oncofertility preserving the future nicole c. rosipal, rn, msn, pnp
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OncofertilityOncofertilityPreserving the FuturePreserving the Future
Nicole C. Rosipal, RN, MSN, PNPNicole C. Rosipal, RN, MSN, PNP
ObjectivesObjectives Incidence of cancer and survivorship among Incidence of cancer and survivorship among Adolescent and Young Adult (AYA) Adolescent and Young Adult (AYA) populationpopulation
Survivorship and significance of fertilitySurvivorship and significance of fertility Effects of cancer and cancer treatment on Effects of cancer and cancer treatment on fertilityfertility
Assessment of fertilityAssessment of fertility Age appropriate fertility preservation Age appropriate fertility preservation options options – Standard and ExperimentalStandard and Experimental
Key considerations when discussing Key considerations when discussing fertility with patients and familiesfertility with patients and families
Cancer and Survivorship Cancer and Survivorship Among Adolescent and Among Adolescent and
Young AdultsYoung Adults Approximately 70,000 Adolescent and Young Approximately 70,000 Adolescent and Young Adult (15-39) and 10,000 children (<15) Adult (15-39) and 10,000 children (<15) are diagnosed with cancer each yearare diagnosed with cancer each year
Childhood cancer survivorship > 70%Childhood cancer survivorship > 70% 1 of 900 individuals in U.S. between 15-45 1 of 900 individuals in U.S. between 15-45 is a childhood cancer survivor is a childhood cancer survivor
Approximately 270,000 cancer survivors Approximately 270,000 cancer survivors originally diagnosed less than 21 years of originally diagnosed less than 21 years of age are currently living in the United age are currently living in the United StatesStates
InfertilityInfertility
““Inability to conceive after 1 year of Inability to conceive after 1 year of intercourse without contraception”intercourse without contraception”
AzoospermiaAzoospermia– No measurable level of sperm in semenNo measurable level of sperm in semen– Obstructive vs. issue with Obstructive vs. issue with spermatogenesisspermatogenesis
Damage to oocyte, follicles or uterusDamage to oocyte, follicles or uterus – Immediate menopause Immediate menopause – Premature menopausePremature menopause
Infertility and General Population
Statistics– 6.1 million Americans – In 2002, 7% of women infertile
Multi-factorial causes– Men– Women– Both
Sexually transmitted diseases Lifestyle factors – smoking, alcohol, obesity
American Society of American Society of Clinical Oncology (ASCO) Clinical Oncology (ASCO)
GuidelinesGuidelines Panel reviewed literature spanning 1997 to 2005Panel reviewed literature spanning 1997 to 2005 Fertility preservation is of Fertility preservation is of great importancegreat importance Lack of knowledge and comfort of health care Lack of knowledge and comfort of health care teamteam
Effects of infertility resulting from cancer Effects of infertility resulting from cancer treatment:treatment:– Psychosocial and emotional distressPsychosocial and emotional distress– Loss of masculinity or femininityLoss of masculinity or femininity– Most survivors prefer to have biological childrenMost survivors prefer to have biological children
Survivors as ParentsSurvivors as Parents– Experience with illness can enrich their roleExperience with illness can enrich their role– High value on family closenessHigh value on family closeness
2006 ASCO Guidelines2006 ASCO Guidelines
““Oncologists should address the Oncologists should address the possibility of infertility with possibility of infertility with patients treated during their patients treated during their reproductive years and should reproductive years and should be considered as early as be considered as early as possible in the treatment possible in the treatment planning”planning”
Urban Legends and CautionUrban Legends and CautionMalesMales
Azoospermia is potentially for life, not Azoospermia is potentially for life, not short termshort term
Can still get someone pregnant!Can still get someone pregnant!– Sperm production can return immediately or Sperm production can return immediately or many years after cancer treatmentsmany years after cancer treatments
Pubertal development does not equal fertilityPubertal development does not equal fertility
Caution!Caution!– Sexually transmitted diseasesSexually transmitted diseases
Urban Legends and CautionFemales
A “period” does not define fertilityA “period” does not define fertility– Amenorrhea is not a definite sign of Amenorrhea is not a definite sign of infertilityinfertility
– Return of a period does not equal fertilityReturn of a period does not equal fertility
Cancer treatment can take years off of Cancer treatment can take years off of the biological clockthe biological clock
Caution!Caution!– STD’sSTD’s
Cancer and Infertility Cancer and Infertility MenMen
Risk is multifactorialRisk is multifactorial– AgeAge– DiseaseDisease– Cancer treatment regimenCancer treatment regimen– Pre-existing conditionsPre-existing conditions
Function of testicle effectedFunction of testicle effected Currently 15-30% of survivors are Currently 15-30% of survivors are sterilesterile
Cancer has been documented to have Cancer has been documented to have effect on quantity and quality of effect on quantity and quality of sperm.sperm.
A Word About Prepubertal Males
Radiation less damaging than chemotherapy
No protective effect against chemotherapy induced gonadal damage
Assessment of FertilityPrior to Beginning Cancer
Treatment Male
Tanner StagingTanner Staging–Related to secondary sexual Related to secondary sexual characteristicscharacteristics
–Average ageAverage age Spermatogenesis - 13 y.o. Spermatogenesis - 13 y.o. Completion of puberty - 15 y.o.Completion of puberty - 15 y.o.
Semen Analysis
Proportion of Patients Proportion of Patients with a Normal Semen with a Normal Semen
AnalysisAnalysisDiagnosis
% Nl
Brain 0
HL 33.3
Leukemia 9.1
Testicular
22.5
Sarcoma/ST
25
NHL 18
Other 0Grey 14-18
yo
White
>18 yo
Overall – 21.1% with normal semen analysis
High Risk for AzoospermiaTotal Body Irradiation (TBI)
Stem Cell Transplant (SCT)
Testicular radiation >2.5 gy men >6 gy boys
Testicular Cancer, ALL, Non-Hodgkin Lymphoma
Alkylating Chemotherapy for SCT conditioning Cyclophosphamide Busulfan Melphalan
SCT Allogeneic Autologous
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
(BEP) X 2-4 cycles
Testicular Cancer
Cumulative Cisplatin dose <400 mg/m2
Testicular Cancer
Cumulative Carboplatin dose < 2 g/m2
Testicular Cancer
Intermediate Risk for Azoospermia
Testicular radiation dose 1-6 Gy
Due to scatter from abdominal/pelvic radiation
Wilm’s tumor and neuroblastoma
Low Risk for Azoospermia
Non-alkylating chemotherapy
ABVD, OEPA, NOVP, COP, CHOP
Hodgkin Lymphoma, Non-Hodgkin Lymphoma
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)
Preventative MeasuresPreventative Measures
Shielding during radiationShielding during radiation– Pre and post pubertal Pre and post pubertal
Hormonal manipulation (GnRH Hormonal manipulation (GnRH analogs) has not proven analogs) has not proven successful in gonadoprotectionsuccessful in gonadoprotection
Banking Options: Post Banking Options: Post Pubertal MalePubertal Male StandardStandard
Sperm Banking:Sperm Banking:– Most effectiveMost effective– Obtained through masturbation then Obtained through masturbation then frozenfrozen
– Outpatient procedureOutpatient procedure– Success rate is generally highSuccess rate is generally high
Reports of 50% successful pregnancy Reports of 50% successful pregnancy raterate
– Potentially compromised sperm count Potentially compromised sperm count and increased risk of genetic damage and increased risk of genetic damage after a single treatmentafter a single treatment
Banking Options: Post Banking Options: Post Pubertal MalesPubertal Males
StandardStandard Sperm Banking ProcessSperm Banking Process
– MD/APN/PA orderMD/APN/PA order– Collection PRIOR to chemotherapy Collection PRIOR to chemotherapy and/or radiation is vitaland/or radiation is vital
– 2-3 samples are recommended2-3 samples are recommended– A sample can be provided every 24 A sample can be provided every 24 hours. hours.
– Collected in a sterile containerCollected in a sterile container At clinic location, hospital, homeAt clinic location, hospital, home Kept at body temperature and brought Kept at body temperature and brought to lab within one hourto lab within one hour
Sperm Banking Process Sperm Banking Process ContinuedContinued
Semen AnalysisSemen Analysis– Sperm count and movement Sperm count and movement – MorphologyMorphology– Semen is placed in individual Semen is placed in individual plastic vials for freezingplastic vials for freezing
CostCost– $125-$250 for analysis$125-$250 for analysis– $225-$375 for one year storage$225-$375 for one year storage
Mandatory Infectious Mandatory Infectious Disease TestingDisease Testing
Serum:Serum:– HIVHIV– Hepatitis A, B and CHepatitis A, B and C– RPR (Syphilis)RPR (Syphilis)– HTLV 1 and 2 (Human T-lymphotropic HTLV 1 and 2 (Human T-lymphotropic virus)virus)
– CMV IgG and IgMCMV IgG and IgM– Gonorrhea and Chlamydia (IgG and IgM)Gonorrhea and Chlamydia (IgG and IgM)– ASTAST
CostCost– Approximately $325Approximately $325
Banking Options: Post Banking Options: Post Pubertal MalesPubertal MalesExperimentalExperimental
ElectroejaculationElectroejaculation– Penile or RectalPenile or Rectal
Mechanical vibrator is placed at the Mechanical vibrator is placed at the base of the penis or in rectum and set base of the penis or in rectum and set to vibrate at a designated frequency to vibrate at a designated frequency and wave amplitude. and wave amplitude.
Vibration travels along the sensory Vibration travels along the sensory nerves to the spinal cord and may nerves to the spinal cord and may induce a reflex ejaculation. induce a reflex ejaculation.
– Approx 50 - 100% success rate of Approx 50 - 100% success rate of ejaculationejaculation
– Cost varies greatlyCost varies greatly
Banking Options: Post Banking Options: Post Pubertal MalesPubertal MalesExperimentalExperimental
Testicular sperm extraction– Outpatient procedureOutpatient procedure– Testicular mappingTesticular mapping– Success RateSuccess Rate
30-70% 30-70% 45% of azoospermic ejaculate after 45% of azoospermic ejaculate after cancer treatment cancer treatment
– Cost $4,000 - $16,000
Banking Options: Prepubertal Banking Options: Prepubertal MalesMales
Experimental OnlyExperimental Only Cryopreservation of testicular Cryopreservation of testicular tissue and stem cellstissue and stem cells– Tissue obtained via biopsy and Tissue obtained via biopsy and frozenfrozen
– In Vitro cultureIn Vitro culture Maturation of testicular stem Maturation of testicular stem cellscells
– Animal studies onlyAnimal studies only– AutotransplantationAutotransplantation
Risk of recurrence?Risk of recurrence?
Options after Cancer Treatment
Use of Frozen Sperm– In Vitro Fertilization (IVF)– Intra Cytoplasmic Sperm Injection Intra Cytoplasmic Sperm Injection ((ICSI)
Donor Sperm– $200 - 500 per vial
Adoption– $2,500 - $35,000
Options in Houston
Baylor College of Medicine – Urology
Medical Center
Houston IVF Memorial City
Advanced Fertility Center of Texas
Medical Center, Katy, Memorial City, Cy Fair, The Woodlands
Cancer and InfertilityCancer and InfertilityWomenWomen
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
Multifactoral process Drug type & dose Radiation location & dose Patient age & pubertal status Pre-treatment fertility
A Word About Prepubertal A Word About Prepubertal FemalesFemales
Early age at time of cancer Early age at time of cancer treatment has a protective treatment has a protective effecteffect– Younger age with larger number of Younger age with larger number of oocytes requiring more radiation oocytes requiring more radiation to cause damageto cause damage
– Less mitotic activityLess mitotic activity
Cancer and InfertilityCancer and InfertilityWomenWomen
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
Cancer and InfertilityCancer and InfertilityWomenWomen
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
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> 15 Gy in pre-pubertal girls> 10 Gy in post-pubertal girls
Wilms’ tumor, neuroblastoma,sarcoma, Hodgkin lymphoma
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 radiation10-<15 Gy in prepubertal girls
Wilm’s tumor
Whole abdominal or pelvic radiation5-<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 women 30-39
Breast cancer
Non-akylating chemotherapy: ABVD, CHOP, COP
Hodgkin lymphoma, NHL
AC AML
Multi-agent therapies ALL
Very Low RiskNegligible effect on menses
Methotrexate, 5 FU Breast cancer
Vincristine (used in multi-agent therapies)
Leukemia, NHL, Hodgkin lymphoma, neuroblastoma, rhabdomyosarcoma, Wilm’s tumor, Kaposi sarcoma
Radioactive Iodine Thyroid cancer
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
Imatinib (Gleevec) CML, GIST
Standard Female Reproductive Options
Embryo freezing Radiation shielding of ovaries Ovarian transposition Radical trachelectomy Donor embryos Donor eggs Gestational surrogacy Adoption
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 / ~ $8,000-12,000 per cycle / $350/year storage fees$350/year storage fees– Donor sperm $200-$500 / vialDonor sperm $200-$500 / vial
Success rate: 20-33%, babies born Special considerations: partner, donor sperm
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
Standard Female Reproductive Options
Donor embryos– Not biologic child
Donor eggs– Offers opportunity for biologic child for father
Gestational surrogacy– Legal implications
Adoption– Inaccessibility to cancer survivors
Experimental Options for Experimental Options for FemalesFemales
Oocyte cryopreservation Oocyte cryopreservation
Process the same, sperm not neededProcess the same, sperm not needed Oocytes are more sensitive to Oocytes are more sensitive to freeze/thaw process and more prone to freeze/thaw process and more prone to damagedamage
Average 2% (range 1-5%) chance of Average 2% (range 1-5%) chance of pregnancy per oocyte (3-4 times less pregnancy per oocyte (3-4 times less than with embryo)than with embryo)
200+ live births to date200+ live births to date ~$12,000/cycle~$12,000/cycle
Experimental Options for Experimental Options for FemalesFemales
Ovarian Tissue cryopreservationOvarian Tissue cryopreservation Laparoscopic procedureLaparoscopic procedure Benefits:Benefits:
– Ovarian stimulation not performedOvarian stimulation not performed– Acquire hundreds of immature oocytesAcquire hundreds of immature oocytes– Less delay in commencement of cancer treatment Less delay in commencement of cancer treatment
HOWEVER – not a location available in Texas!HOWEVER – not a location available in Texas!
ConcernsConcerns– Reimplantation increase risk of recurrence?Reimplantation increase risk of recurrence?
How to develop the immature oocytes?How to develop the immature oocytes? Autotransplantation - Orthotopic vs. heterotopicAutotransplantation - Orthotopic vs. heterotopic XenotransplantationXenotransplantation
Two live births reported (2005)Two live births reported (2005) ~$12,000 for procedure; storage and reimplantation with ~$12,000 for procedure; storage and reimplantation with
additional costadditional cost Retrieval of immature oocytes with in vitro maturation (5 Retrieval of immature oocytes with in vitro maturation (5
y.o. youngest reported)y.o. youngest reported) Post chemotherapy preservation possible; however, lower Post chemotherapy preservation possible; however, lower
yieldyield
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 Experimental Options for FemalesFemales
GnRH agonistGnRH agonist Lupron – 1 month or 3 month injectionLupron – 1 month or 3 month injection Creates a prepubertal state, suppressing ovulationCreates a prepubertal state, suppressing ovulation When to give?When to give?
– 2-3 weeks prior to chemotherapy to prevent breakthrough 2-3 weeks prior to chemotherapy to prevent breakthrough bleeding from occurring during time of cytopenia.bleeding from occurring during time of cytopenia.
– Give up to 2 doses or 6 months total – bone demineralizationGive up to 2 doses or 6 months total – bone demineralization What does the literature say?What does the literature say?
– Potential risks in hormone sensitive tumors unknownPotential risks in hormone sensitive tumors unknown– Does not protect follicles from radiationDoes not protect follicles from radiation– Mixed review Mixed review
No benefit vs. Menses resuming with or without pregnancy No benefit vs. Menses resuming with or without pregnancy achievementachievement– 98% vs. 40% resumption of menses 6 months post 98% vs. 40% resumption of menses 6 months post chemotherapychemotherapy
Do agree – decrease risks associated with menses during Do agree – decrease risks associated with menses during time of cytopeniatime of cytopenia
Window of opportunity Window of opportunity Cost - $500/monthCost - $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 friendlyFacility not adolescent friendly TimeTime Parental anxietyParental anxiety Spiritual concernsSpiritual concerns
Resources
Fertility Consult Service– Anna Franklin, MD– Donna Herrera-Bell– Nicole Rosipal, RN, MSN, CPNP
Services Provided– Discussion of infertility risk and available options
– Referral Process
– Consult Request– Wednesday, Thursday and Friday afternoons
ResourcesResources
LIVELIVESTRONGSTRONG Survivor Care Survivor Care– www.LIVESTRONG.org/survivorcare– Information about fertility preservation, Information about fertility preservation, financial, insurance and employment concernsfinancial, insurance and employment concerns
– LIVE:ONLIVE:ON Fertile HopeFertile Hope
– www.fertilehope.org– Sharing Hope programSharing Hope program– Self referralSelf referral
Oncofertility ConsortiumOncofertility Consortium Heroes for children – up to 22 Heroes for children – up to 22
– http://www.heroesforchildren.org/– Social worker completes assessment and application Social worker completes assessment and application – Assistance is based on financial need ($750 Assistance is based on financial need ($750 towards expenses)towards expenses)
Current Research at MD Anderson
Banking on Fatherhood
St. Jude’s Questionnaire– Attitude about sperm banking
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