Having Children After Cancer

Diana E. Chavkin, MD

GENESISMaimonides Medical Center

Cancer:

>130,000 reproductive age

patients diagnosed annually

Improved Survival:

77% Diagnosed under 45

Survive ≥≥≥≥ 5 years

Reproductive

Medicine:Improved

FP Options

Delayed

Childbearing:Maternal Age at 1st Birth:

25.2 years (USA)All Time High

Oncofertility

Landscape

U.S. Cancer Incidence by Site - 2010

Breast cancer and fertility

• Breast cancer is the most common malignancy to affect

women younger than 45

• 25,000 patients under 45 are diagnosed with breast cancer in

the United States annually

• Reproductive-aged patients face unique concerns regarding

cancer treatment and survivorship goals

• 57% concerned about fertility

• 29% of concerns influenced treatment plan

Patients at risk

National cancer Institute report:

�1 out of 250 adults will be a survivor of childhood

cancer by 2015

Tangir, 2003

Fertility in Survivors

• Approximately 75% of childless cancer survivors want children

in the future

• Adult survivors of childhood cancer report increased anxiety

regarding finding a mate and are not prepared for long-term

side effects of treatment

• Overall, young men and women have equal concerns

regarding fertility

• Only 61% of women were informed of fertility preservation

options

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

The Reproductive Cycle

The Reproductive Cycle

6,000,0001,000,000 300,000 “0”

20 weeks

in utero

Birth Puberty Menopause 51

Num

ber

of

eg

gs in t

he o

varies

Fertility Risks for Females

Pubertal Failure

PrematureMenopause

<40 yearsEarlyMenopause

Cancer therapies destroy eggs and accelerate ovarian aging

Timing of exposure influences puberty and menstrual function

How does cancer treatment harm the

ovaries?

• Chemotherapy may cause egg depletion, ovarian

failure and chromosomal damage in the egg

• Radiation has adverse effects on ovarian function at

all ages and may impair hormone production

Chemotherapy effect on ovarian

function

Increasing toxicity to the ovaries

Unknown Low High

Taxanes

Oxaliplatin

Monoclonal

Antibodies

Tyrosine Kinase

Inhibitors

Methotrexate

5-Fluorouracil

Vincristine

Bleomycin

Actinomycin-D

Cisplatin

Adriamycin

Cyclophosphamide

Chlorambucil

Melphalan

Busulfan

Nitrogen mustard

Procarbazine

1. Lee SJ et al. J Clin Oncol. 2006;24:2917-2931.2. Oktem & Urman. Obstet Gynecol Surv. 2010;65(8):531-542.

Effects of Cancer Treatments:

Chemotherapy

http://www.fertilehope.org/tool-bar/risk-calculator.cfm

How does chemotherapy affect a

woman’s menstrual cycle?

• Usually, during treatment, a woman does not get her period

• Recovery of menses usually takes 6 months-1 year

• Return of menses does not imply return of fertility

• Different regimens have varying effects on recovery of

menses

• The younger a woman is at time of exposure the greater the

chance of recovery of normal menses

Assessing Fertility After Cancer

Blood tests:

•Follicle Stimulating Hormone

(FSH)

•Estradiol

•Inhibin B

•Anti-Mullerian Hormone

(AMH)

Ultrasound:

•Antral Follicle Count

•Ovarian Size

‘Biological Clock’

Fertility and Cancer Treatment PlanningModification of treatment plans for cancer care

• Less aggressive resection for uterine, cervical and ovarian

cancer

• Planning radiation fields to shield the ovaries

• Moving ovaries out of the radiation field prior to treatment

(“transposition”)

• Chemotherapy drugs that are less toxic to the ovaries

• (i.e. less alkylating agents)

• Modification of doses

• Timing of treatment for breast cancer: can delay

chemotherapy one month to allow for fertility preservation

Options for Fertility Preservation

Current Fertility Preserving Options

• Embryo Cryopreservation

• Egg Cryopreservation

• Sperm Cryopreservation

• Experimental options

Considerations

• Age

• 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

Artificial Reproductive Techniques

Freeze Embryos

SpermMature Egg

Freeze Tissue

Freeze Mature Eggs

Freeze

Mature Eggs

Collect Immature Eggs

In Vitro Maturation

**Most Data on success rates NOT in cancer population

Who Needs Fertility Preservation?

• All patients should be informed of the

potential risks and options available

• Fertility preserving technologies may pose

some risk

– May delay cancer therapy and can be costly and

invasive

Embryo and Egg Banking Requires

Ovarian Stimulation

• Only possible in post

pubertal females

• Risks:– Delay in cancer therapy

– High estrogen levels

– Ovarian hyper-stimulation

– Theoretical thrombosis risk

– Cost: $5-12K + storage

-

In-Vitro Fertilization - IVF

Egg Retrieval

• Eggs retrieved

transvaginally under

ultrasound guidance

• Follicular fluid

aspirated and sent to

the laboratory

Embryo Cryopreservation (freezing)

• Most established fertility preservation technique for women with cancer

– First birth from Embryo Cryopreservation in 1983

• Requires about 2 weeks of ovarian stimulation, followed by needle

aspiration to collect eggs

• Eggs are then fertilized in vitro (outside the body), and frozen for later use

• Freezing possible at different stages of embryo development

How Successful is Embryo

Freezing?

Embryo Banking Success RatesEstablished Method - Partner or Donor Sperm required

Oocyte

Donors< 35 35-37 38-40 41-42 > 42

Fresh Cycle:

Live birth/Cycle - 41.7 31.9 22.1 12.5 4.1

Cancellations % - 6.6 10.0 12.9 16.5 22.0

Fresh Cycle:

Live birth/ET 55.6 47.8 38.4 28.1 16.8 6.3

Thawed

Live birth/ET34.8 38.7 35.1 28.5 21.4 15.3

Ave No. ET 2.0 1.9 1.9 2.1 2.2 2.1

Data from 2010 SART Statistics (146,693 cycles)

Thousands of live births in patients without cancer

Embryo Cryopreservation

• Requires:

– Partner

– High estrogen environment

– Pubertal

– Time (less of an issue for breast cancer)

• Is costly

Mature Egg Banking

…. reproductive autonomy

American Society of Reproductive Medicine

“Evidence indicates that oocyte vitrification and

warming should no longer be considered

experimental”

2012 ASRM Practice Committee Opinion

Egg Freezing

• Frozen eggs seem to be as good as fresh eggs

• Result in similar pregnancy rates

• Requires:

– 2 weeks of daily hormone injections

– Office procedure to collect eggs

Egg Cryopreservation

Benefits over embryo cryopreservation:• No partner needed

• Reproductive autonomy

But:• Success rates possibly not as good

Egg CryopreservationHistory

• Why are eggs more difficult to freeze

than embryos?

– Large cell size

– High water content with ice crystal

formation

– Potential for chromosomal damage

– Hardening of the zona pellucida can effect

fertilization

• First human pregnancy was reported in 1986

• Early results disappointing

– Poor egg survival, fertilization and pregnancy rates

– Use of slow freeze rather than vitrification

Live Births from Egg Cryopreservation

0

50

100

150

200

250

300

1986-88 1997-99 2000-02 2003-05 2006-08

Slow Freeze

Vitrification

Both

936 births:

532 from slow freeze

392 vitrification

Noyes et al. Reprod Biomed Online, 2009.

What are the chances of success?

28 year old woman has 6 eggs retrieved..

•If egg fertilized immediately:

– Chance of pregnancy is 40-50%

•If egg vitrified or ‘flash-frozen’ and fertilized later:

– Similar chance of pregnancy

•If egg is ‘slow-frozen’ and fertilized later:

– Somewhat less chance of pregnancy

Do Babies Born from Frozen Eggs have a Higher rate of Birth Defects?

Birth DefectIncidence Birth Defects

Unassisted Conception

Birth Defects per

936 Egg Cryo Births

All 1/33 12 (1/78)

Skin hemangioma 1/50-225 1

Cardiac defects 1/125 3 (1/312)

Neural tube defects 1/385 0

Cleft lip/palate 1/710 1

Clubfoot 1/735 3 (1/312)

Arnold-Chiari malformation 1/1200 1

Coanal atresia 1/7000 1

Biliary atresia 1/10-15,000 1

Rubinstein-Taybi syndrome 1/100-125,000 1

Noyes et al. Reprod Biomed Online 2009;18:769.

Ovarian Stimulation in Cancer Patients

• Rapid access and team approach

• Hormones used to stimulate the ovaries can theoretically also stimulate breast and uterine cancer

• Medications such as Letrozole and Tamoxifen are used to decrease circulating hormone levels

Early breast cancer

SurgerySurgery

ChemotherapyChemotherapy

RadiationRadiation

TamoxifenTamoxifen HerceptinHerceptin

At diagnosis

4- 6 months

4-6 weeks

5 – 10 years 1 year

Refer Here!!

Is fertility preservation possible

without administering hormones?

• Ovarian tissue freezing

• Ovarian tissue biopsy with culture of eggs

from tissue

Does Pregnancy After Breast Cancer Increase Chance of Cancer Recurrence?

• Studies have shown that women who become

pregnant after breast cancer do NOT have an

increased risk for disease recurrence or

poorer survival

• At least 2 studies indicate that pregnancy is in

fact protective against disease recurrence

Pregnancy Outcomes in Cancer

Survivors

• In general, no risk of congenital malformations, genetic

diseases or cancer in children of cancer survivors

• However, possible risk (miscarriage/birth defects) if conceived

within 3 months of chemotherapy

• Recommend to delay conception until 3 months after

completion of chemotherapy

• With increased age there is an increased risk of miscarriage

Weeding out cancer genes….

Preimplantation genetic diagnosis (PGD)

Technology that allows for detection of ‘cancer genes’ in

embryos

● BRCA1, BRCA2, familial adenomatous polyposis, Gorlin

syndrome

● Lynch syndrome/HNPCC, Li-Fraumeni syndrome, MEN,

neurofibromatosis

● Retinoblastoma, tuberous sclerosis, Von Hippel-Lindau

disease

HNPCC = hereditary nonpolyposis colorectal cancer; MEN = multiple endocrine neoplasia

Pregnancy after cancer

• Assess health of survivor

– Cancer therapies may have significant toxicities

– Maternal-fetal medicine (MFM) consultation

recommended

– Surrogacy may be an option

• Legal consultation

• Costly

• Paid surrogacy not available in all states

Fertility Preservation:Investigational Techniques

• Ovarian Tissue Cryopreservation

• Transplantation of ovarian tissue

• In-vitro maturation of ovarian follicles

Ovarian Tissue Banking… an experimental option

Ovarian Tissue Banking

• No ovarian stimulation, minimal delay in treatment, no partner

needed, only option in pre-pubertal girls

• Autologous transplantation:

Surgical removal of ovarian tissue prior to cancer treatment and

replacement after treatment

• 25 human births to date

• Risk of seeding cancer cells in cancer that involve the ovaries

(hematologic, ovarian and breast cancers)

• Repeat surgeries required

• Follicle Maturation in vitro – no human births yet

• Ongoing research as part of Oncofertility Consortium

Males: Fertility Preservation

• Men should be given the opportunity to bank sperm before

cancer treatment

• Boys who have started sexual development should be offered

this option

• There is currently no option to preserve fertility in pre-pubertal

boys

• Important to obtain adequate volume of semen

• Infectious disease screening (based on FDA guidelines) should

be offered

Genesis Experience

• Embryo Freezing (2012):

• 230 embryos in 111 cycles

• Sperm Freezing (2012):

• 189 samples

• Egg Freezing:

• (2006-2014): 150 oocytes frozen for 20 patients

• (2011-2014):

• 9 embryo transfers from frozen/thawed eggs

• 4 of those transfers resulted in clinical pregnancies

Oncofertility Guideline Adherence National Survey Data

• Typically only 2% to 4% of eligible women pursue

fertility preservation

• Only 47% of oncologists routinely refer patients to a

reproductive endocrinologist

Letourneau JM et al. Cancer 2012;4579-4588

Estimated Treatment Costs

Type of Treatment Average Cost Sharing Hope

Sperm Banking $100 & $100 q6months -

Testicular Tissue Freezing/TESE $8,000 -

Embryo Freezing $10,000 + meds $5,700

Egg Freezing $7,000 + meds $5,700

Ovarian Tissue Freezing $12,000Under IRB (usually

no charge)

GnRH Analog Treatments $500/month -

Donor sperm, eggs or embryos $10,000-$30,000 -

Adoption (domestic, international, public, private)

$2,500 - 35,000 -

Surrogacy (Not in NY State) $20,000 -100,000 -

Covering Costs

• Sharing Hope program works with REI

practices to offer reduced cost to eligible

patients

• Many programs offer free medications

• Insurance coverage is highly variable- It is

worth appealing

• Flexible strategies for covering cost

Patient Resources

Patient Resources

Summary of Options

• Established Fertility Preservation:– Embryo freezing, egg freezing, conservative surgery, and

sperm freezing

• Experimental Fertility Preservation Options:

– Ovarian tissue freezing

• Other options:

– Adoption, egg donation, surrogacy

Future Directions

• Increased Need for Advocacy and Awareness

�Many patients learn about options for preserving

fertility after cancer therapy

• Decision making process

�Only 30% of those who present for an oncofertility

consultation pursue treatment

Crucial Points

• Fertility treatments and pregnancy do not

worsen cancer prognosis

• Prior treatment with chemotherapy or

radiation has not been show to cause birth

defects in offspring

• There are multiple options to ease the cost

associated with fertility preservation for

patients with cancer

Contraception

be o

Contraception should be offered to all reproductively-

aged patients actively undergoing cancer treatment

•Irregular cycles or lack of menses during treatment does not

necessarily mean that a woman can not conceive

•Pregnancy during cancer treatment may alter the course of the

disease

•Cancer treatment can affect the pregnancy

•Non hormonal options for breast cancer survivors

THANK YOU

Physicians:

Richard Grazi, MD David Seifer, MD

Jennifer Makarov, MD

Diana Chavkin, MD

Katherine Melzer, MD

Administration and Billing

Alan Sloane

Michael PagliucaLisa Scire

Christine Malesko

Miriam Serrano

Charlene Eastington

Nicle Shannon

Shannon Allen

Sarah Alperin

LaboratoryHenry Malter, PhD , DirectorLyudmila Bakunenko

Mark Petrisch

Cynthia LayAya Tal

Nursing

Joanne Soffing, RN

Irena Shvartser, RNRachel Najiri, RN

Natalya Eppel, RN

Toby Barsky, RN

Roxanne Diaz, RNNellie Badalova, RNVahida Gillic, RN

Toby WernerMarcy Parker, RNRosa Fernandez, RN

Counseling servicesKris Bevilacqua, PhD, Psychological ServicesKatherine Mah, MS, Genetic Counseling

Genesis TeamClinical assistantsMarina YessayanTara Nieves

Cindy Ammirable

Christina JaquezChristina Andon

Linh Luong

Marcia MorrisDiane Piele-Fair

Slide from NAGY

Slow freeze vs Vitrification