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  • Lee S.J., Schover L.R., et al., JCO, 2006.
  • Rajkovic A., Semin Reprod Med , 2007.
  • 12a levine texas aya1

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