Fer$lity Preserva$on - Issues in Cancer Pa$ents Hakan Cakmak, MD Assistant Professor UCSF Center for Reproduc;ve Health 03/18/2016 Nothing to disclose. 1
A. K. 34 yo G0, single, with ER (- ) PR (- ) breast cancer, had lumpectomy and axillary lymph node dissec;on a week ago, found to have (+) LN. Plan for chemotherapy in 3 weeks Desiring to have fer;lity preserva;on Why fer$lity preserva$on is important? Up to 75% of women is interested in having children axer cancer treatment. Up to 29% of women refuses life- saving treatments because of fear of becoming infer;le. Schover LR. Pediatr Blood Cancer. 2009. Partridge AH et al. J Clin Oncol. 2004. 2
Incidence rates of cancer for females aged 0-39 Surveillance, epidemiology, and end results (seer) program (www.seer.cancer.gov) Cancer survival is increasing Surveillance, epidemiology, and end results (seer) program (www.seer.cancer.gov) 3
Delaying first pregnancy Murk and Seli, Fer$lity Preserva$on 2012, Springer Natural Ovarian Aging Women are born with a fixed number of oocytes Average age ~ 52 1-2 K 5-7 M 1 M 0.5 M <1 K 4
Folliculogenesis FSH dependent FSH independent Total ~ 1 year Greenspan s Basic and Clinical Endocrinology Ovarian Reserve Primordial follicle Primary follicle 5
3/18/16 Growing Follicles Secondary follicle Antral follicle Preantral follicle Gonadotoxic Treatment Chemotherapy and radia;on therapy Destruc;on of growing follicles Loss of primordial follicles Direct or indirect effects Apoptosis Vascular injury Loss of local regulatory factors Accelerated recruitment of primordial follicles Meirow et al. Hum Reprod 2007 6
Gonadotoxic effects of chemotherapy Depends on: Age of the pa;ent Prepubertal ovaries appear to be more resistant to cytotoxic agents: More follicles or no ac;ve folliculogenesis Type of chemotherapy Cumula;ve dose of chemotherapy Cohen L. Ann N Y Acad Sci. 2008 Gonadotoxic effects of chemotherapy Primary ovarian insufficiency overt (menses are absent or irregular) à may regain regular menses. occult (the ovary is damaged but menses remain regular) Both may result in higher risk of infer;lity and premature manopause. The majority of women who remain amenorrheic 1 year axer treatment will not regain ovarian func;on. Kil WJ et al. Breast Cancer Res Treat. 2006 7
Gonadotoxic effects of chemotherapy Letourneau JM et al. Cancer 2012 Gonadotoxic effects of chemotherapy Letourneau JM et al. Cancer 2012 8
Gonadotoxic effects of chemotherapy Letourneau JM et al. Cancer 2012 Effects of Radia$on Therapy Depends on Age of the pa;ent (Size of the primordial follicle pool) Dose (total dose and frac;ona;on schedule) Single dose is more gonadotoxic than frac;onated doses Radia;on field dependent Direct damage to the ovary Damage to the hypothalamic- pituatory axis delayed puberty Also effects uterine func;ons Altered vasculature, decreased elas;city and volume. Higher risk of miscarriage, IUGR and preterm deliveries. Kriseman and Kovanci, Fer$lity Preserva$on 2012, Springer 9
Radiotherapy ESD decreases with increasing age ESD: effec;ve sterilizing dose - dose of ovarian failure occurs immediately axer treatment in 97.5% of pa;ents. At birth: 20.3 Gy At 10 years: 18.4 Gy At 20 years: 16.5 Gy At 30 years: 14.3 Gy. <40 yrs of age: 5-10 Gy radia;on directly to the pelvis result in amenorrhea in more than 95% of women. >40 yrs of age: 3.75 Gy radia;on directly to the pelvis result in amenorrhea in almost 100% of women. Wallace WH et al, Int J Radiat Oncol Biol Phys, 2005 Issues to be considered before fertility preservation The risk of sterility with the proposed treatment The overall prognosis for the pa;ent The poten;al risks of delaying treatment The impact of any future pregnancy upon the risk of tumor recurrence The impact of any required hormonal manipula;on on tumor itself The possibility of tumor contamina;on of the harvested ;ssue 10
Op$ons for fer$lity preserva$on Recommended Embryo or mature oocyte cryopreserva;on Ovarian transposi;on or shielding Inves$ga$onal Cor;cal and whole ovary cryopreserva;on with transplanta;on or in- vitro matura;on Ovarian suppression with GnRH agonist ASRM and ASOC guidelines Op$ons for fer$lity preserva$on Should be tailored according to: Pa;ent s age Type of disease Planned treatment Time available Whether she has a partner 11
Fer$lity Preserva$on Embryo cryopreserva$on Well- established Integral part of the IVF programs >25 yrs Highest success rates Oocyte cryopreserva$on Avoids requirement for partner or donor sperm Follicle Development LH Classical Teaching Progesterone Estrogen FSH Ovula$on Antral follicle Preovulatory follicles atresia 1 Cycle Days 14 28 12
Ovarian S;mula;on Gonadotropins GnRH antagonist 36 h Oocyte retrieval hcg or GnRH agonist Antral follicle 1 Cycle Days 14 Embryo and oocyte cryopreserva$on Problems: Ovarian s;mula;on with gonadotropins conven;onally starts during menstrua;on Time interval needed for ovarian s;mula;on and oocyte retrieval is 2-6 weeks. Time may not be available for cancer pa;ents Ovarian s;mula;on associated with high estrogen levels which may not be safe in cases of hormone sensi;ve tumors such as breast cancer use of aromatase inhibitors. Von Wolff et al. Fer$l Steril 2009 Cakmak and Rosen Fer$l Steril 2013 13
Random Start Ovarian S$mula$on Conven$onal Start (n=88; 103 cycles) Late Follicular Phase Start (n=29; 31 cycles) Luteal Phase Start (n=39; 42 cycles) P value Age (yrs) 33.8 ± 5.3 33.8 ± 4.2 34.5 ± 5.0 NS Antral follicle count 13 (9-19) 11 (5.5-21) 12.5 (7-17) NS Days of ovarian s$mula$on 9 (8-10) 11 (10-11.5) 11 (10-12) <0.001 Follicles 13 mm 12 (6-17) 13 (7.8-17.8) 13 (9-19) NS Oocytes retrieved 15 (9-23) 14 (8.8-25) 15.5 (9-25) NS Mature oocytes (MII) retrieved 11 (6-16) 9 (5-16.3) 11 (5-18) NS Data are presented as mean ± SD or median (interquar$le range 25%- 75%). Cakmak et al. Fer$l Steril 2013 Oocyte Competence Conven$onal Start (n=88; 103 cycles) Late Follicular Phase Start (n=29; 31 cycles) Luteal Phase Start (n=39; 42 cycles) P value Fer$liza$on rate amer ICSI (2PN/MII) 0.83 (0.69-0.91) 0.80 (0.76-0.95) 0.86 (0.77-0.96) NS Not enough embryo transfers in random start group to compare pregnancy outcomes. Data are presented as median (interquar$le range 25%- 75%). Cakmak et al. Fer$l Steril 2013 14
Ovarian protec$on against radiotherapy Ovarian shielding Ovarian transposi;on prior to local radiotherapy: reduces dose to 5-15% can be done with laparoscopy success rate (preserva;on of short- term menstrual func;on) is ~ 50%. (Scaner radia;on and altera;on of ovarian blood supply- failures). If IVF is needed axer ovarian transposi;on, however, the oocyte retrieval becomes more challenging. Tulandi et al. Fer$l Steril 2004 Ovariopexy: in the case of craniospinal irradiation, the ovary is fixed as far as possible from the midline. Jadoul P et al. Hum. Reprod. Update 2010;16:617-630 15
Post-operative identification of a transposed right ovary before radiotherapy using (A) radiography and (B) computed tomography. Jadoul P et al. Hum. Reprod. Update 2010;16:617-630 Ovarian $ssue cryopreserva$on Ovarian ;ssue is removed laparoscopically and frozen. A huge pool of oocytes No requirement for partner or sperm donor Op;on for prepubertal girls Avoids ovarian s;mula;on 16
Cortical ovarian biopsy from a 12-year-old girl. Jadoul P et al. Hum. Reprod. Update 2010;16:617-630 Orthotopic transplanta$on Resumption of Cycles Spontaneous Conception Meirow D. N Engl J Med. 2005 17
Heterotopic transplanta$on Growing follicle Oktay K et al. Fertil Steril. 2003 Ovarian transplants 14 live births (All orthotopic transplant) 1 case: Induc;on of puberty 30 transplants??? (repor;ng bias) Challenges/Limita;ons Risk for cancer recurrences Short life (3-5 yrs) ischemia General anesthesia Donnez et al 2004 and 2010 Meirow et al. 2005 Demeestere et al. 2007 Silber et al. 2008 Sanchez et al. 2009 18
GnRH agonist co- treatment with chemotherapy Belief that pre- pubertal girls are more resistant to gonadotoxic cancer treatment Protec;ve effect of GnRH agonist in Rhesus monkeys Primordial follicle loss axer cyclophosphamide tx 65% vs 29% Ataya et al. Biol Reprod 1995 Protec;ve effect of GnRH agonist in case series (compared with historic controls) Castelo- Branco et al. Fer;l Steril 2007 Blumenfeld et al. Hum Reprod Update 2008 Prospec$ve Randomized Trials n Cancer Follow up (mo) POF Rate CT POF Rate CT + GnRHa Badawy 78 Breast 8 67% 11% Sverrisdopr 123 Breast 36 90% 64% Del Mastro 281 Breast 12 26% 9% Song 183 Breast 12 59% 40% Gerber 56 Breast 24 43% 30% Munster 47 Breast 24 10% 12% Elgindy 100 Breast 12 20% 20% Moore 135 Breast 24 22% 8% Demeestere 84 Lymphoma 12 19% 20% Age, follow up, CT regimen, defini$on of POF resump$on of menses 19
GnRH agonist co- treatment 4 Meta- analyses 0 2 2 Harm Benefit No effect Rate of resump$on of spontaneous menses Data regarding to spontaneous pregnancy is missing Why counseling is important? Visi;ng a fer;lity specialist and preserving fer;lity were associated with improvements in overall sa$sfac$on with life axer cancer treatment. Counseling by a fer;lity specialist about reproduc;ve loss before treatment reduces long- term regret about having or not having preserved fer;lity. Letourneau JM et al. Cancer 2012 20
Barriers to fer$lity preserva$on Only 35-50 % of women could recall a discussion on reproduc;ve health risks or fer;lity preserva;on ever taking place. A reproduc;ve specialist sees only 2 5 % of women before they undergo treatment. Letourneau JM et al. Nat Rev Clin Oncol. 2011. Quinn GP et al. J Clin Oncol. 2009. Barriers to fer$lity preserva$on high financial costs not able to integrate care with a fer;lity specialist urgency to start treatment. inadequate counseling by oncologist due to lack knowledge of fer;lity preserva;on op;ons have insufficient ;me to discuss believe that pa;ents cannot delay treatment assume that if pa;ents did not raise the issue themselves they were not interested. 21
A. K. 34 yo G0, single, with ER (- ) PR (- ) breast cancer, had lumpectomy and axillary lymph node dissec;on found to have (+) LN. Had egg freezing cycle (random start) and 20 mature eggs were frozen Started GnRH agonist treatment before chemotherapy. Mitchell Rosen, MD Marcelle Cedars, MD Evelyn Mok- Lin, MD Cathy Chin, RN Elizabeth Gomes, RN Audra Katz, RN Thank You Eve Harris, Pa;ent Navigator 22