Download Fertility Preservation - Iowa Cancer Consortium

Fertility
Preservation
In Cancer
Patients
Barbara J. Stegmann, MD, MPH
Assistant Professor
Reproductive Endocrinology and Infertility
University of Iowa
[email protected]
Patients diagnosed with cancer in US in 2005
4% under age 35
1,372,910 patients
55,000 under the age of 35
12,000 under the age of 19
Lee et al, J Clin Onc 2006
Estimated Number of Cancer
Survivors in U.S
(1971 to 2004)
Cancer & Fertility Crossroads
Increasing Cancer Survival Rates
+
Increased Emphasis on Quality of Life
+
New Fertility Preservation &
Post-treatment Parenthood Options
=
Patients Need Information About
Fertility Risks & Options
Are cancer patients interested in
interventions to preserve fertility?
• Fertility preservation is of great importance to
people diagnosed with cancer
• Most cancer survivors prefer to have biological
offspring despite serious concerns
• Increased emotional distress in those who
become infertile after cancer treatment
• Long-term quality of life is affected by unresolved
grief and depression
• Patients may choose a less effective treatment
strategy in order to avoid or reduce the risk of
infertility
Objectives
• What are the current and future options
to preserve fertility in males?
• What are the current and future options
to preserve fertility in females?
• Who will benefit from fertility
preservation counselling?
Causes of Male Infertility
• The disease itself—Hodgkin’s Lymphoma
• Retrograde ejaculation or anejaculation
• 1o or 2o hormone insufficiency
• Damage or depletion of germinal stem cells
Anti-tumor agents that can
cause prolonged azoospermia
Radiation
(2.5 GY to testis)
Chlorambucil
(1.4 g/m2)
Cisplatin
(500 mg/m2)
Procarbazine
(4 g/m2)
Cyclophosphamide
(19 g/m2)
Melphalan
(140 mg/m2)
•Currently do not know how new agents affect sperm production
•New agents include: oxaliplatin, irinotecan, monoclonal
antibodies, tyrosine kinase inhibitors and taxanes
Current options for
Preservation of Fertility in
Males
• Sperm cryopreservation
– Antegrade ejaculate
– Retrograde ejaculate
– Testicular aspirate (outpatient surgery)
• Gonadal shielding during radiation
• Testicular suppression with GnRH
analogs or antagonists – not effective
Use of cryopreserved sperm
• 10%-30% of the men who banked
sperm before cancer treatment return
to use the sperm
• Storage fees are rarely the reason for
specimen discard.
Couple Bear Child Using 14Year-Old Frozen Semen
Before they got married, Rick
explained to Jessica all about his
cancer history and the possibility
that he might be infertile. She was
not intimidated by the news.
“We knew we had options,” she
said, referring to the banked sperm.
“We had more anxiety when we
went to do this.”
Quad City Times, Nov 11, 2010
Causes of Female Infertility
•DNA damage to oocytes
•Destruction of the primordial follicles
•Hormonal imbalances due to damage
to the pituitary
•Damage to uterus, ovaries and tubes
Effect of Radiation on
Female Fertility
• Direct & indirect damage to DNA
of oocytes
• Small primordial and growing
follicles damaged
• Damage to the pituitary
High Risk of Amenorrhea
•
•
•
•
•
•
•
Bendamustine
Busulfan
Carboplatin
Chlorambucil
Cisplatin
Cyclophosphamide
Dacarbazine
•
•
•
•
•
•
Isofamide
Mechlorethamine
Melphalan
Procarbazine
Temozolomide
Thiotepa
Fertile Hope, Fast Facts for Oncology Professionals, 2007
Risk of ovarian involvement
LOW RISK
• Wilm’s
• Lymphomas
• Stage I-III breast CA
(infiltrating & ductal)
• Nongenital
rhabdomyosarcoma
• Osteogenic
sarcoma
• Squamous cell
cervix
• Ewing sarcoma
MODERATE RISK
• Stage IV breast
• Adeno cervix
• Colorectal
HIGH RISK
•Leukemia
•Neuroblastoma
•Stage IV lobular breast
Sonmezer & Oktay Human Reprod Update 2004.
Oocyte Development
Assessing Ovarian Reserve
in Cancer Patients
• FSH
– Late biomarker
– Indirect measure of ovarian “health”
Lie Fong et al. Hum Reprod 2008;23(3):674-8.
Initiation of Puberty
Assessing Ovarian Reserve
in Cancer Patients
• Ovarian volume
Assessing Ovarian Reserve
in Cancer Patients
• Antral Follicle Count (AFC)
Assessing Ovarian Reserve
in Cancer Patients
• AMH (anti-mullerian hormone)
Assessing Ovarian Reserve
in Cancer Patients
• Cycle regularity - use caution
– Regular cycles ≠fertile
– Amenorrhea ≠ Infertile
– **Remember to offer contraception
when fertility is not desired
Options for Fertility
Preservation
The Now
• Embryo cryopreservation
Near Future
• Oocyte cryopreservation
– Still considered experimental
Long Range Planning
• Ovarian tissue cryopreservation
• Cytotoxic protectants
Embryo Cryopreservation
• Most established technique for fertility
preservation
• Requires 8-12 days of ovarian stimulation
• Retrieval is an outpatient surgical
procedure
• May delay treatment 2-6 weeks
• Success rate varies, depending on
female’s age
Limitations of embryo
cryopreservation
• Time
– Need 2-6 weeks -> may delay therapy
• Relationship status
– Must have partner or donor sperm
• Age
– Not acceptable for children
• Cost
– $12-15,000 / cycle and storage fees
• Risks
– Hyperstimulation syndrome
– Exposure to higher level of estradiol
Oocyte cryopreservation
• Reproductive age women without
partners
• Women with an ethical or religious
objection to embryo storage
• An option for pubertal girls
Limitations of oocyte
cryopreservation
• Time
• Cost
• Risks
}
Similar to embryo
cryopreservation
Oocyte cryopreservation is technically
challenging
Ovarian Tissue
Cryopreservation
• Advantages
–No partner required
–No ovarian stimulation
required
–May be feasible for prepubertal
children
Ovarian Tissue
Cryopreservation
• Tissue is removed laparoscopically and
cryopreserved
• Primordial and primary follicles
• Reimplanted when ready to have children
• Oocytes are matured in the lab and
fertilized
Limitations of ovarian tissue
cryopreservation
• Large follicular loss due to ischemia (about 25% of
primordial follicles are lost)
• Possibility of residual malignant cells
• Oocytes arrested in prophase I so must undergo in-vitro
maturation if not reimplanted
• Cost:
– $12,000 for harvest, freeze
– $10,000 for transplantation
– -$15,000 for IVF
Cytoprotective Agents
• NRF2 activators
–Sulforaphane
• Amifostine
• Trental/Vitamin E
• Dexrazoxane
Cytoprotective Agents
• GnRH analogs or antagonists
– ? proven benefit
– ? Lower incidence of premature ovarian
failure and infertility in prepubertal girls
receiving alkylator
– Highly controversial—being used without
clear evidence of efficacy or
understanding of risks/benefits
Cytoprotective Agents
• GnRH analogs or antagonists
– Theorhetical mechanisms
• Downregulation of the ovary
• Antiapoptotic
• Decreases blood flow to ovary so less
exposure
Ovarian Transposition
• Oophoropexy offered with pelvic
radiation is used for cancer
treatment
• Must be performed close to the time
of radiation treatment (risk of
remigration)
• May be performed laparoscopically if
laparotomy is not needed for
treatment
Ovarian Transposition
• Success rate judged by short-term
menstrual function is 50%.
• Failure is attributed to scatter
radiation, alteration of the ovarian
blood supply and total radiation
dose.
• Ovarian repositioning may or may not
be required.
Special considerations for
pediatric cancer patients
• Impaired fertility difficult to conceptualize
• Spermarche occurs at 13-14 years
• Established methods (sperm and embryo
cryopreservation) require BOTH patient
assent and parental consent
• Experimental methods should only be
attempted under IRB-approved protocols
Post-Treatment
Pre-Treatment
Average Treatment Costs
Nationally
UIHC
Sperm Banking
$1500
$218 & $150/yr
Testicular tissue freezing
$10,000
$5500 & $150/yr
Embryo Freezing
$10,000
$10,000 - $11,000
Egg Freezing
$8,000
NA
Ovarian Tissue Freezing
$12,000
NA
GnRH analog treatment ♀
$500/mo
In Vitro Fertilization
$10 – 14,000
$11 - 13,000
Donor gametes or embryos
$ 25,000
$20 - 25,000
Adoption
$2,500 – 35,000
Surrogacy
$20 – 100,000
$20 - $100,000
Barriers to accessing care
(From fertile HOPE fertility resources for cancer patients)
• Up to 90% of young cancer patients are at risk for
infertility following treatment
• <25% of oncologists inform eligible patients about
their risks and options
• Fears and misconceptions exist from fertility
treatments and the safety of pregnancy after
cancer
Conclusions
• Fertility preservation is often possible
• Sperm and embryo cryopreservation are
the only non-experimental procedures
available.
• A broader application of fertility
preservation requires
– Education
– Provision of financial resources for these
interventions
– Better understanding of the risks associated
with fertility preservation
Conclusions
• Information is important, but do not give
false hope
– Consider referring to our study or our
clinic for consultation
• Fertility preservation should not be pursued
at the expense of cancer treatment and
overall welfare