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ART in Cancer Survivors Semih Kaleli Cerrahpaşa Medical Faculty

ART in Cancer Survivors Semih Kaleli Cerrahpaşa Medical Faculty Dept. of Obstetrics and Gynecology and IVF Unit. Cancer Patients in Reproductive Era. Breast cancer - 15 % of all BC under 45 yrs - 1.5-2 % of women will have BC under 45 Cervix cancer

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ART in Cancer Survivors Semih Kaleli Cerrahpaşa Medical Faculty

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  1. ART in Cancer Survivors Semih Kaleli Cerrahpaşa Medical Faculty Dept. of Obstetrics and Gynecology and IVF Unit

  2. Cancer Patients in Reproductive Era • Breast cancer - 15 % of all BC under 45 yrs - 1.5-2 % of women will have BC under 45 • Cervix cancer - 25 % of all CC premenopausal • Leukemia, lymphoma, thyroid cancer, CNS tumor and gonadal tumors relatively high in both sexes • Childhood cancers/juvenile cancers - leukemia (ALL), lymphoma, neuroblastoma, osteosarcoma, Wilm’s tumor - It is estimated 1 in 250 adults will be childhood cancer survivor by 2010

  3. IVF Outcome in Cancer Patients * 1 stage I ovarian cancer patients died of recurring disease within 1 yr Genital cancers 24 Lymphoma-leukemia 20 Skin cancers 10 CNS tumors 7 Thyroid 4 n:70 Ginsburg. IVF in cancer patients and survivors. Fertil Steril 2001

  4. IVF Outcome in Cancer Patients Oocytes No.Em. No ET Cryo-cycle Delivery rate Women local Tx 14.5 7.5 4.1 2 40.0 % (14/56) syst.Tx 10.3 7.0 4.1 0 13.3 % (2/15) freeze 18.7 11.3 - 12 - Men local Tx 6.8 3.8 3.8 0 0 % (0/5) syst.Tx 13.2 6.8 3.4 2 18.2 % (2/11) (pre-chemo) syst.Tx 12.9 7.5 4.0 3 37.5 % (9/24) (post-chemo) Ginsburg. IVF in cancer patients and survivors. Fertil Steril 2001

  5. Tam-IVF vs Natural-IVF in Breast Cancer Patients Variable TamIVF NCIVF p • Peak E2 442 278 NS • Total follicles 1.3 1.3 NS • Follicles >17 mm 1.2 0.9 NS • Total oocytes 1.8 1.7 NS • Mature oocytes 1.6 0.7 0.03 • Total Embryos 1.6 0.6 0.02 n:25 Oktay K. Hum Reprod 2003;18:90-95

  6. Tam-IVF vs TamFSH-IVF vs LetrozoleFSH-IVF in Breast Cancer Patients Variable Tam-IVF TamFSH-IVF Letrozole-IVF p • Peak E2 ↓ ↑ ↓ S • Total follicles 2 ± 0.3 6 ± 1.0 7.8 ± 0.9 S • Mature oocytes 1.5 ± 0.35.1 ± 1.1 8.5 ± 1.6 S • Total Embryos 1.3 ± 0.2 3.8 ± 0.8 5.3 ± 0.8 S * Hazard ratio of recurrence in letrozole group : 1.5 (CI O.29-7.4) after an average 554 days (153-1441) of follow-up n:60 Oktay K. J Clin Oncol 2005;23(19):4347-53

  7. Clinical Outcome in Breast Cancer Survivors Who had Subsequent PregnancyCompared with Those Who did not • Cooper-Butterfield’70 Better survival • Mignot’86 No difference • Ariel-Kempner’89 No difference • Sankila’94 Better survival • Von Schultz’95 Lower risk • Kroman’97 Lower risk • Velengtas’99 No difference • Gelber’01 Better survival • Blakely’04 Lower risk • Ives’07 Better survival Modified from Gadduci A. Gynecological Endocrinology 2007;23(11):625-31

  8. ART in Conservatively Treated Ovarian Cancer • Multicenter retrospective study • Follow-up average of 372 months (1971-2002) 27 BOT 10 nonepithelial OC 35 IVF, 5 IUI 3 epithelial OC 17 pregnancies 3 BOT recurrences Fortin A et al. Gynecol Obstet Fertil 2005;33:488-97

  9. IVF in Early Stage BOT Survivors n follow-up no.IVF PR relapse • Mantzavinos’94 2 60 2 50 % 0 • Herschkovitz’98 3 54 3 - - • Madelenat’99 16 46 - 34 % 0 • Beiner’01 7 50 7 71 % 28.5 % • Fasouliotis’04 5 39 17 42.9 % 20.0 % • Park’07 5 30 10 42.9 % 0 ~10 % Recurrence rate of BOT in women receiving IVF therapy is not different from those who did not receive

  10. Efficacy of Infertility Treatment in Conservatively Managed BOT Fasouliotis Park • Histology 5 serous 3 serous 2 musinous • No. Patients 5 5 • No.of IVF 17 10 • Av.follow-up (mos) 39 30 • Mean oocyte 7.9±4.0 9.0 • Fertilization rate 57.1 % - • Pregnancy rate/ET 42.9 % 42.9 % • Recurrence One patient 0 had three relapses Fasouliotis SJ et al.Fertil Steril 2004;82(3):568-72 Park CW et al. Korean Med Sci 2007;22:S134-S138

  11. IVF in Endometrial Carcinoma • Paulson’90 35 Long GnRHa singleton progestin/D&C • Sardi’98 35 - singleton - • Zuckerman’98 26 - twin hysterectomy • Shibara’99 32 Long GnRHa singleton D&C • Ogawa’01 31 - singleton D&C • Pinto’01 29 Long GnRHa triplet LAVH+BSO ovarian adeno Ca • Lowe’03 38 Donor oocyte twin VH+BSO • Yarali’04 32 Long GnRHa singleton D&C • Nakao’04 37 - twin D&C 35 - singleton D&C • Juretzka’05 37 Cryo ET singleton LAVH+BSO cervical involvement Modified from Azim A. Fertil Steril 2007;88:657-64

  12. Letrozole for IVF in Endometrial Carcinoma Patient Age G/P BMI Stage Gr. Treatment Hyst. • Case 1 32 0/0 31.2 Ic 2 Megace 1.5 y. After 1st IVF + letrozole 6 m. • Case 2 29 0/0 24.6 Ia 1 Megace 2 yrs. Before IVF • Case 3 31 0/0 40 Ia 2 None After IVF • Case 4 39 2/1 25 Ia 2 None After IVF Protocol D 2-12 Letrozole , D > 15 Letrozole No recurrence after D 4-12 FSH/hMG 3-30 months follow-up D 8-12 GnRH antagonist Azim A. Fertil Steril 2007;88:657-64

  13. Importance of Gonadal Damage in Cancer Survivors/Patients • Real number of germ cells decrease before and after birth prenatal 5. month…6.8 million at birth……………...1-2 million puberty……………..0.3 million menopause.….…… 0.1 million • Chemo/radiotherapy further decreases the number of germ cells in a constant rate

  14. Chemotherapy-induced Ovarian Damage • Cytotoxic drugs RR (ovarian failure) Other Alkylating agents 3.98 ovarian fibrosis, (e.g. cyclophosphamide) follicle depletion Cisplatin and analogs 1.77 induction chr. mutations Vinca alkaloids 1.0 induction of aneuploidy Antimetabolites - Anthracyclines - female-specific dominant (adriamycine/bleomycine) lethal mutations • CT before conception does not affect the prognosis of pregnancy • Regular menses/reproduction does not guarantee the ovarian function Meirow’95, 01, 05

  15. Radiotherapy-induced Ovarian Damage • Abdominopelvic RT Infertility RR of POF < 20 Gy - 1.02 20-35 Gy 22 % 1.32 > 35 Gy 32 % 3.27 • LD50 is about 4 Gy • > 40 yrs women are more sensitive to radiation damage • Type of RT. TBI in single dose is more harmful than frTBI • Miscarriage rate increases within after 1-year of completion of RT Chiarelli’99 Wallace’89 Lashbaugh-Casarett’76 Thibaud’98 Fenig’01

  16. Ovarian transposition GnRH analogs Sex steroids Progesterone Apoptotic inhibitors Cryopreservation of embryos Cryopreservation of oocytes Cryopreservation of ovarian tissue Construction of artificial gametes Sperm cryopreservation Hormonal therapy Testicular tissue cryopreservation In vitro spermatogenesis Fertility Preservation Options Female Male

  17. IVF in Cancer SurvivorsSummary • There is no clear evidence that OI/IVF increases the risk of recurrence of any cancer • Recurrence rate in ovarian cancer, especially BOT needs attention ! • Aromatase inhibitors might be a safe alternative to standard OI/IVF treatments in breast cancer • Outcome of IVF is very promising in cancer patients • Physicians/patients must be aware of fertility preserving procedures

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