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  • Lee S.J., Schover L.R., et al., JCO, 2006.
  • Rajkovic A., Semin Reprod Med , 2007.
  • Transcript

    • 1. Jennifer Levine, MD, MSW Division of Pediatric Oncology Columbia University Medical Center San Antonio, Texas October 2, 2010 Fertility Preservation in Adolescents and Young Adults with Cancer
    • 2. Fertility Preservation for Adolescents and Young Adults IMPROVED REPRODUCTIVE TECHNOLOGY PATIENT AWARENESS/ ADVOCACY: QUALITY OF LIFE IMPROVED SURVIVAL
    • 3. ASCO Guideline Summary 2006 “ As part of informed consent prior to therapy, oncologists should address the possibility of infertility with patients as early in treatment planning as possible.”
    • 4. Counseling on Fertility Preservation
          • Risks for Infertility
              • Is fertility preservation necessary?
              • Is it necessary before therapy or after?
          • Fertility Preservation Options
          • Barriers to Accessing Options
    • 5.
      • Risks: Men
    • 6. Reproductive Review: Males
      • Spermatogenesis starts at puberty, continues uninterrupted until death
      • Immature Sperm produced in seminiferous tubules, maturation and storage in epididymis
      • Maturation process takes approximately 70 days
      • Temporary infertility common and lasts post therapy
    • 7. Risk Factors
      • Disease
      • Treatment: Type, Cumulative Dose, Location
          • Radiation
            • Direct to Testes
            • Total Body Irradiation
            • Cranial RT
          • Chemotherapy
            • Alkylating Agents
            • Platins
          • Surgery
            • Removal of Testes
      • Pre-Treatment Fertility Status
    • 8. Potential Impact of Cancer and Treatment on Fertility
      • Germ cell loss
        • Decreased, damaged, or absent sperm
      • Damage to ductal system for sperm transport
        • Obstruction
        • Ejaculatory dysfunction
      • Damage to pelvic nerves
        • Sexual and ejaculatory dysfunction
      • Damage to brain (pituitary)
        • Sexual dysfunction via the neuroendocrine system
    • 9. Gonadotoxicity of Treatment Regimens
    • 10.
      • Options: Men
    • 11. Sperm Banking
      • Most reliable and well established means of preserving fertility for males
      • Can be done outpatient or inpatient
      • Reports of successful pregnancies from sperm stored up to 28 years
      • Banking post start of chemotherapy is controversial
      • Cost: $750-$1,000 initial cryopreservation, $350-$500/year storage
    • 12. Sperm Banking - Limitations
      • Pressure to start chemotherapy
          • Optimal: 48 hour abstinence and collection of more than one sample
          • Can deposit every 24 hours
          • Even one deposit may be sufficient
      • Inability to produce sperm due to age, discomfort, illness
          • Alternatives
              • Testicular Sperm extraction
              • Electro-ejaculation
      • Cost: $750-$1000 Semen Analysis, $350-$500 annual ongoing storage
    • 13. Testicular Sperm Extraction (TESE)
      • Can be done before or after cancer treatment as outpatient surgical procedure
      • If no sperm in semen, testicular tissue is removed, processed and examined for sperm.
      • If sperm are found, they are removed and used immediately or banked for future use.
      • Sperm retrieval success rates range from 30-90% in men with non-obstructive azoospermia.
      • Cost: $5,000-$8,000
    • 14. Intracytoplasmic Sperm Injection (ICSI)
      • Injection of a single sperm into the middle of the egg.
      • Allows banking of very
      • small amount of sperm
      • Very effective method to fertilize eggs in the IVF lab after they have been retrieved from the female.
    • 15. Testicular Tissue Freezing
      • Experimental
      • Only option for pre-pubertal boys
      • Testicular tissue surgically removed, frozen and stored
      • Outpatient procedure, can be done during other procedures
      • Early germ cells preserved; may be valuable in future
      • Currently no methods for maturation
      • Concern for involvement of testes with cancer cells
    • 16. Parenthood After Treatment
      • Natural conception
          • Wait post therapy
      • Assisted Reproduction
          • Banked Sperm: +/- ICSI
          • Low Counts:
              • TESE
              • ICSI
          • Donor Sperm
      • Adoption
    • 17. Levine et al, JCO, May 2010
    • 18.
      • Risks: Women
    • 19. Reproductive Review: Females
      • Cycle of oogenesis begins before birth
      • Females are born with all the eggs they will ever have
      • Depletion occurs through apoptosis and ovulation
      • Ovulate 400 eggs over lifetime
    • 20. Normal Ovarian Reserve AGE FOLLICLE COUNT 25,000 37 1,000 51 Menopause birth 1,000,000 12 Menarche
    • 21. Acute Ovarian Failure Follicle Count 25,000 (37) 1,000 (51) Cancer Treatment (16) Traditionally measured by amenorrhea, FSH, estradiol
    • 22. Premature Menopause Follicle Count 25,000 (37) 1,000 (51) Cancer Treatment (25) (30)
    • 23. Risk Factors
      • Disease
      • Treatment: Type, Cumulative Dose, Location
        • Radiation
          • Direct to the ovaries or uterus
          • TBI
          • Cranial RT
        • Chemotherapy
            • Alkylating agents
        • Surgical removal of the ovaries or uterus
      • Age at administration
      • Pre-treatment fertility status
    • 24. Potential Impact of Cancer and Treatment on Fertility
      • Germ cell loss: depletion in number of oocytes
      • Damage to uterus (fibrosis, vascular insufficiency)
        • Inadequate environment for implantation of embryo
        • Inability to maintain a full-term pregnancy
      • Damage to brain (pituitary)
        • Sexual dysfunction via the neuroendocrine system
    • 25. Gonadotoxicity of Treatment Regimens
    • 26.
      • Options: Women
    • 27. Embryo Cryopreservation
      • Currently the only routinely successful method of preserving fertility
          • Approximately 30% success of pregnancy per embryo thawed
          • Highly dependent on age of female
      • Method:
          • Ovarian stimulation at the start of a menstrual cycle
          • Collection of mature oocytes
          • In vitro fertilization – partner or donor sperm
          • Cryopreservation of embryo
          • Thawing and Implantation post therapy
    • 28. Embryo Cryopreservation: Limitations
      • Only possible post-puberty
      • Requires male partner or donor sperm
      • Requires 2-6 weeks to stimulate ovaries
            • Delay start of chemotherapy
            • Hormone sensitive tumors
      • Expensive
            • $10,000 plus medications
            • May not be covered by insurance
      • Ethics: What happens to the embryos if the patient dies
    • 29. Oocyte Cryopreservation
      • Initial process is similar to embryo cryopreservation
      • Retrieval of mature eggs
      • Retrieved eggs are frozen and stored
      • Cost $8,000 plus medications
    • 30. Oocyte Cryopreservation
      • Advantages
          • More than 900 children have been born by this method
            • Clinical Live Births per transfer 21%
          • Does not require sperm
      • Limitations
          • Still considered experimental
          • Oocytes are much more susceptible to the cryoinjury than embryos
          • Requires ovarian stimulation
            • Not feasible for pre-pubertal girls
          • Delay in treatment
    • 31. Ovarian Tissue Cryopreservation
      • Method:
          • Surgically remove ovarian tissue
            • can be done laproscopically
            • contains hundreds of primordial follicles
          • Process into strips that can be cryopreserved
          • Requires subsequent maturation of primordial follicles to oocytes
              • autotransplantation(orthotopic/heterotopic)
              • in vitro maturation (follicle or organ)
              • Studies ongoing
    • 32. Ovarian Tissue Cryopreservation
      • Experimental
      • Only option in pre-pubertal girls
      • Does not require ovarian stimulation
      • 10 live births reported
      • Concern for ovarian involvement with some cancers such as leukemia
      • May actually increase infertility in lower risk patients
      • Most appropriate candidates are those at high risk for acute ovarian failure
      • Costs: $12,000
    • 33. Protection of Ovaries
      • Shield ovaries during radiation
      • Fractionate radiation doses
      • Surgical transposition of ovaries out of radiation field
          • Can be done laproscopically
    • 34. GnRH Agonist/Antagonist
      • Suppress ovarian function, preserving primordial follicles
      • Studies to date inconclusive
      • POEMS: large randomized SWOG study (n > 400) currently recruiting
    • 35. Parenthood Post Treatment: Acute Ovarian Failure
      • Thaw and transfer cryopreserved embryos
      • Thaw oocytes, fertilize (partner or donor sperm), transfer embryos
      • Assisted Reproduction Techniques
          • Donor Oocyte
          • Donor Embryo
      • Adoption
    • 36. Parenthood Post Treatment: Diminished Ovarian Reserve Follicle Count 25,000 (37) 1,000 (51) Cancer Treatment (25) (30) Serum Levels: AMH, Inhibin B Vaginal Ultrasound: Antral follicle count, Ovarian Volume
    • 37. Parenthood Post Treatment: Diminished Ovarian Reserve
      • Embryo Cryopreservation
          • Partner Sperm
          • Donor Sperm
      • Oocyte Cryopreservation
    • 38. Parenthood Post Treatment: Premature Menopause
      • Assisted Reproduction Techniques
          • IVF
          • Donor Oocyte
          • Donor Embryo
      • Adoption
    • 39. Parenthood Post Treatment: Uterine Incompetency
      • Traditional Surrogacy
          • Partner or donor sperm used to impregnate the surrogate
      • Gestational Surrogacy
          • Embryos (self or donor) transferred to uterus of another woman
          • Live Birth rates range from 18-30%
    • 40. Pregnancy Post Treatment
      • Delay 6 months-2 years
          • Risk of Relapse
          • Damage by Chemo and RT
      • Potential High Risk Pregnancy
          • Chance of multiples with assisted reproduction
      • Late Effects of Treatments
          • Cardiac
          • Pulmonary
    • 41.  
    • 42.
      • Challenges and Solutions
    • 43. Information is still limited as to who is at risk
      • On-going studies – before and after therapy
          • Exposure risk
          • Individual variation
    • 44. Physicians are often reticent to discuss infertility and options
      • On-going educational seminars
      • Fertility Preservation Consult Services
      • Fertility Preservation Educator
      • Pre-prepared educational material
    • 45. Lack of information about resources
      • Utilization of existing websites
          • www.fertilehope.org
          • www.livestrong.org
          • www.oncofertility.northwestern.edu
      • Create local partnerships
    • 46. High cost of fertility preservation/lack of insurance coverage
      • Sharing Hope
          • www.livestrong.org
      • Advocate for insurance reform
    • 47. Don’t forget to discuss:
      • RISK of infertility ≠ infertility
            • Still need to use birth control
      • RISK of infertility ≠ protection from sexually transmitted infections
            • Still need to use condoms
    • 48. References
      • Chemaitilly W, et al: Acute ovarian failure in the childhood cancer survivor study.J Clin Endocrinol Metab. 2006 May;91(5):1723-8. 2006
      • Fallat ME, ; Preservation of fertility in pediatric and adolescent patients with cancer.American Academy of Pediatrics Committee on Bioethics; American Academy of Pediatrics Section on Hematology/Oncology; American Academy of Pediatrics Section on Surgery.Pediatrics. 2008 May;121(5):e1461-9.
      • Green DM, et alFertility of Female Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. Clin Oncol. 2009 Apr 13. [Epub ahead of print]
      • Lee SJ, et al: American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of Clinical Oncology 24:2917-31, 2006
      • Levine, J, Canada, A, Stein, C, Fertility Preservation in Young Adults, JCO, May 2010 (eprint)
      • Sklar CA, et al: Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. 2006 Jul 5;98(13):890-6.
      • Sonmezer M, Fertility preservation in female patients. Hum Reprod Update. 2004 May-Jun;10(3):251-66. Review.
      • West ER, et al. Preserving female fertility following cancer treatment: Current options and future possibilities. Pediatr Blood Cancer. 2009 Mar 19. [Epub ahead of print]
    • 49.
      • Thank you!

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