For Cancer Patients Human Oocyte Nicole Noyes M.D. Professor - - PowerPoint PPT Presentation

Oocyte Cryopreservation And Other Reproductive Options For Cancer Patients

Nicole Noyes M.D.

Professor

Co-Director of Oocyte Cryopreservation Program NYU Fertility Center New York University School of Medicine

Human Oocyte

Learning Objectives

• At the conclusion of this session, participants should:

– Be aware of the fertility preservation options available for patients diagnosed with malignancies (as well as other illnesses whose treatment will result in iatrogenic ovarian compromise) – Appreciate the complexity that may exist and the communication necessary to successfully include fertility preservation into a patient’s cancer care

Cancer:

Improved Dx/Rx → Increased Survival: 77% Dx’d @ <45 y Live ≥5 y

Improved ART & Communication:

Egg Freezing & FP Options Email and PDAs

BIRTH AGE:

Maternal Age @ 1st Birth: >25 y US; Globally up to 31 All Time High

Oncofertility

Landscape Has Changed

U.S. Female Cancer Incidence/Mortality by Site - 2010 *

Percent of malignancies diagnosed <45 y: 40% cervical 13% breast 12% ovarian 8% endometrial

American Cancer Society 2011

Goodwin, P. J. et al. J Clin Oncol 1999;17:2365.

Probability of Menopause During 1st Year after Breast Cancer Diagnosis

• Goldhirsch. Ann Oncol 1990;1:183
• Bianco. Br J Cancer 1991;63:799

Cobleigh.Proc Am Soc Clin Oncol 1995;14:A158

• Bines. J Clin Oncol 1996;14:1718

Del Mastro. Br Cancer Res Treat 1997;43:183

• Meirow. Hum Reprod Update 2001;7:535
• Partridge. Proc Am Soc Clin Oncol 2005;25:687
• Partridge. J Cancer 2007;43:1646

Given the choice, both men and women prefer

Reproductive Autonomy

U.S. Census Data

Women 65 million of reproductive age Birthrate Decline teenage 20-29 yrs 30-34 yrs Birthrate Rise 35-39 yrs 40-44 yrs (highest since 1969)

When are Women Having Babies?

years

OECD.org

Human Oogenesis

20 weeks gestation: 6-7 x 106 oocytes No further germ cell proliferation Progressive atresia begins Birth: 1-2 x 106 oocytes Puberty: 300,000 (15%) oocytes Monthly cohort of follicles initiate growth and development

• ne “ovulates”
• thers become atretic

Age 30: 240,000 (~12%) oocytes Age 40: 60,000 (~3%) oocytes accelerated atresia Accelerated atresia coincides with decrease quantity and quality of oocytes

Considerations

• Age (suspected ovarian reserve)
• Type of cancer and treatment planned
• Presence of partner
• Willingness to use donor gametes
• Available time before cancer treatment
• Health of the patient
• More than one option may be possible for a

given patient

2006 ASCO Guideline Summary

As part of informed consent prior to therapy, oncologists should address the possibility of infertility with patients as early in treatment planning as possible 1

1 Lee SJ, Schover LR, et al., Journal of Clinical Oncology, 2006

FP important, if not necessary, consideration when planning cancer treatment in reproductive-age patients

Fertility Preservation Options

Assisted Reproductive FP Techniques

Options

Mature Oocyte Freeze Embryos Sperm Freeze Mature Oocytes Freeze Tissue Freeze Mature Oocytes Collect Immature Eggs (Germinal Vesicle & MI) In Vitro Maturation

• 1. Embryo Banking

Standard of Care

• Readily available technology in most developed

countries

• Good option if male partner committed to co-

parenting exists

• Disposition issues - Cancer associated with

increased morbidity and mortality limiting ultimate usage

Embryo Banking

Supernumerary Embryo Data

Age < 35 35-37 38-40 41-42 Fresh

Live birth/ET 48% 38% 28% 17%

Thawed

Live birth/ET 36% 31% 26% 22%

Data from 2009 SART Statistics (90,310 Fresh non-donor cycles; 21,646 Thawed non-donor cycles)

Live Birth Rate: ~33% FET

Average # embryos transferred: 1.5 per fresh and 2 per FET

• 2. Oocyte Banking

Considered experimental

• Rapidly evolving FP technology
• Theoretically, the optimum alternative for women

not in a committed male-female relationship

• Less disposition issues

Oocyte Cryopreservation

Despite experimental label Occurring worldwide Survey of USA IVF centers:

• 442 centers contacted:

282 (64%) responded over 49 states

• 51% of programs currently
• ffer oocyte cryopreservation
• 337 live births from 857 thaw

cycles: 39.3% live birth rate ~Similar to embryo thawing success

Rudick, Opper, Paulson, Bendikson, Chung. Fertil Steril 2010 Epub ahead

• f print DOI: 10.1016/j.fertnstert.2010.04.079

Oocyte Cryopreservation

• First human pregnancy was reported in 1986
• Early results disappointing

– Techniques not reproducible – Low oocyte survival, fertilization and pregnancy rates after IVF with thawed oocytes

• Oocytes difficult to freeze because of ice crystal formation

– Large cell size (100 micrometers) – High water content – Chromosomal arrangement (meiotic spindle)

Zenzes 2001 Fertil Steril 75; 769

Spindle / Chromosomes - Effect of Cooling

Human oocyte cooled to 0° C. Arrows indicate precocious segregation of single chromatids. Careful dehydration to avoid ice-crystal formation

Female Fertility Preservation

Oocyte Cryopreservation Advances

Human Oocyte Cryopreservation

Literature-Reported Live Births

9 yrs

n = 609

Slow Freeze (n = 308) Vitrification (n = 289) Both (n = 12)

Births

Safety:

Oocyte Preservation Cumulative Data

No increase in birth anomalies

Oocyte Cryopreservation

Donor Oocyte Cycles

16/20 = 80%

15 ♀ delivered 26 babies

89% 88% 68% Nagy et al. Fertil Steril 2009;92:520

Currently >200 babies born

Oocyte Cryopreservation

Donor Oocyte Cycles

RCT - vitrified vs. fresh Vitrified Oocytes n = 295 Fresh Oocytes n = 289 Mean age of egg donor (y) 26.7 26.6 Estradiol day hCG (pg/ml) 2879 2892 Mean no. oocytes 10.3 11.2 Fertilization % 74.2 73.3 Mean no. embryos transferred 1.7 1.7 Implantation rate % 39.9 40.9 Clinical pregnancy rate/transfer % 55.4 55.6

• No significant difference in any parameter

Cobo et al. Human Reprod 2010;25:2239

Now have >600 liveborn babies

Oocyte Cryopreservation

Donor Oocyte – Fresh vs. Vit

77 transfers – oocytes divided 2 (n=31) or 3 (n=5)

Oocyte Cryopreservation

Randomized Sibling Oocyte Trial

Oocyte Cryopreservation

Donor and Autologous Thaw Cycles

Noyes et al. Fertil Steril 2011;94:2078-2082

NYU Fertility Center Thaw Data

44 cycles – 20 women delivered 28 Babies (12 singleton, 8 twin) 45% delivered rate

Oocyte Recipient (n = 15) Autologous <35 y (n = 18) Autologous 35-40 y (n = 9) Autologo us >41 y (n = 2) Mean Age @ Oocyte Harvest

28 32 38 43

Mean # Oocytes

11* 20 14 9

MII Oocytes

10 16 12 9

Pregnancies

11 (73%) 9 (50%) 4 (44%)

Miscarriage

2 1 1

Delivered

9 (60%) 8 (44%) 3 (33%)

Single/Twin

4 singleton, 5 twin 5 singleton, 3 twin 3 singleton *no. assigned to recipient

NYU, unpublished data

½ slow, ½ vitrification

NYU Fertility Center Update

Medical Oocyte Freeze Cycles

9/2005 - 9/2010: n = 90

38% GYN, 30% breast, 19% hematologic, 13% other

NYU, unpublished data

Rapid communication with pt and between oncologist and RE essential

Noyes et al. 1st 50 cycles. JARG 2010;27:495-499

OC - Cancer

(n = 50)

OC with thaw – Non-Cancer

(n = 32) P Age (y) 31 ± 1 32 ± 1 0.9

• No. oocytes retrieved

19 ± 2 22 ± 2 0.2

• No. mature oocytes

cryopreserved 15 ± 2 14 ± 2 0.9

NYU News 3 transfers in cancer survivors to date First pregnancy one week ago ßhCG level today (day 33): 750 IU/L Breast cancer survivor Frozen at age 40; thawed at 43

Egg/Embryo Freezing

The process takes ~2 Weeks

Menstrual Cycle Day

2 11 13 14 21

Gonadotropin SQ hCG or lupron

• vulation

trigger Egg retrieval/evaluation Egg freeze If embryos: insemination Zygote freeze Estradiol rise OCP +/- GnRH antagonist and/or Letrozole

• 3. In Vitro Maturation (IVM) of Immature Oocytes

Considered experimental

• Retrieval and banking of immature oocytes after no or

limited gonadotropin stimulation or hCG

• Advantages

– Shorter duration – Potentially less cost – Lower risk of ovarian hyperstimulation syndome (OHSS)

• Disadvantages

– Lower success rates – Limited outcome data

IVM

With and without priming

No Priming

(n = 100)

hCG alone

10,000 IU (n = 100)

FSH alone

150IU/day x 3d (n = 100)

FSH + hCG

(n = 100) Age (y)

33.1 33.1 33.6 33.2

# Oocytes

5.3 5.3 4.8 5.4

MII at retrieval

5.7% 20.3%

Fertilization

78% 72% 73% 73%

Clin Preg Rate/cycle

11% 5% 13% 26%

Clin Preg Rate/ET

15.3% 7.6% 17.3% 29.9%

Implantatioin Rate

9.2% 4% 10.6% 16.4%

Fadini et al. Reprod Biomed Online 2009;19:343 FSH started cycle day 3, IVM x 30 hours, ICSI Mean # transferred = 1.8, No ET in 21%

Currently 156 babies born. Not in cancer pts; more PCO

IVM and tissue cryopreservation in children and adolescents

No births to date

• 4. Ovarian Tissue Banking

Considered experimental

• No ovarian stimulation, minimal delay in treatment,

no partner needed, only option in prepubertal girls

• Requires surgical removal of ovarian tissue

– Autologous pelvic transplantation – human births – Maturation in vitro – no human births

• Exciting technology but few successes and many

unanswered questions

Laparoscopic Removal of Cortical Tissue

Ovarian Tissue Banking Sheep Data

Ovarian follicular reserve significantly compromised by ischemia that occurs in the long period of time from grafting to neovascularization.

Greatest Hurdle: Tissue Ischemia

Diagnosis Age (y) Method Transplant Site Pregnancy Type of Pregnancy Reference Hodgkin 25 Unilat Bx Ortho Live birth Spontaneous Donnez 2004 Non-Hodgkin Lymphoma 26 Unilat Bx Ortho Live birth IVF Meirow 2005, 2007 Hodgkin 24 USO Ortho/Hetero Same pt Same pt Miscarriage Live birth Live birth Spontaneous Spontaneous Spontaneous Demeestere 2005 2006 2009 Hodgkin 28 USO Ortho/Hetero Biochemical IVF/ICSI from heterotopic site Rosendahl 2006 Ewing’s 27 USO Ortho/Hetero Same pt Live birth Miscarriage IVF IVF Andersen 2006 Ernst 2010 Hodgkin 27 USO Ortho Live birth IVF Andersen 2008 Premature Ov Failure 24 USO Ortho in twin Live birth Spontaneous Silber 2008 Breast Cancer 36 USO Ortho Live birth - twins Oocyte vit -IVF Sanchez-Serrano 2010 Periarteritis Nodosa 27 USO Ortho Ectopic preg IVF Piver 2009 Sickle Cell 20 USO Ortho Live birth Spontaneous Roux 2010

Ovarian Tissue Cryopreservation

Summary of Published Pregnancies from Orthotopic Transplants

10 Live Births (8 in Cancer Patients)

*Note: All babies born were in women that still had an ovary in situ. Total number of transplants performed not known

• 5. Whole Ovary

Transplantation

Considered experimental

Review - Bromer J, Patrizio P. Placenta: 2008;S200-205

Duration and subsequent function limited, mostly due to ischemia resulting from thrombosis. Microsurgical techniques have led to improved survival.

1 . 4 . 5 . 6 . 3 . 2 .

Challenges

Cost can be a barrier  Insurance/Government coverage is highly variable around the world  USA: legislation currently being considered in CA

Other Challenges

• Limited data on effectiveness of some of newer technologies
• Timing of treatment
• Choosing appropriate candidates
• Treating a sick patient
• Oocyte/Embryo disposition
• Need for a gestational carrier and/or donor gametes in the

future

• Consenting children undergoing experimental procedures

Case

• 29 year old female was diagnosed with invasive cervical

adenocarcinoma demonstrating neuro-endocrine components. It was recommended she undergo hysterectomy.

• She was in a 4-year committed relationship and the couple elected to

freeze both oocytes and embryos.

• Prior to hysterectomy, she underwent ovarian stimulation.
• 15 mature oocytes and 14 pronuclear zygotes were cryopreserved.
• The patient underwent radical hysterectomy 2 weeks

later and is now considered free of disease.

Case

• One year after surgery, the patient and her partner were married.
• 2 months later, they came to discuss use of their frozen tissues.
• The patient’s sister was married with 2 healthy children and agreed to

be the couples gestational carrier. Catch: the sister has a didelphic uterus.

• A lengthy discussion with both couples, including a psychologist

meeting with each couple and then with all 4 together was performed.

• Note: the sister delivered at 36 and 39 weeks with her 2 prior births.

Case

• The decision was made to perform a single embryo transfer in the left

horn of the uterus where the 2 prior pregnancies had been successfully carried.

X

• The pregnancy progressed without complication.
• The patient’s sister delivered a healthy baby at 39 weeks gestation.

What were the issues?

• Losing uterus

– Gestational carrier needed

• Cost
• Who
• Intrapartum or post-partum decisions/complications
• Psychological concerns
• Potential posthumous use of tissues

Summary

Of all fertility preservation measures, oocyte cryopreservation has made the greatest strides in achieving successful outcomes, making it an applicable modality not only for cancer patients but also for those with

• ther indications (age-related infertility, oocyte donation, medical illness

requiring gonadotoxic treatments – lupus, scleroderma, sickle-cell, etc). Oncofertility is a new and rapidly-emerging discipline and applicable to a multitude of malignancies occurring in the reproductive years.

Oncologists, fertility specialists and gynecologists are working together in unprecedented ways to:

• Educate patients – bring awareness
• Make fertility preservation possible
• Create multidisciplinary models of care delivery to meet the needs
• f patients
• Importantly, keep patient’s interests at the forefront

Thank You