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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!