1. Fertility Sparing in Gynecological Cancers Fırat Ortaç, MD Güven Hospital Güven Hospital Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology

2. Cancer Treatment Objective Cure Adverse Effects Psychological effects Psychological effects Cosmetic problems Cosmetic problems Loss of organ function Loss of organ function Sexual and reproductive dysfunction Sexual and reproductive dysfunction Fertility sparing surgery

3. Goals of Fertility-Sparing Surgery(FSS) Preservation of reproductive potential Preservation of hormonal function Preservation of healthy body image No compromise in curability

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

5. Defining prognostic factors Evidence-based Data Fertility Sparing Surgery Physician

6. Fertility-Sparing in Gynecologic Oncology The patient and family must be: The patient and family must be:  aware of the problem  involved in the final decision Once the fertility has been completed, demolitive procedure should be considered Once the fertility has been completed, demolitive procedure should be considered

7. Fertility-Sparing in Gynecologic Oncology Age Age Desire to preserve fertility Desire to preserve fertility Tumor factors Tumor factors Histologic type, grade, others Stage of disease Stage of disease

8. Principles in Treatment of Early- Stage Cervical Cancer Patient’s general status Desire of fertility Tumor factors Depth and width of invasion Size of cervical lesion LVSI

9. Traditional treatment of early stage cervical cancer beyond micro-invasion Radical hysterectomy +PPLND Loss of fertility

10. LVSI Pelvik lenf nodu metastazı Pelvik rekürens Lenfadenektomi – Radikal cerrahi

11. Spread of Cervical Cancer Laterally (Dominant)  Parametrium Vertically (rare) Stage Ib and IIa  0% Stage IIb  20%

12. Fertility Sparing Surgery in Early-Stage Cervical Cancer ID<3 mm LVSI(-) MARGIN (-) CONIZATION FOLLOW-UP

13. Cold Conization

14. CONIZATION < 10 mm Does not affect fertility potential Clin. Exp. Obstet. Gynecol, 1992: 19(1):40-2

15. Effect of Con on Pregnancy Outcome < 18 mm < 15 mm NO EFFECT > 18 mm 25% PRETERM LABOR 18% PROM Sadler L. Et al., Am J Med Ass, 2004 Frencezy A, 1995 Haffenden DK, 1993 Tan L, 2004 > 15 mm

16. Fertility Sparing Surgery in Early-Stage Cervical Cancer Stage Ia 1 (LVS +) Stage Ia 2 (LVS  ) Stage Ib-IIa (  2cm) Desire of fertility Lymph Node Dissection (L/S, L/T) Node (-) Node (+) RVT RT Sentinel Lymph Node RATRATRATRAT

17. Sentinel lymph node

18. Radical Trachelectomy 1994  Dargent

19. Vaginal Radical Trachelectomy (VRT) in Early-Stage Cervical Cancar by Dargent in Lyon, France Modification of the Schauta-Stoeckel technique of vaginal radical hysterectomy L/S Pelvic lymphadenectomy Preservation of the upper endocervix and uterine corpus

20. Radical Trachelectomy (RT)

21. VRT-AbRT Indications Patient who desires preservation of fertility Patient who desires preservation of fertility FIGO Stage Ia 1 (+LVSI), Ia2, Ib1 FIGO Stage Ia 1 (+LVSI), Ia2, Ib1 Lesions  2 cm in diameter Lesions  2 cm in diameter Limited endocervical involvement Limited endocervical involvement - MRI and colposcopy

22.  Lymph node dissection(Sentinel lymph node)  Parametrectomy  Trachelectomy (FS analyse- free margin 5-8 mm)  Cervical circlage Surgıcal procedure

23. RTRTFeasibility  No evidence of lymph node metastasis (Frozen section at L/S)(ultrastaging)  Upper endocervical margins free of tumor (Frozen section)

24. VRTVRTResults  Dargent (Lyon) 82  Plante and Roy (Quebec) 44  Covens (Toronto) 58  Shepherd (London, UK) 40  Total224

25. VRTVRT Oncologic Outcome (N:24) Follow-up (months)30 Recurrences7(3.1%)  Parametrium 3  Pelvic side wall1  Distant 3 No cervico-uterine recurrence

26. Pregnancy Results after VRT nFertility Desire No.of Pregn/ Patient Livebirth 964256/3334 724248/3128 933922/1818 301314/89 1944/32 1044/42 315144148/9793 Fertil Steril 2005;84:156

27. VRTVRTConclusions Abdominal way is possible Abdominal way is possible The risk of recurrence is unchanged The risk of recurrence is unchanged Fertility is preserved Fertility is preserved But pregnancies are at high risk But pregnancies are at high risk An international study is required to confirm indications and limits of this conservative technique An international study is required to confirm indications and limits of this conservative technique

28. Preserving Fertility in Endometrial Cancer 2% -14 % of endometrial cancer 2% -14 % of endometrial cancer  40 years  40 years Up to 25% PCOS Up to 25% PCOS G 1 G 1 Early stage Respond to progestin treatment Respond to progestin treatment

29. Stage Ia, G 1 Stage Ia, G 1 Standart treatment Standart treatment TAH + BSO TAH + BSO Preserving Fertility in Endometrial Cancer

30. Endometrial Cancer Endometrial Cancer Fertility Desire Fertility Desire Pretreatment Evaluation Pretreatment Evaluation Tumor TumorGrade Depth Depth of MI Tumor TumorSize Hormone Hormone receptor status Flow cytometric analysis Flow cytometric analysis Favorable Favorable prognosis prognosis Preserving Fertility in Endometrial Cancer

31. Inclusion Criteria  Age < 40 years  Nulliparous status  Endometrioid Carcinoma  G1  Presence of PgR  Normal serum levels of CA 125 (<35 u/mL) and CEA (< 5 ng/mL)  Tumor DNA index < 1.3  Absence of MI or extrauterine spread (by vaginal USG and MRI),surgıcal staging Preserving Fertility in Endometrial Cancer

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

33.  Explain the patient the risk of conservative treatment  Evaluate the patient for prognosis  Medical treatment (Megestrol acetate 40-160 mg/d, MPA 30 mg/d  Tamoxifen 30 mg/d or GnRHa)  Repeated D&C; hysteroscopy (+tubal blockage)  No residual disease  Assisted reproduction  Elective hysterectomy when the patient no longer desires to maintain fertility Preserving Fertility in Endometrial Cancer

34. Progestogenic Agents MPA 30/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

35. There is no consensus Which progesterone formulation to use What schedule to use What dose to use How long to treat How often to resample

36. 72 cases in literature Preserving Fertility in Endometrial Cancer Positive response histologically documented histologically documented 55 cases (76%)

37. Endometrial Cancer Literature Overview (1966-2006) No pts.= 53 80% were nulliparous In 96% of them the tumor was well differentiated At least 36 pregn. were obtained by ART 70% of pts. Underwent a hysterectomy after completing gestation

38. Diagnosis Diagnosis  Pre-operative?  Intra-operative frozen section?  Histopathological evaluation of hysterectomy or myomectomy specimen. Uterine Leiomyosarcoma (LMS)

39. Incidence Uterine LMS patients operated for presumed leiomyoma 0.1-0.3%

40. Safe margin: 3-5 mm. ? Safe margin: 3-5 mm. ? <10 mitoses/per 10 HPF <10 mitoses/per 10 HPF Solitary pedinculated mass Solitary pedinculated mass Fertility Sparing Surgery in LMS

41. Accurately restage the patients  Color doppler USG  Hysteroscopy  Chest X-ray  MRI or CT scan Fertility Sparing Surgery in LMS

42. Cesarean section Multiple uterine biopsies should be taken. Fertility Sparing Surgery in LMS DeliveryDelivery

43. Lissoni A (Gynecol Oncol 70(3): 348-50 (1998) Between 1982-1996 (8 patients) Between 1982-1996 (8 patients) Median age: 29 Median age: 29 All nulliparous All nulliparous Tumor was confined to myoma Tumor was confined to myoma Mean mitotic count 6 per 10 HPF Mean mitotic count 6 per 10 HPF 3 pregnancies 3 pregnancies Median follow-up 42 months Median follow-up 42 months 7 patients alive 7 patients alive One patient died (26 months after diagnosis). One patient died (26 months after diagnosis). Fertility Sparing Surgery in LMS

44. Fertility Sparing in Epithelial Ovarian Cancer and Borderline Tumors

45. Optimal Staging: USO or cystectomy (in BOT) USO or cystectomy (in BOT) Peritoneal washing and cytology Peritoneal washing and cytology Inspection of the contralateral ovarian surface, biopsies of any suspicious lesions Inspection of the contralateral ovarian surface, biopsies of any suspicious lesions Wedge resection of the opposite ovary? Staging biopsies of the peritoneal cavity Staging biopsies of the peritoneal cavity Sampling of retroperitoneal lymph nodes or radical lymphadenectomy since 1990 Sampling of retroperitoneal lymph nodes or radical lymphadenectomy since 1990 Omentectomy, appendectomy. Omentectomy, appendectomy. Fertility Sparing Surgery in Epithelial Ovarian Cancer and Borderline Tumors

46. Recurrence rate in the patients underwent conservative surgery for border-line tumors is %7 Recurrence rate in the patients underwent conservative surgery for border-line tumors is %7 Gynecol Oncol 55;552-6, 1994. Fertility Sparing Surgery in Borderline Tumors

47. Retrospective review Retrospective review 82 patients 82 patients 39 patients underwent conservative management 39 patients underwent conservative management Three patients had a contralateral recurrence (7%) Three patients had a contralateral recurrence (7%) 22 pregnancies were achieved. 22 pregnancies were achieved. Border-line Tumors of the Ovary Conservative Management and Pregnancy Outcome Cancer 1998 Jan, 1;82(1):141-6

48. Stage Ia G1 and Border-line No further treatment Stage Ia G2, G3 Chemotherapy Stage Ic-III Selected cases Requested by patients herself Preliminary reports. FROZEN Invasive Epithelial Ovarian Cancer and Border-Line Tumors Desire for fertility Endometrial biopsy Optimal Staging

49. Can conservative surgical approach be used in selected young patients with ovarian cancer who would usually undergo radical operations. Cancer 1998 Jan, 1;82(1):141-6 Retrospective study between 1980-1994 Retrospective study between 1980-1994 10 patients with high grade or limited extraovarian disease 10 patients with high grade or limited extraovarian disease Stage Ia G32Stage Ia G32 Stage Ic2Stage Ic2 Stage IIIa2Stage IIIa2 Stage IIIc4Stage IIIc4 All patients were given adjuvant CT All patients were given adjuvant CT All patients were alive median follow-up 70 months All patients were alive median follow-up 70 months 9 patients were menstruating regularly 9 patients were menstruating regularly Three had became pregnant. Three had became pregnant.

50. Ovarian Cancer Treatment with Fertility-Sparing Therapy Stage IA and IC epithelial ovarian cancer Stage IA and IC epithelial ovarian cancer 1965 to 2000, n=52 1965 to 2000, n=52 20 (%38) received chemotherapy 20 (%38) received chemotherapy 9 (17%) eventual TAH 9 (17%) eventual TAH 5(10%) recurred, 2 died 5(10%) recurred, 2 died 24 (46%) attempted, 17 (33%) conceived 24 (46%) attempted, 17 (33%) conceived  26 term, 5 SAb  33% take home baby  33% take home baby Schilder et al., Gynecol Oncol, 2002

51. Fertility Sparing Surgery in Epithelial Ovarian Cancer and Borderline Tumors CONCLUSIONS For more advanced stages, additional investigation is needed. For more advanced stages, additional investigation is needed. After completion of fertility, residual ovary should be taken out. After completion of fertility, residual ovary should be taken out.  Incidence of ovarian cancer gets higher with age.  Screening method are unreliable.

52. Germ Cell Tumors of the Ovary Incidence: less than %5 of all ovarian neoplasm. Incidence: less than %5 of all ovarian neoplasm. Age: the first and second decade Age: the first and second decade Usually unilateral Usually unilateral

53. 1978 Forney first reported a case of successful pregnancy in a 18 year-old with EST of ovary. Obstet Gynecol 52, 360-62 (1978) 1985 Gershenson at the MD Anderson Hospital. 48 patients with malignant germ cell tumors Full-term pregnancies in 6 cases Cancer 56, 2756-2761 (1985) FSS in Germ Cell Tumors of the Ovary

54. Rationales Unilaterality of tumor Unilaterality of tumor Improvement of prognosis by modern combination chemotherapy Improvement of prognosis by modern combination chemotherapy 1970s the VAC regimen 1980s the PVB regimen POMP/ACE. POMP/ACE.

55. A Report of 28 Cases / Cancer 42, 1152-1160 (1978) Tumor was confined to one ovary in all cases. Tumor was confined to one ovary in all cases. All patients were taken chemotherapy except two with stage I immature teratoma. All patients were taken chemotherapy except two with stage I immature teratoma. More than 5 years survival in 13 cases (59.1%) More than 5 years survival in 13 cases (59.1%) 7 of 12 married patients, became pregnant, all had term delivery. 7 of 12 married patients, became pregnant, all had term delivery. Treatment of Malignant Ovarian Germ Cell Tumors With Preservation of Fertility

56. ObstetricObstetric Author% PregnancyTerm Delivery Abort.EktopicAnomaly Gershenson 1988 100 (12/16)22000 Perrin 1999 ------8-- 0 Low 2000 95 (19/20)16-- 0 Zanetta 2001 80 (16/20)269--3 Tangir 200376 (25/33)382--0 Toplam87.75 (72/89) 1101103 Outcome in GCT

57. Conclusion Conclusion Regardless of the stage is a safe and practicable procedure in the absence of involvement of CONTRALATERAL OVARY AND UTERUS Regardless of the stage is a safe and practicable procedure in the absence of involvement of CONTRALATERAL OVARY AND UTERUS Fertility Sparing Surgery in Germ Cell Tumors of the Ovary

59. History of ART The new millenium: The new millenium:  2001 Clinic Specific Success about 28% per cycle overall  Oocyte and ovarian slice cryopreservation with function (Oktay)  İnvitro maturation matures

60. Lancet, March 13, 2004

61. Fertility Preservation Strategies Treatment can be delayed Treatment cannot be delayed IVF – embryo freezing Oocyte freezing Ovarian tissue freezing Add tamoxifen or aromatase inhibitors for estrogen-sensitive In vitro maturation in high risk for ovarian involvement

62. As we discover what can be done, we need to learn what should done

63. Thank you…

65. Fertility-Preserving Treatment in Endometrial Adenocarcinoma Stage IA, grade 1, 1991-9 Stage IA, grade 1, 1991-9 N=9, average 32 years N=9, average 32 years Megace, tamoxifen, +GnRHa Megace, tamoxifen, +GnRHa 8 CR, 1 TAH 8 CR, 1 TAH 4 pregnant 4 pregnant  2 term after ART, 2 ectopic %22 take home baby %22 take home baby Wang et al., Cancer, 2002