Surgical consideration for future fertility in gynecologic malignancies

Transcription

1 Surgical consideration for future fertility in gynecologic malignancies Hyun Hoon Chung, M.D., Ph.D. Department of Obstetrics and Gynecology Seoul National University College of Medicine

2 Conflict of Interest: None

3

4 Oncologic outcome Pregnancy outcome

5 Contents 1. Cervical cancer 2. Endometrial cancer 3. Ovarian cancer

6 Cervical Cancer

7 Options for Fertility Preservation Medical options Surgical options Embryo cryopreservation Ovarian transposition Oocyte cryopreservation Trachelectomy Ovarian cryopreservation Ovarian re-implantation

8 Morice P et al., Fertil Steril 1998;70: Morice P et al., Fertil Steril 2000;74:744-8 Ghadjar P et al., Radiat Oncol 2015;10:50 Feeney D et al., Gynecol Oncol 1995;56:3-7 Wo J et al., Int J Radiat Oncol Biol Phys 2009;73: CxCa Ovarian Transposition Moving ovaries out of the field of radiation Lower the amount of radiation exposure of ovaries One or both ovaries separated from the uterus Attached to the wall of the abdomen

9 CxCa Lateral Abdominal Wall Median Transposition Paracolic Gutter Gubbala et al., J Ovarian Res 2014;7:69 Sella et al., AJR 2005;184:

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12 Fallopian tube stump as the anchoring stem Pahisa et al., Int J Gynecol Cancer 2008;18:584-9

13 CxCa Ovarian Transposition If performed: Permanent suture Suture to a structure with strength Not peritoneum alone Consider multiple anchors

14 CxCa Considerations 25% risk of benign ovarian cysts Efficacy of transposition: 50% Risk of damage to blood supply Risk of occult metastasis Scatter radiation still cause significant damage (50 90%) Radiation to uterus Morice P et al., Fertil Steril 1998;70: Morice P et al., Fertil Steril 2000;74:744-8 Ghadjar P et al., Radiat Oncol 2015;10:50 Feeney D et al., Gynecol Oncol 1995;56:3-7 Wo J et al., Int J Radiat Oncol Biol Phys 2009;73:

15 CxCa Considerations Repositioning of the ovaries / IVF Necessary for achievement of pregnancy following transposition Importance of ovarian location Accessibility of transposed ovaries for oocyte collection Paracolic gutter: inaccessible for safe retrieval Zapardiel et al., Hum Reprod Update 2016;22: Chan et al., Gynecol Oncol 2017;144:631-6

16 Trachelectomy IA1 IA2-IB1

17 Trachelectomy Indications Women < 40 YO Cancers up to stage IB (IIA) < 2 cm in longest diameter Exclusion: Neuroendocrine Adenoma malignum Radical vs. Simple

18 Shim et al., Plos One 2018 in press Speiser et al., Arch Gynecol Obstet 2017;296: Benoit et al., Gynecologic Oncology Handbook 2 nd edition, 2018 Extent of Surgery Stage Type of surgery IA1 without LVSI Conization Simple trachelectomy considerable IA1 with LVSI Conization + PLND Simple trachelectomy + PLND Radical trachelectomy + PLND considerable IA2 IB1 IA1 with LVSI Radical trachelectomy + PLND (+/-) PALND

19 Shim et al., Plos One 2018 in press Speiser et al., Arch Gynecol Obstet 2017;296: Benoit et al., Gynecologic Oncology Handbook 2 nd edition, 2018 Extent of Surgery Stage Type of surgery IA1 without LVSI Conization Simple trachelectomy considerable IA1 with LVSI Conization + PLND Simple trachelectomy + PLND Radical trachelectomy + PLND considerable IA2 IB1 IA1 with LVSI Radical trachelectomy + PLND (+/-) PALND

20 Oncologic Outcome Stage IA1 Fertility-sparing conization vs. Rad. hysterectomy Stage IA2-IB1 Rad. Trachelectomy with PLND vs. Rad. hysterectomy 1,400 women < 40 yo 60% hyst my: 40% conization Comparable 5Y survival (99% : 98%) 587 patients < 2 cm No difference in recurrence No difference in survival Low morbidity Wright et al., Obstet Gynecol 2010;115: Gien et al., Gynecol Oncol 2010;117:350-7 Xu et al., Acta Obstet Gynecol Scand 2011;90:1200-9

21 Considerations Cervical stenosis: central problems Locating the exact position of the neo-cervix Contraception for 6-12 months 2 nd trimester abortion / PROM / Preterm delivery Chorioamnionitis Shim et al., Plos One 2018 in press Plante et al., Int J Gynecol Cancer 2017;27: Speiser et al., Arch Gynecol Obstet 2017;296:559-64

22 Feichtinger et al., Gynecol Oncol Res Pract 2016;3:8 Robova et al., Gynecol Oncol 2014;135:213-6 Pareja et al., Gynecol Oncol 2015;137: CxCa Fertility-sparing Surgery Indication Type of surgery Reproductive outcome Oncologic outcome IA1 LEEP / CKC No fertility impairment OR 1.7 for preterm delivery OR 2.69 for PPROM No different neonatal outcome Similar outcome compared with hysterectomy IA2, IB1 < 2 cm CKC + BPLND ST + BPLND 47% of spontaneous conception 14.3% of prematurity rate 97% 5-year DFS IA2, IB1 RT + BPLND > 60% of spontaneous conception 28% of prematurity rate Comparable recurrence and mortality with radical hysterectomy 98.4% long-term survival 4.5% relapse rate IB1 > 2 cm NAC + RT + BPLND 86% of spontaneous conception 86% of live-birth rate 90% of survival rate 7.6% of relapse rate

23 Corpus Cancer

24 EMCa Endometrial Cancer 7.1% of female cancers Median age of diagnosis: 62 YO 7% of EM cancer patients < 45 YO Gr1 without MM invasion/no extra-uterine involvement MM evaluation by MRI is mandatory for counseling Siegel et al., CA Cancer J Clin Oncol 2016;66:7 30 Froeding et al., Int J Gynecol Cancer 2015;25: Ben-Shachar et al., Gynecol Oncol 2004;93:233 7

25 EMCa Progesterone Treatment Oral (600 mg MPA daily or 160 mg MA daily) No consensus regarding Agent Dose Duration of treatment IUD (levonorgestrel-releasing IUD) Kim MK et al., Am J Obstet Gynecol 2013;209:358. e1-4 Gallos ID et al., Hum Reprod 2013;28: Gallos ID et al., Hum Reprod 2013;28: Abu Hashim H et al., Am J Obstet Gynecol 2015;213:469 78

26 EMCa Progesterone Treatment Superiority of MPA over MA Similar response rate Significantly higher risk of recurrence with MA Better response with MPA 600 mg Individualized treatment to minimize risks Thrombophlebitis Weight gain Headache Mood / libido change Leg cramp Park et al., Eur J Cancer 2013;49: Gallos et al., Am J Obstet Gynecol 2012;207:266 Ushijima et al., J Clin Oncol 2007;25:

27 EMCa Progesterone Treatment Better response in IUD treatment Comparative cohort study Complex hyperplasia 94.8% (237/250) LNG-IUS vs. 84.0% (79/94) oral progestogens (adjusted OR = 3.04, 95% CI , P = 0.001) Lower relapse rates Lower hysterectomy rates Kim et al., Am J Obstet Gynecol 2013;209:358. e1-4 Gallos et al., Hum Reprod 2013;28: Gallos et al., Hum Reprod 2013;28: Abu Hashim et al., Am J Obstet Gynecol 2015;213:469 78

28 EMCa Relapse after Progesterone Frequent up to 50 % of cases Followed-up Hysteroscopic examinations every 3 month Endometrial sampling 2 nd cycle of treatment: response rates of 89 % Combination of resection and progesterone Good oncologic and pregnancy outcomes Ushijima et al., J Clin Oncol 2007;25: Gunderson et al., Gynecol Oncol 2012;125: Park et al., Gynecol Oncol 2013;129:7 11 Mazzon et al., Fertil Steril 2010;93:

29 EMCa Minimizing the Estrogen Effect Addition of Letrozole Women with estrogen-sensitive tumors Ovarian stimulation with LNG-IUD in utero Minimize the effect of estrogenic stimulation on the EM Hysterectomy and BSO after childbearing Oktay et al., Reprod Biomed Online 2010;20:783 8 Rodriguez-Wallberg et al., Oncologist 2012;17: Juretzka et al., Fertil Steril 2005;83:1041 Niwa et al., BJOG 2005;112:317 20

30 EMCa Ovarian Preservation KGOG study: no difference in recurrence or survival Counseling recommended Early onset uterine cancer: associated with HNPCC 10% chance of ovarian cancer 25% rate of adnexal pathology in young patients Without BSO: comprehensive staging impossible Consideration of salpingectomy Lee et al., Gynecol Oncol 2013;131: Wright et al., Obstet Gynecol 2016;127:101-8 Benoit et al., Gynecologic Oncology Handbook 2 nd edition, 2018

31 Ovarian Cancer

32 EOC Epithelial Ovarian Cancer Early stage (IA) USO with staging, OM, pelvic and para-aortic LND Normal-looking contralateral ovary Most authors discourage sampling Impairment of ovarian reserve Causation of additional adhesions Laparoscopic fertility-sparing (FS) surgery (> IA, G3) Non-impaired survival rates reported Limited level of evidence Bentivegna E et al., Fertil Steril 2015;104: Morice P et al., Hum Reprod 2005;20: Ditto A et al., Gynecol Oncol 2015;138:78 82

33 EOC Non-Clear Cell Carcinoma No differences in survival rates Between FS surgery & radical surgery Overall 5-year survival rate: 87% 12% of recurrence rate after fertility-sparing surgery Platinum-based chemotherapy after FS surgery High-risk ovarian cancer (IAG2 or higher) Clear-cell carcinoma Kajiyama H et al., Hum Reprod 2011;26: Zapardiel I et al., Hum Reprod Update 2016;22: Ditto A et al., Gynecol Oncol 2015;138:78 82 Fruscio R et al., Ann Oncol 2013;24:138 44

34 Reports & Guidelines Japanese study Italian study Non-clear cell Stage IA, IC, grade 1 2 Clear cell Stage IA All patients with stage I except grade 3 GCIG NCCN Non-clear cell Clear cell Not for stage IC All patients with IA and IC Satoh T et al., J Clin Oncol 2010;28: Fruscio R et al., Ann Oncol 2013;24: National Cancer Institute, Okamoto A et al., Int J Gynecol Cancer 2014;24:S20 S25

35 EOC Tissue or Oocyte Cryopreservation Highly controversial Auto-transplantation Risk of reintroducing malignant cells Alternatives Culture & maturation of oocytes Protocol still under-development Donnez J et al., Nat Rev Endocrinol. 2013;9: Abir R et al., Hum Reprod 2016;31:750 62

36 EOC Risk-reducing Salpingo-Oophorectomy Lifetime risk of ovarian cancer BRCA1 mutation carrier: 39-46% BRCA2 mutation carrier: 12-20% Periodic screening with CA125 and TV-USG After the age of 30 ~ 35 years 5 ~ 10 years before the youngest age in the family RRSO reduce the risk of ovarian cancer by % Should be offered to women with mutation by age 40 Or after the conclusion of childbearing ACOG. Routine Screening for Hereditary Breast and Ovarian Cancer Recommended. March 23, 2009

37 BOT Borderline Ovarian Tumor 10-20% of ovarian epithelial tumors < 40 years: 1/3 of ovarian cancer cases had BOT Conservative surgery performed in most BOT cases Skirnisdottir I et al., Int J Cancer 2008;123:

38 BOT Borderline Ovarian Tumor USO on the affected side recommended Cystectomy associated with higher recurrence In case of bilateral BOTs USO and contralateral cystectomy Oncological prognoses similar with radical surgery Micropapillary serous BOT A higher level of lethal recurrence reported Zanetta G et al., J Clin Oncol 2001;19: Vasconcelos I et al., BJOG 2016;123:

39 BOT Borderline Ovarian Tumor Conservative Tx associated with high recurrence rates Very low mortality rate after a follow-up of 7 years Fertility-sparing surgery in advanced BOT (IC III) Not associated with relapse or mortality Zanetta G et al., J Clin Oncol 2001;19: Fauvet R et al., Cancer 2004;100: Suh-Burgmann E et al., Gynecol Oncol 2006;103:841 7 Helpman L et al., Fertil Steril 2015;104:138 44

40 Quirk JT et al., Gynecol Oncol 2005;99: Smith HO et al., Obstet Gynecol 2006;107: Chan JK et al., J Surg Oncol 2008;98:111 6 Mangili G et al., Int J Gynecol Cancer 2011;21: Park JY et al., Gynecol Oncol 2015;137: GCT Germ Cell Tumors Malignant GCT Rare (3-5% of ovarian tumor) Most common ovarian tumor in very young women < 20 YO Majority diagnosed with stage I disease Due to rapidly growing character Encouraging overall survival rate Fertility-sparing surgery not associated with poor outcome

41 GCT Germ Cell Tumors Heterogeneous disease Bilateral disease: uncommon Biopsy of Normal-looking contralateral ovary Not recommended Due to the risk of adhesions / impairment of ovarian reserve Kurman RJ et al., Hum Pathol 1977;8: Gershenson DM et al., J Clin Oncol 2007;25:

42 GCT Germ Cell Tumors Immature Teratoma Yolk-Sac Tumor Dysgerminoma Treatment Fertility-sparing surgery : USO, peritoneal staging, omentectomy Fertility-sparing surgery with Standard chemotherapy Fertility-sparing treatment at all stages Survival Rate Complete staging associated with favorable outcomes at advanced stage 5-yr > 93% 5-yr > 90% 10-yr DFS> 90% 10-yr OS 100% Recurrence High in Gr 2-3 tumor

43 Uterine Transplantation For patients with radical hysterectomy Uterine transplantation is the only possibility Successful results reported by Swedish group in 2015 The procedure expected to extend in the future Brannstrom M et al., Lancet 2015;385: Pondrom S. Am J Transplant 2016;16:375 6

44 2013, Sweden 35-year-old woman with congenital absence of uterus Donor: 61-year-old parous woman IVF with 11 cryopreserved embryos Preeclampsia C/S at 31+5 weeks Male / 1775 g /

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46 Summary Fertility preservation strategies for future fertility Gynecologic surgery Radiation therapy Chemotherapy Early cervical cancer: Conization / Trachelectomy Early endometrial cancer: Progestin therapy Early ovarian cancer: Conservative surgery Pelvic shielding Ovarian transposition Embryo cryopreservation Oocyte cryopreservation Embryo cryopreservation Oocyte cryopreservation

47 Summary Potential Fertility Preservation Strategy Cervical cancer Conization Trachelectomy (Simple vs. Radical) Ovarian transposition prior to radiation treatment Oocyte / embryo cryopreservation Progestins (oral, LNG-IUD or combinatory) Endometrial cancer Ovarian cancer Hysteroscopic resection Hysterectomy with ovarian preservation Oocyte / embryo cryopreservation Unilateral oophorectomy Oocyte / embryo cryopreservation

48 Zapardiel et al., Hum Reprod Update 2016;22:

49 Zapardiel et al., Hum Reprod Update 2016;22:

50 Thank you for your attention.

51 Summary Fertility-preservation with early-stage GYN cancers Oncological safety most important Obstetric outcome Women with sub-fertility may need to undergo ART Guidelines for fertility preservation Importance of timely discussion The impact of cancer treatment on future fertility

52 Strategies for Fertility Preservation GYN cancer Cervical cancer Endometrial cancer Ovarian cancer Conization Potential Fertility Preservation Strategy Radical trachelectomy Ovarian transposition prior to radiation treatment Uterine sparing radiation Oocyte/embryo cryopreservation Medical management with progestins (Oral, IUD or combinatory) Hysteroscopic resection Hysterectomy with ovarian conservation Oocyte/embryo cryopreservation Unilateral oophorectomy Oocyte/embryo cryopreservation

53 Von Wolff M et al., Fertil Steril 2009;92: Bedoschi G et al., Fertil Steril 2013;99: Donnez J et al., Nat Rev Endocrinol. 2013;9: Dahhan T et al., Hum Reprod 2014;29: Green D et al., J Clin Oncol 2009;27: CxCa Oocytes or Embryo Cryopreservation Before cancer treatment Ovarian stimulation Cryopreservation of oocytes or embryos Problem Irreversible damage of irradiated uterus Unsuccessful results expected with a heavily irradiated uterus Need for other uterus / surrogate

54 CxCa Tissue Cryopreservation A viable option Oocyte or embryo cryopreservation not feasible Later re-transplantation Transplantation site Heterotopic transplantation Orthotopic transplantation Checking resumption of ovarian function > 60 live-birth after ovarian tissue transplantation Donnez J et al., J Assist Reprod Genet 2015;32: Donnez J et al., Fertil Steril 2013;99: Kim SS et al., Fertil Steril 2009;91:

55 CxCa Tissue Cryopreservation Concerns The risk of reseeding cancer cells at time of retransplantation Possibility of presence in the tissue preserved Reported ovarian metastasis 6 % of patients with adenocarcinoma 1 % of patients with squamous cell carcinoma No reported relapse 5 published cases of retransplantation of ovarian tissue NakaNIshi T et al., Gynecol Oncol 2001;82:504 9 Donnez J et al., Nat Rev Endocrinol. 2013;9: Kim SS et al., Fertil Steril 2009;91:

56 CxCa Quality of Life Persistently reduced QoL. Bladder-emptying problems in more than 40 % Lymphedema in more than 10 % of cases Lower QoL after vaginal or abdominal trachelectomy. Cold-knife conization and laparoscopic LND Not associated with reduced sexual satisfaction and QoL. Froeding L et al., J Sex Med 2014;11: Froeding L et al., Int J Gynecol Cancer 2015;25: Fanfani F et al., J Reprod infertility 2014;15:29 34

57 GCT Chemotherapy Immature Teratoma Yolk-Sac Tumor Dysgerminoma Stage I, grade 2 3 BEP in advanced stage Early stage Chemotherapy Adjuvant chemotherapy vs. Expectant approach with chemotherapy only in relapse Favorable OS rates No compromised fertility Recommended in relapse

58 GCT Chemotherapy Rationale of expectant approach with chemotherapy only in relapse situations GCT survivors treated with chemotherapy High chemotherapy-related secondary malignancy Reproductive function Relatively good Travis LB et al., J Natl Cancer Inst 2010;102: