Dr. Diana Chavkin, Reproductive Endocrinology and Infertility (REI) specialist at Genesis Fertility and Reproductive Medicine, made this presentation at SHARE about fertility preservation options before and after cancer treatment. If you'd like to hear the audio, visit www.sharecancersupport.org/chavkin The information in this presentation is not intended to be a substitute for professional medical advice, diagnosis or treatment. The presentation was given on May 15, 2014.

1. Having Children After Cancer
Diana E. Chavkin, MD
GENESIS
Maimonides Medical Center

2. 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

3. U.S. Cancer Incidence by Site - 2010

4. 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

5. Patients at risk
National cancer Institute report:
1 out of 250 adults will be a survivor of childhood
cancer by 2015
Tangir, 2003

6. 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

7. 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

8. The Reproductive Cycle

9. The Reproductive Cycle

10. 6,000,000
1,000,000 300,000 “0”
20 weeks
in utero
Birth Puberty Menopause 51
Numberofeggsintheovaries
Fertility Risks for Females
Pubertal
Failure
Premature
Menopause
<40 years
Early
Menopause
Cancer therapies destroy eggs and
accelerate ovarian aging
Timing of exposure influences puberty and menstrual function

11. 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

12. 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.

13. Effects of Cancer Treatments:
Chemotherapy
http://www.fertilehope.org/tool-bar/risk-calculator.cfm

14. 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

15. Assessing Fertility After Cancer
Blood tests:
•Follicle Stimulating Hormone
(FSH)
•Estradiol
•Inhibin B
•Anti-Mullerian Hormone
(AMH)
Ultrasound:
•Antral Follicle Count
•Ovarian Size

16. ‘Biological Clock’

17. Fertility and Cancer Treatment Planning
Modification 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

18. Options for Fertility Preservation

19. Current Fertility Preserving Options
• Embryo Cryopreservation
• Egg Cryopreservation
• Sperm Cryopreservation
• Experimental options

20. 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

21. 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

22. 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

23. 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

24. -
In-Vitro Fertilization - IVF

25. Egg Retrieval
• Eggs retrieved
transvaginally under
ultrasound guidance
• Follicular fluid
aspirated and sent to
the laboratory

27. 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

28. How Successful is Embryo
Freezing?

29. Embryo Banking Success Rates
Established 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/ET
34.8 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

30. Embryo Cryopreservation
• Requires:
–Partner
–High estrogen environment
–Pubertal
–Time (less of an issue for breast cancer)
• Is costly

31. Mature Egg Banking
…. reproductive autonomy

32. American Society of Reproductive Medicine
“Evidence indicates that oocyte vitrification and
warming should no longer be considered
experimental”
2012 ASRM Practice Committee Opinion

33. 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

34. Egg Cryopreservation
Benefits over embryo cryopreservation:
• No partner needed
• Reproductive autonomy
But:
• Success rates possibly not as good

35. Egg Cryopreservation
History
• 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

36. 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.

37. 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

38. Do Babies Born from Frozen Eggs have a
Higher rate of Birth Defects?
Birth Defect
Incidence 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.

39. 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

40. Early breast cancer
SurgerySurgery
ChemotherapyChemotherapy
RadiationRadiation
TamoxifenTamoxifen HerceptinHerceptin
At diagnosis
4- 6 months
4-6 weeks
5 – 10 years 1 year
Refer Here!!

41. Is fertility preservation possible
without administering hormones?
• Ovarian tissue freezing
• Ovarian tissue biopsy with culture of eggs
from tissue

42. 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

43. 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

44. 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

46. 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

47. Fertility Preservation:
Investigational Techniques
• Ovarian Tissue Cryopreservation
• Transplantation of ovarian tissue
• In-vitro maturation of ovarian follicles

48. Ovarian Tissue Banking
… an experimental option

49. 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

50. 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

51. 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

54. 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

55. 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 $12,000
Under 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 -

56. 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

57. Patient Resources

58. Patient Resources

59. 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

60. 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

61. 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

62. 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

64. THANK YOU

65. Physicians:
Richard Grazi, MD
David Seifer, MD
Jennifer Makarov, MD
Diana Chavkin, MD
Katherine Melzer, MD
Administration and
Billing
Alan Sloane
Michael Pagliuca
Lisa Scire
Christine Malesko
Miriam Serrano
Charlene Eastington
Nicle Shannon
Shannon Allen
Sarah Alperin
Laboratory
Henry Malter, PhD , Director
Lyudmila Bakunenko
Mark Petrisch
Cynthia Lay
Aya Tal
Nursing
Joanne Soffing, RN
Irena Shvartser, RN
Rachel Najiri, RN
Natalya Eppel, RN
Toby Barsky, RN
Roxanne Diaz, RN
Nellie Badalova, RN
Vahida Gillic, RN
Toby Werner
Marcy Parker, RN
Rosa Fernandez, RN
Counseling services
Kris Bevilacqua, PhD, Psychological
Services
Katherine Mah, MS, Genetic Counseling
Genesis Team
Clinical assistants
Marina Yessayan
Tara Nieves
Cindy Ammirable
Christina Jaquez
Christina Andon
Linh Luong
Marcia Morris
Diane Piele-Fair

66. Slide from NAGY
Slow freeze vs Vitrification