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  1. 1. Fertility Preservation in 2008 Options for patients facing gonadotoxic therapies September 19, 2008 Emily S. Jungheim, M.D. Instructor Reproductive Endocrinology & Infertility Department of Obstetrics & Gynecology Washington University
  2. 2. Cancer treatment and fertility… <ul><li>Treatment for men & pre-menopausal women —most common breast, melanoma, cervical, non-Hodgkin’s lymphoma & leukemia </li></ul><ul><ul><li>Increased survival </li></ul></ul><ul><ul><li>Quality of life… </li></ul></ul><ul><ul><ul><li>Risks to fertility? </li></ul></ul></ul><ul><li>Gonadotoxic agents </li></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Radiation </li></ul></ul><ul><li>Surgical therapy </li></ul><ul><li>Time needed for endocrine therapy </li></ul>
  3. 3. Questions… <ul><li>Treatment effects on fertility? </li></ul><ul><li>Options for fertility preservation? </li></ul>
  4. 4. Addressing the need for information… <ul><li>2004 President’s Cancer Panel </li></ul><ul><ul><li>“ Report on Survivorship” </li></ul></ul><ul><ul><ul><li>Infertility a top concern </li></ul></ul></ul><ul><li>The American Society for Reproductive Medicine, 2004 </li></ul><ul><ul><li>Fertility Preservation Special Interest Group </li></ul></ul><ul><li>NICHD, 2005 </li></ul><ul><ul><li>Fertility preservation research section </li></ul></ul><ul><li>ASCO Recommendations on Fertility Preservation in Cancer Patients, 2006 </li></ul>
  5. 5. What can we offer men?
  6. 6. Effects of cancer treatment on male fertility Lee et al. JCO, 2006 ? <ul><li>Newer agents </li></ul>Only temporary reductions in counts at doses used in conventional regimens, but additive effects are possible <ul><li>Amacrine, Bleomycine, Dacarbazine, Daunorubicin, Epirubicin, Etoposide, Fludarabine, 5-Fluorouracil, 6-Mercaptopurine, Methotrexate, Mitoxantrone, Thioguanine </li></ul>Can be additive with above agents in causing prolonged azoospermia, but cause only temporary reductions in counts when used alone <ul><li>Doxorubicin, Thiotepe, Cytosine arabinoside, Vinblastine, Vincristine </li></ul>Prolonged azoospermia not often observed at indicated dose <ul><li>Carboplatin </li></ul>Azoospermia likely, but always given with other highly sterilizing agents <ul><li>Busulfan, Ifosfamide, BCNU, Nitrogen Mustard, Actinomycin D </li></ul>Azoospermia in adulthood after treatment before puberty <ul><li>BCNU, CCNU </li></ul>Prolonged azoospermia <ul><li>Radiation to the testes, Chlorambucil, Cyclophosphamide, Procarbazine, Melphalan, Cisplatin </li></ul>Effect on sperm Agents
  7. 7. Fertility preservation for men: Sperm Banking
  8. 8. How do we counsel? <ul><li>Try to bank sperm prior to therapy… </li></ul><ul><ul><li>Optimal counts </li></ul></ul><ul><li>Sperm quality before, during, and after completion of therapy? </li></ul><ul><ul><li>Evidence for increased risks of aneuploidy and DNA damage? </li></ul></ul><ul><ul><ul><li>Sperm—yes </li></ul></ul></ul><ul><ul><ul><li>Offspring—no </li></ul></ul></ul><ul><li>Keep in mind… </li></ul><ul><ul><li>Does the patient have a partner? </li></ul></ul><ul><ul><ul><li>Get the partner involved </li></ul></ul></ul><ul><ul><ul><li>Partner’s age </li></ul></ul></ul><ul><ul><li>Goals for family building </li></ul></ul>Tempest et al. Human Reproduction, 2008
  9. 9. Fertility preservation for men @ Washington University… Sperm banking <ul><li>Outpatient </li></ul><ul><ul><li>Consultation </li></ul></ul><ul><ul><ul><li>(314)-286-2400 </li></ul></ul></ul><ul><ul><li>ID testing </li></ul></ul><ul><ul><ul><li>HIV 1 & 2, Hep B & C, RPR </li></ul></ul></ul><ul><ul><li>Collection appointment </li></ul></ul><ul><ul><ul><li>Before 1 P.M. </li></ul></ul></ul><ul><ul><ul><li>(314) 286-2431 </li></ul></ul></ul><ul><li>Inpatient </li></ul><ul><ul><li>Call to arrange </li></ul></ul><ul><ul><ul><li>314-286-2400 </li></ul></ul></ul><ul><ul><ul><li>Rush ID testing </li></ul></ul></ul><ul><ul><ul><li>In-house consultation </li></ul></ul></ul><ul><ul><ul><li>Consent forms </li></ul></ul></ul><ul><ul><ul><li>Bring specimen within 1 hour of collection </li></ul></ul></ul><ul><ul><ul><ul><li>9 A.M. - 1 P.M. </li></ul></ul></ul></ul>
  10. 10. What’s next? <ul><li>Inseminations for partner if counts are adequate </li></ul><ul><li>If not? </li></ul><ul><ul><li>IVF with ICSI </li></ul></ul><ul><ul><ul><li>In vitro fertilization </li></ul></ul></ul><ul><ul><ul><li>Intracytoplasmic sperm injection </li></ul></ul></ul><ul><ul><ul><ul><li>1 sperm injected into 1 egg… </li></ul></ul></ul></ul>
  11. 11. What can we offer women?
  12. 12. Risks of Permanent Amenorrhea after Chemotherapy & Radiotherapy Lee et al. JCO, 2006 <ul><li>Taxanes </li></ul><ul><li>Oxaliplatin </li></ul><ul><li>Irinotecan </li></ul><ul><li>Monoclonal antibodies </li></ul><ul><li>Tyrosine kinase inhibitors </li></ul>? <ul><li>Vincristine </li></ul><ul><li>Methotrexate </li></ul><ul><li>5-fluorouracil </li></ul>Very low or no risk <ul><li>CHOP X 4-6 cycles </li></ul><ul><li>CVP </li></ul><ul><li>AML therapy (anthracycline/cytarabine) </li></ul><ul><li>ALL therapy (multi-agent) </li></ul><ul><li>CMF, CEF, CAF x 6 cycles in women age less than 30 </li></ul>Lower risk (<20%) <ul><li>CMF, CEF, CAF x 6 cycles in women age 30-39 </li></ul><ul><li>AC x 4 in women age 40 and older </li></ul>Intermediate risk <ul><li>Hematopoietic stem cell transplantation with cyclophosphamide/total body irradiation or cyclophosphmide/busulfan </li></ul><ul><li>External beam radiation to a field that includes the ovaries </li></ul><ul><li>CMF, CEF, CAF x 6 cycles in women age 40 and older </li></ul>High risk (>80%) Treatment Degree of Risk
  13. 13. Fertility preservation: the options for women… <ul><li>Standard care </li></ul><ul><ul><li>“ Embryo banking” </li></ul></ul><ul><ul><ul><li>Assisted reproduction with embryo freezing </li></ul></ul></ul><ul><li>Experimental </li></ul><ul><ul><li>“ Oocyte banking” </li></ul></ul><ul><ul><ul><li>Assisted reproduction with oocyte freezing </li></ul></ul></ul><ul><ul><li>Ovarian tissue freezing </li></ul></ul><ul><li>Require a partner </li></ul><ul><li>or donor sperm </li></ul><ul><li>Must be pubertal </li></ul><ul><li>Don’t require sperm </li></ul><ul><li>Must be pubertal </li></ul><ul><li>Don’t require sperm </li></ul><ul><li>Can be prepubertal </li></ul>
  14. 14. Assisted Reproductive Technologies for fertility preservation: “Emergency I.V.F.” <ul><li>Steps : </li></ul><ul><li>Controlled Ovarian Hyperstimulation </li></ul><ul><ul><li>Follicle stimulating hormone </li></ul></ul><ul><ul><ul><li>( + letrozole for women with estrogen-sensitive cancers) </li></ul></ul></ul><ul><li>Oocyte retrieval </li></ul>In Vitro Fertilization & Embryo Cryopreservation (allows for preimplantation genetic diagnosis) Oocyte Cryopreservation Washington University Experimental Protocol - OR-
  15. 15. Embryo and oocyte cryopreservation for fertility preservation… <ul><li>Cornell University (Azim et al, JCO 2008) </li></ul><ul><ul><li>79 patients with breast cancer using letrozole protocol </li></ul></ul><ul><ul><ul><li>Froze embryos or oocytes </li></ul></ul></ul><ul><ul><ul><li>Average peak E2: 406 </li></ul></ul></ul><ul><ul><ul><li>23 month follow up </li></ul></ul></ul><ul><ul><ul><li>Hazard ratio for recurrence 0.56 </li></ul></ul></ul><ul><li>Washington University: </li></ul><ul><ul><li>10 patients total (embryos only): </li></ul></ul><ul><ul><ul><li>Average age 29, 4 with children in the past </li></ul></ul></ul><ul><ul><ul><li>4 breast cancer, 2 rectal cancer, 2 uterine cancer, 1 lung cancer, 1 lymphoma </li></ul></ul></ul><ul><ul><li>Average peak estradiol in patients (5) undergoing Letrozole protocol: 455 </li></ul></ul>? limited # of embryos/oocytes?
  16. 16. Ovarian tissue cryopreservation… <ul><li>Patient can be prepubertal </li></ul><ul><li>Do not need sperm </li></ul><ul><li>Can be done quickly </li></ul><ul><ul><li>Tissue removed laparoscopically </li></ul></ul><ul><ul><ul><li>As an outpatient </li></ul></ul></ul><ul><ul><ul><ul><li>-OR- </li></ul></ul></ul></ul><ul><ul><ul><li>Coordinated with another procedure </li></ul></ul></ul><ul><ul><ul><li>Tissue brought to the IVF laboratory for freezing </li></ul></ul></ul>-Experimental protocol-
  17. 17. Ovarian tissue cryopreservation… <ul><li>Documented pregnancies & live births </li></ul><ul><ul><li>Case reports—tissue back into the pelvis </li></ul></ul><ul><li>Washington University Protocol </li></ul><ul><ul><li>First retrieval in 2001 </li></ul></ul><ul><ul><li>To date, no one has returned to use their tissue </li></ul></ul><ul><li>Oncofertility Network @ Northwestern University </li></ul><ul><ul><li>National Physicians Cooperative & Washington University </li></ul></ul><ul><li>Mechanism for: </li></ul><ul><li>Tissue storage at a national facility </li></ul><ul><li>Research on ovarian tissue freezing & </li></ul><ul><li>“ in vitro maturation” </li></ul><ul><li>Data sharing for most “up-to-date” information </li></ul><ul><li>Follow up data </li></ul>
  18. 18. National Physician’s Cooperative <ul><li>Eligibility criteria: </li></ul><ul><ul><li>Ages 18-41 facing treatment that will likely compromise ovarian function </li></ul></ul><ul><ul><li>Healthy enough for laparoscopic surgery </li></ul></ul><ul><ul><li>Functional ovaries (FSH<10) </li></ul></ul><ul><ul><li>Defer treatment for ~1 week </li></ul></ul>
  19. 19. Why this is important? <ul><li>Rapid advances in fertility treatment—this is possible… </li></ul>
  20. 20. Barriers… <ul><li>Timely and accurate information </li></ul><ul><ul><li>Coordinating care </li></ul></ul><ul><ul><li>Addressing the “unknowns” of fertility preservation technology </li></ul></ul><ul><li>COST </li></ul>Storage fees and further processing of ovarian tissue, ?Gestational carrier? Storage fees, oocyte fertilization, and embryo transfer, ?Gestational carrier? Storage fees and embryo transfer, ?Gestational carrier? Future Costs: Initial Cost: Options: ~$12,000 Ovarian tissue freezing ~$8,000 + medications IVF with oocyte freezing ~$10,000 + medications IVF with embryo cyropreservation
  21. 21. On the horizon… <ul><li>Wash U REI Website: </li></ul><ul><ul><li>Quick information for physicians and patients </li></ul></ul><ul><ul><li>Link to fertility preservation site on the way… </li></ul></ul><ul><li>Collaborative group? </li></ul><ul><ul><li>To address the “unknowns” </li></ul></ul><ul><ul><ul><li>Case discussion </li></ul></ul></ul><ul><ul><ul><li>Research studies </li></ul></ul></ul><ul><li>“ Patient navigator”? </li></ul><ul><ul><li>Facilitate referral and access </li></ul></ul><ul><li>Financial help? </li></ul><ul><ul><li>For emergency IVF, sperm cryopreservation, ovarian cryopreservation </li></ul></ul>
  22. 22. Resources for physicians & patients… <ul><li>Wash U. website link coming soon @ </li></ul><ul><li> </li></ul>
  23. 23. Thank you!