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

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

IVF Outcome in Cancer Patients Ginsburg. IVF in cancer patients and survivors. Fertil Steril 2001 * 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

IVF Outcome in Cancer Patients Oocytes No.Em. No ET Cryo-cycle Delivery rate Oocytes No.Em. No ET Cryo-cycle Delivery rateWomen local Tx % (14/56) local Tx % (14/56) syst.Tx % (2/15) syst.Tx % (2/15) freeze freeze Men local Tx % (0/5) local Tx % (0/5) syst.Tx % (2/11) syst.Tx % (2/11) (pre-chemo) (pre-chemo) syst.Tx % (9/24) syst.Tx % (9/24) (post-chemo) (post-chemo) Ginsburg. IVF in cancer patients and survivors. Fertil Steril 2001

Tam-IVF vs Natural-IVF in Breast Cancer Patients Variable TamIVF NCIVF p Variable TamIVF NCIVF p Peak E NS Peak E NS Total follicles NS Total follicles NS Follicles >17 mm NS Follicles >17 mm NS Total oocytes NS Total oocytes NS Mature oocytes Mature oocytes Total Embryos Total Embryos Oktay K. Hum Reprod 2003;18:90-95 n:25

Variable Tam-IVF TamFSH-IVF Letrozole-IVF p Variable Tam-IVF TamFSH-IVF Letrozole-IVF p Peak E2 ↓ ↑ ↓ S Peak E2 ↓ ↑ ↓ S Total follicles 2 ± ± ± 0.9 S Total follicles 2 ± ± ± 0.9 S Mature oocytes 1.5 ± ± ± 1.6 S Mature oocytes 1.5 ± ± ± 1.6 S Total Embryos 1.3 ± ± ± 0.8 S Total Embryos 1.3 ± ± ± 0.8 S * Hazard ratio of recurrence in letrozole group : 1.5 (CI O ) after an average 554 days ( ) of follow-up after an average 554 days ( ) of follow-up Oktay K. J Clin Oncol 2005;23(19): Tam-IVF vs TamFSH-IVF vs LetrozoleFSH-IVF in Breast Cancer Patients n:60

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

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

IVF in Early Stage BOT Survivors n follow-up no.IVF PR relapse n follow-up no.IVF PR relapse Mantzavinos’ % 0 Mantzavinos’ % 0 Herschkovitz’ Herschkovitz’ Madelenat’ % 0 Madelenat’ % 0 Beiner’ % 28.5 % Beiner’ % 28.5 % Fasouliotis’ % 20.0 % Fasouliotis’ % 20.0 % Park’ % 0 Park’ % 0 ~10 % Recurrence rate of BOT in women receiving IVF therapy is not different from those who did not receive

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

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

Letrozole for IVF in Endometrial Carcinoma Patient Age G/P BMI Stage Gr. Treatment Hyst. Patient Age G/P BMI Stage Gr. Treatment Hyst. Case / Ic 2 Megace 1.5 y. After 1st IVF Case / Ic 2 Megace 1.5 y. After 1st IVF + letrozole 6 m. + letrozole 6 m. Case / Ia 1 Megace 2 yrs. Before IVF Case / Ia 1 Megace 2 yrs. Before IVF Case /0 40 Ia 2 None After IVF Case /0 40 Ia 2 None After IVF Case /1 25 Ia 2 None After IVF Case /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 4-12 FSH/hMG 3-30 months follow-up D 8-12 GnRH antagonist D 8-12 GnRH antagonist Azim A. Fertil Steril 2007;88:657-64

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

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

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

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

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 IVF in Cancer Survivors Summary