSI (-) 1a1 LVSI (+) 1b1 2 cm Der:1 cm In selected cases with stage Ib-IIA ovarian transposition,oocyte and/or embryo criopreservation Cone Only Pelvic LND* + Radikal Trachelectomy** *Endoscopic/ Laparotomy / Sentinel Node **Vaginal /Abdominal

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

Clinical importance of margin and ECC Variables Residual tumor Margin Negative 3% Positive 22% Margin and ECC 4% 33%

Pelvic Node Metastasis in Stage IA1 Depth of Invasion LNM + 1mm or less 0,1 1-3 mm 0,5

Stage IA1 with LVSI (+) IA2 Pelvic lymphadenectomy Radical trachelectomy* plus Cervical cerclage *Free margin >at least 5mm-1 cm

Why lymphadenectomy in Stage IA2 Variables % LNM Metas. LNM + 7.3 Invasive Rec 3.1 Death of Dis. 2.3 Van Nagell et al..... Creasman et al

Pelvic lymphadenectomy + Radical trachelectomy FSS in Stage IB1 Lesion ≤ 2cm Depth of Inv ≤ 1cm LNM negative Upper cervical involvement (-) Pelvic lymphadenectomy + Radical trachelectomy

Radical trachelectomy (1994 Dargent) Removal of primary tumor Parametrectomy 1/3 upper vaginectomy Preserving uterine fundus Pelvic lymphadenectomy

Radical trachelectomy Abdominal Vaginal Lymphadenectomy (Open and Endoscopic)

Radical trachelectomy and No difference between Radical trachelectomy and Radical hysterectomy for Recurrence and Death

Pregnancy Results after VRT Fertility Desire No.of Pregn/ Patient Livebirth 96 42 56/33 34 72 48/31 28 93 39 22/18 18 30 13 14/8 9 19 4 4/3 2 10 4/4 315 144 148/97 Mathevet 2003, Plante 2004, Steed-Covens 2003, Shephard 2001, Burnett 2003, Schlaerth 2003 Fertil Steril 2005;84:156

Reproductive Outcome after Trachelectomy %25-43 infertility Pre-operative (STD) ve post-operative (stenosis) Loss of fertility desire in %25 Pregnancy rate %71 Delivery rate % 41 First trimester loss %21 Second trimester loss %8 Preterm delivery %20-%30 Cervical Insufficiency (Cerclage Saling Procedure, Ab, USG ??) PPROM Informed Consent !!!!! Boss et al, Gynecol Oncol, 2005

Conclusion-I Fertility Preservation Options in Females Conservative surgery Embryo cryopreservation Oocyte cryopreservation Ovarian tissue cryopreservation Ovarian supression (GnRH analogs)

Conclusion-II Fertility Preservation Strategies Treatment can be delayed Treatment cannot be delayed IVF-Embriyo Freezing Oocyte freezing Ovarian Tissue Freezing In vitro maturation in high risk for ovarian involvement Add TMX or Aromatase Inhibitors for Est-sensitive

Thank you…