Download Pubertal events girls

Oncofertility
Preserving the Future
Nicole C. Rosipal, RN, MSN, PNP
Objectives
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Incidence of cancer and survivorship among
Adolescent and Young Adult (AYA) population
Survivorship and significance of fertility
Effects of cancer and cancer treatment on
fertility
Assessment of fertility
Age appropriate fertility preservation options
– Standard and Experimental

Key considerations when discussing fertility with
patients and families
Cancer and Survivorship Among
Adolescent and Young Adults
Approximately 70,000 Adolescent and Young Adult (1539) and 10,000 children (<15) are diagnosed with
cancer each year
 Childhood cancer survivorship > 70%
 1 of 900 individuals in U.S. between 15-45 is a childhood
cancer survivor
 Approximately 270,000 cancer survivors originally
diagnosed less than 21 years of age are currently living
in the United States
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Infertility
“Inability to conceive after 1 year of
intercourse without contraception”
 Azoospermia
– No measurable level of sperm in semen
– Obstructive vs. issue with spermatogenesis

Damage to oocyte, follicles or uterus
– Immediate menopause
– Premature menopause
Infertility and General Population
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Statistics
– 6.1 million Americans
– In 2002, 7% of women infertile
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Multi-factorial causes
– Men
– Women
– Both
 Sexually transmitted diseases
 Lifestyle factors – smoking, alcohol, obesity
American Society of Clinical
Oncology (ASCO) Guidelines
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Panel reviewed literature spanning 1997 to 2005
Fertility preservation is of great importance
Lack of knowledge and comfort of health care team
Effects of infertility resulting from cancer treatment:
– Psychosocial and emotional distress
– Loss of masculinity or femininity
– Most survivors prefer to have biological children
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Survivors as Parents
– Experience with illness can enrich their role
– High value on family closeness
2006 ASCO Guidelines
“Oncologists should address the possibility
of infertility with patients treated during
their reproductive years and should be
considered as early as possible in the
treatment planning”
Urban Legends and Caution
Males
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Azoospermia is potentially for life, not short term
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Can still get someone pregnant!
– Sperm production can return immediately or many
years after cancer treatments
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Pubertal development does not equal fertility
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Caution!
– Sexually transmitted diseases
Urban Legends and Caution
Females
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A “period” does not define fertility
– Amenorrhea is not a definite sign of infertility
– Return of a period does not equal fertility
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Cancer treatment can take years off of the
biological clock
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Caution!
– STD’s
Cancer and Infertility
Men
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Risk is multifactorial
–
–
–
–
Age
Disease
Cancer treatment regimen
Pre-existing conditions
Function of testicle effected
 Currently 15-30% of survivors are sterile
 Cancer has been documented to have effect on
quantity and quality of sperm.

A Word About Prepubertal Males
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Radiation less damaging than
chemotherapy
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No protective effect against chemotherapy
induced gonadal damage
Assessment of Fertility
Prior to Beginning Cancer Treatment
Male
 Tanner
Staging
– Related to secondary sexual
characteristics
– Average age
 Spermatogenesis - 13 y.o.
 Completion of puberty - 15 y.o.
 Semen
Analysis
Proportion of Patients with a
Normal Semen Analysis
Overall – 21.1% with normal semen analysis
Diagnosis
%
Nl
Brain
0
HL
33.3
Leukemia
9.1
Testicular
22.5
Sarcoma/ST 25
NHL
18
Other
0
Grey
14-18 yo
White
>18 yo
High Risk for Azoospermia
Total Body Irradiation
(TBI)
Testicular radiation
>2.5 gy men
>6 gy boys
Stem Cell Transplant
(SCT)
Testicular Cancer, ALL,
Non-Hodgkin Lymphoma
Alkylating Chemotherapy SCT
for SCT conditioning
Allogeneic
Cyclophosphamide
Autologous
Busulfan
Melphalan
High Risk for Azoospermia
Any alkylating agent + TBI,
pelvic or testicular radiation
Testicular Cancer, SCT, ALL,
NHL, sarcoma, Hodgkin,
neuroblastoma
Any protocol with
Procarbazine
Hodgkin Lymphoma
Cyclophosphamide 7.5gm/m2
Sarcoma, NHL,
neuroblastoma, ALL
Cranial brain radiation >40 Gy Brain Tumor
Intermediate Risk for Azoospermia
Bleomycin, Etoposide,
Cisplatin
Testicular Cancer
(BEP) X 2-4 cycles
Cumulative Cisplatin
dose <400 mg/m2
Testicular Cancer
Cumulative Carboplatin
dose < 2 g/m2
Testicular Cancer
Intermediate Risk for Azoospermia
Testicular radiation dose Wilm’s tumor and
1-6 Gy
neuroblastoma
Due to scatter from
abdominal/pelvic
radiation
Low Risk for Azoospermia
Non-alkylating
chemotherapy
Hodgkin Lymphoma,
Non-Hodgkin Lymphoma
ABVD, OEPA, NOVP, COP,
CHOP
Testicular radiation
0.2-0.7 Gy
Testicular Cancer
Very Low/No Risk for Azoospermia
Testicular radiation
<0.2 Gy
Multiple Cancers
Interferon a
Multiple Cancers
Radioactive Iodine
Thyroid
Unknown Risk for Azoospermia
Irinotecan
 Bevacizumab (Avastin)
 Cetuximab (Erbitux)
 Erlotinib (Tarceva)
 Imatinib (Gleevec)
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Preventative Measures
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Shielding during radiation
– Pre and post pubertal
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Hormonal manipulation (GnRH analogs)
has not proven successful in
gonadoprotection
Banking Options
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Pre vs. Post Pubertal
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Standard vs. Experimental
Banking Options: Post Pubertal Male
Standard
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Sperm Banking:
–
–
–
–
Most effective
Obtained through masturbation then frozen
Outpatient procedure
Success rate is generally high
 Reports of 50% successful pregnancy rate
– Potentially compromised sperm count and
increased risk of genetic damage after a single
treatment
Banking Options: Post Pubertal Males
Standard
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Sperm Banking Process
– MD/APN/PA order
– Collection PRIOR to chemotherapy and/or
radiation is vital
– 2-3 samples are recommended
– A sample can be provided every 24 hours.
– Collected in a sterile container
 At clinic location, hospital, home
 Kept at body temperature and brought to lab
within one hour
Sperm Banking Process Continued
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Semen Analysis
– Sperm count and movement
– Morphology
– Semen is placed in individual plastic vials for
freezing
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Cost
– $125-$250 for analysis
– $225-$375 for one year storage
Mandatory Infectious Disease
Testing
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Serum:
–
–
–
–
–
–
–
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HIV
Hepatitis A, B and C
RPR (Syphilis)
HTLV 1 and 2 (Human T-lymphotropic virus)
CMV IgG and IgM
Gonorrhea and Chlamydia (IgG and IgM)
AST
Cost
– Approximately $325
Banking Options: Post Pubertal Males
Experimental

Electroejaculation
– Penile or Rectal
 Mechanical vibrator is placed at the base of the
penis or in rectum and set to vibrate at a
designated frequency and wave amplitude.
 Vibration travels along the sensory nerves to the
spinal cord and may induce a reflex ejaculation.
– Approx 50 - 100% success rate of ejaculation
– Cost varies greatly
Banking Options: Post Pubertal Males
Experimental

Testicular sperm extraction
– Outpatient procedure
– Testicular mapping
– Success Rate
 30-70%
 45% of azoospermic ejaculate after cancer
treatment
– Cost
 $4,000 - $16,000
Banking Options: Prepubertal Males
Experimental Only
 Cryopreservation of testicular tissue
and stem cells
– Tissue obtained via biopsy and frozen
– In Vitro culture
 Maturation of testicular stem cells
– Animal studies only
– Autotransplantation
 Risk of recurrence?
Options after Cancer Treatment

Use of Frozen Sperm
– In Vitro Fertilization (IVF)
– Intra Cytoplasmic Sperm Injection (ICSI)
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Donor Sperm
– $200 - 500 per vial
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Adoption
– $2,500 - $35,000
Options in Houston
Baylor College of
Medicine – Urology
Medical Center
Houston IVF
Memorial City
Advanced Fertility Center Medical Center, Katy,
of Texas
Memorial City, Cy Fair,
The Woodlands
Assessment of Fertility
After Cancer Treatment
 Semen
analysis
 Blood Work
 FSH
 Inhibin B
Cancer and Infertility
Women
Cancer itself does not appear to affect
fertility in women.
 Cancer treatments pose spectrum of risk

 Immediate infertility
 Premature menopause
 Compromised ability to carry a pregnancy
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Multifactoral process
 Drug type & dose
 Radiation location & dose
 Patient age & pubertal status
 Pre-treatment fertility
A Word About Prepubertal Females
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Early age at time of cancer treatment has
a protective effect
– Younger age with larger number of oocytes
requiring more radiation to cause damage
– Less mitotic activity
Cancer and Infertility
Women
Surgery can impair ability to become
pregnant and/or carry pregnancy
 Radiation can damage uterus and increase
risk of miscarriage
 Advise survivors who have received pelvic
radiation should seek high-risk OB
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Cancer and Infertility
Women
Damage to oocytes and follicles can lead
to immediate menopause or premature
menopause years after treatment.
 Menstruation does not equal fertility
 Treatment affect on stromal function and
ovarian blood vessels
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High Risk
>80% of women develop amenorrhea post-treatment
Whole abdominal or pelvic radiation doses
> 6 Gy in adult women
Multiple cancers
Whole abdominal or pelvic radiation doses Wilms’ tumor, neuroblastoma,
> 15 Gy in pre-pubertal girls
sarcoma, Hodgkin lymphoma
> 10 Gy in post-pubertal girls
TBI radiation doses
Stem cell transplant
CMF, CEF, CAF x 6 cycles in women 40 +
Breast cancer
Cyclophosphamide 5 g/m2 in women 40+
Multiple cancers
Cyclophosphamide 7.5 g/m2 in girls < 20
Non-Hodgkin lymphoma,
neuroblastoma, ALL, sarcoma
High Risk
>80% of women develop amenorrhea post-treatment
Alkylating chemotherapy
(cyclophosphamide, busulfan,
melphalan) conditioning for
transplant
Stem cell transplant
Any alkylating agent
(e.g.cyclophosphamide,
ifosfamide, busulfan, BCNU,CCNU)
+ TBI or pelvic radiation
Stem cell transplant,
ovarian cancer, sarcoma,
neuroblastoma, Hodgkin lymphoma
Protocols containing procarbazine:
MOPP, COPP, BEACOPP,
MOPP/ABVD,COPP/ABVD
Hodgkin lymphoma
Cranial/brain radiation >40 Gy
Brain tumor
Intermediate Risk
~30-70% of women develop amenorrhea post-treatment
CMF or CEF or CAF x 6 cycles in
women 30-39
Breast cancer
Anthracycline & cyclophosphamide
women 40 +
Breast cancer
Whole abdominal or pelvic radiation
10-<15 Gy in prepubertal girls
Wilm’s tumor
Whole abdominal or pelvic radiation
5-<10 Gy in postpubertal girls
Wilm’s tumor, neuroblastoma
Spinal radaition >25 Gy
Spinal tumor, brain tumor,
neuroblastoma, relapse ALL or NHL
Low Risk
<20% of women develop amenorrhea post-treatment
AC (anthracycline,
cytarabine)
in women 30-39
Breast cancer
CMF, CEF or CAF x6 cycles in Breast cancer
women 30-39
Non-akylating
Hodgkin lymphoma, NHL
chemotherapy: ABVD, CHOP,
COP
AC
AML
Multi-agent therapies
ALL
Very Low Risk
Negligible effect on menses
Methotrexate, 5 FU
Breast cancer
Vincristine (used in multiagent therapies)
Leukemia, NHL, Hodgkin
lymphoma, neuroblastoma,
rhabdomyosarcoma, Wilm’s
tumor, Kaposi sarcoma
Thyroid cancer
Radioactive Iodine
Unknown Risk
Paclitaxel, docetaxel
Breast cancer
Oxaliplatin
Ovarian cancer
Irinotecan
Colon cancer
Bevacizumab (Avastin)
Colon, non-small cell lung
Ceftuximab (Erbitux)
Colon, head & neck
Trastuzamab (Herceptin)
Breast cancer
Erlotinib (Tarceva)
Non-small cell lung,
pancreatic
CML, GIST
Imatinib (Gleevec)
Standard Female Reproductive
Options
Embryo freezing
 Radiation shielding of ovaries
 Ovarian transposition
 Radical trachelectomy
 Donor embryos
 Donor eggs
 Gestational surrogacy
 Adoption
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Embryo Freezing
Eggs are harvested and undergo in vitro
fertilization. Embryos are frozen for later
implantation.
 Time requirement
 Cost: ~ $8,000-12,000 per cycle / $350/year
storage fees

– Donor sperm $200-$500 / vial
Success rate: 20-33%, babies born
 Special considerations: partner, donor sperm
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Radiation Shielding of Ovaries
Shielding reduces scatter to reproductive
options
 Time requirement: non-issue
 Cost: included in cost of radiation
 Success rate: limited to selected radiation
fields
 Special considerations: No protection from
chemotherapy

Ovarian Transposition
Surgical repositioning of ovaries away
from radiation field
 Time requirement: Outpatient procedure
 Cost: Maybe covered by insurance
 Success rate: Approximately 50%
 Special considerations: Expertise required

Radical Trachelectomy
Surgical removal of the cervix with
preservation of uterus
 Time requirement: During treatment
 Cost: Included in treatment cost
 Success rate: No evidence of higher
recurrence rate
 Special considerations: Early stage cervical
cancer, limited centers
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Standard Female Reproductive
Options
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Donor embryos
– Not biologic child
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Donor eggs
– Offers opportunity for biologic child for father
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Gestational surrogacy
– Legal implications
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Adoption
– Inaccessibility to cancer survivors
Experimental Options
Egg/oocyte freezing
 Ovarian tissue preservation
 GnRH
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Experimental Options for Females
Oocyte cryopreservation
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Process the same, sperm not needed
Oocytes are more sensitive to freeze/thaw
process and more prone to damage
Average 2% (range 1-5%) chance of pregnancy
per oocyte (3-4 times less than with embryo)
200+ live births to date
~$12,000/cycle
Experimental Options for Females
Ovarian Tissue cryopreservation
Laparoscopic procedure
 Benefits:

– Ovarian stimulation not performed
– Acquire hundreds of immature oocytes
– Less delay in commencement of cancer treatment


HOWEVER – not a location available in Texas!
Concerns
– Reimplantation increase risk of recurrence?

How to develop the immature oocytes?
 Autotransplantation - Orthotopic vs. heterotopic
 Xenotransplantation
Two live births reported (2005)
 ~$12,000 for procedure; storage and reimplantation with additional cost
 Retrieval of immature oocytes with in vitro maturation (5 y.o. youngest
reported)
 Post chemotherapy preservation possible; however, lower yield

Assessment of Fertility
Difficult to predict reproductive horizon post
treatment
 Regaining menses post treatment does not imply
intact fertility
 Risk of premature ovarian failure is real
 Current assessment is:

– Day 3 of cycle
 FSH
 LH
 Transvaginal ultrasound to assess antral follicle count
– AMH (anti-mullerian hormone): determine ovarian
reserve
Experimental Options for Females
GnRH agonist
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Lupron – 1 month or 3 month injection
Creates a prepubertal state, suppressing ovulation
When to give?
– 2-3 weeks prior to chemotherapy to prevent breakthrough bleeding from
occurring during time of cytopenia.
– Give up to 2 doses or 6 months total – bone demineralization
What does the literature say?
– Potential risks in hormone sensitive tumors unknown
– Does not protect follicles from radiation
– Mixed review
 No benefit vs. Menses resuming with or without pregnancy achievement
– 98% vs. 40% resumption of menses 6 months post chemotherapy
 Do agree – decrease risks associated with menses during time of
cytopenia
 Window of opportunity
Cost - $500/month
Options in Houston
Embryo freezing- Fertile Hope referrals
 Radiation shielding- Radiation Oncologist
 Ovarian transposition- Surgery
 Radical Trachelectomy- MDACC, Pedro
Ramirez, MD
 Exploring option with Baylor group for
ovarian tissue preservation

Potential Barriers for
Men and Women
Lack of information of treating oncologist
 Lack of referral network
 Perceived financial burden to families
 Facility not adolescent friendly
 Time
 Parental anxiety
 Spiritual concerns
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Resources
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Fertility Consult Service
– Anna Franklin, MD
– Donna Herrera-Bell
– Nicole Rosipal, RN, MSN, CPNP
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Services Provided
– Discussion of infertility risk and available options
– Referral

Process
– Consult Request
– Wednesday, Thursday and Friday afternoons
Resources
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LIVESTRONG Survivor Care
– www.LIVESTRONG.org/survivorcare
– Information about fertility preservation, financial, insurance and
employment concerns
– LIVE:ON

Fertile Hope
– www.fertilehope.org
– Sharing Hope program
– Self referral
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Oncofertility Consortium
Heroes for children – up to 22
– http://www.heroesforchildren.org/
– Social worker completes assessment and application
– Assistance is based on financial need ($750 towards expenses)
Current Research at
MD Anderson
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Banking on Fatherhood
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St. Jude’s Questionnaire
– Attitude about sperm banking
Discussion
References
Biro, F. M., et al. (2010) Normal Puberty. Up to Date. www.uptodate.com
 Blumenfeld, Z. (2008). GnRH-agoinst in fertility preservation. Curr Opin
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Endocrinol Diabetes Obes, 15, 523-26.
Blumenfeld, Z. & Eckman, A. (2005). J Natl Cancer Inst Monogr, (34), 403.
Boss, E. A., van Golde, R. J., & Massuger, L. F. (2005). Pregnancy after
radical trachelectomy: a real option? Gynecol Oncol, 99(3 supp 1), 152-6.
 Fertility preservation and reproduction in cancer patients. (2005). Fertil
Steril, 83(6), 1622-1628.
 Green, D. M., Sklar, C. A., Boice, J. D., Jr., Mulvihill, J. J., Whitton, J. A.,
Stovall, M., et al. (2009). Ovarian failure and reproductive outcomes after
childhood cancer treatment: results from the Childhood Cancer Survivor
Study. J Clin Oncol, 27(14), 2374-2381.
 Lee, S. J., Schover, L. R., Partridge, A. H., Patrizio, P., Wallace, W. H.,
Hagerty, K., et al. (2006). American Society of Clinical Oncology
recommendations on fertility preservation in cancer patients. J Clin Oncol,
24(18), 2917-2931.
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References
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Neal, M. S., Nagel, K., Duckworth, J., Bissessar, H., Fischer, M. A., Portwine, C., et al.
(2007). Effectiveness of sperm banking in adolescents and young adults with cancer:
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Author, A. A., & Author, B. B. (Year of publication). Late effects of childhood cancer
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Pediatric Oncology (1503-06). Philadelphia, PA: Lippincott Williams & Wilkins.
Revel, A., Revel-Vilk, S., Aizenman, E., Porat-Katz, A., Safran, A., Ben-Meir, A., et al.
(2009). At what age can human oocytes be obtained? Fertil Steril, 92(2), 458-463.
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www.fertilehope.org
www.livestrong.org
Zakak, N. N. (2009). Fertility issues of childhood cancer survivors: the role of the
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