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  • I’m sure many of your premenopausal patients have questions and concerns about the effects of treatment on their fertility. I know you all raise the possibility of fertility preservation with patients as we are seeing more and more women present to discuss the options available in our clinic. Both of these questions can be difficult as they depend on the woman’s age, what her baseline fertility is, and what her treatment plan is going to be. Both options for treatment in oncology and in reproductive technologies are constantly changing, so we kind of have to work together if we are going to keep on the same page…
  • The availability and discussion is increasing nationally. And, we’re also seeing a lot more national attention on the issues of infertility after cancer treatment and fertility preservation. The 2004 President’s cancer panel where infertility was cited as a top concern for survivors. The American Society for Reproductive Medicine, our sort of governing body in reproductive endocrinology since we don’t have a lot of government regulation, formed the fertility preservation special interest group. In 2005, a fertility preservation research section was established at the National Institute of Child Health and Human Development, and through this institute last year, a 21 million dollar grant was awarded to Northwestern University to study fertility preservation. In 2006 ASCO released it’s own recommendations on fertility preservation for cancer patients, and in the paper outline these guidelines, they acknowledged the difficulty in counseling women cancer patients about their fertility. ASCO recommends oncologists be prepared to discuss possible fertility preservation options or to refer appropriately, however many of the available strategies for fertility preservation have not been fully evaluated in terms of efficacy and safety. These limitations likely hamper discussion of fertility concens, referrals, and the enthusiasm for patients and providers to embrace some of the available options.
  • As Estimating the risk of infertility after cancer treatment is difficult.: Type and doseof chemo, method of administration, the age of the patient, the pretreatment fertility of a patient, Decrease in number of primordial follicles Regular menstruation does not guarantee normal fertility Duration of fertility may be limited even if their fertility is seemingly okay Treatments with Associated risks of infertility difficult as data are poor and heterogeneous. Most data for amenorrhea…not a real surrogate for fertility. In addition to address possibility of infertility with patients treated during their reproductive years, ASCO also recommended: 1. Being prepared to discuss possible fertility preservation options 3. Referring appropriate and interested patients to reproductive specialists 4. Sperm and embryo cryopreservation are considered standard practice and are widely available; other methods are considered investigational and should be performed in centers with the necessary expertise…this is us! WHAT DOES THIS MEAN???
  • What’s involved for an IVF cycle? Time: depends on where patient is in her cycle…need about 2-3 weeks from the time someone starts their cycle. Receive concomitant Letrozole & FSH. FSH to stimulate follicular growth and oocyte maturity, Letrozole to keep estradiol levels low as you stimulate follicular growth. GnRH antagonist is given as well to keep the patient from having an LH surge, then we give hCG to mature their oocytes. Oocyte retrieval, then fertilization with a partner or donor’s sperm or oocyte cryopreservation. Initial paper presenting this IVF protocol published in 2005 out of Cornell. Previously they had used Tamoxifen to keep estradiol levels low.
  • Coordinating care can be difficult, especially for patients who are not familiar with the medical system, also it can be difficult for patients to make the decision to proceed with fertility preservation when they receive different messages from different doctors…we need more information about what is possible and what is not… Insurance coverage for IVF is rare, and time to plan is simply not available
  • So, my primary objective for today was to let you know where we are at with things as far as fertility preservation options go as we are gaining experience and learning more. Also, though I wanted the opportunity to reach out to any of you who may be interested in collaborating for case discussion and perhaps for studies that may provide more insight into the effects of the treatments you use on ovarian function. Finally, I’m currently trying to find a funding mechanism to help patients gain access to some of the techniques I discussed, and also to perhaps fund a patient navigator—either a social worker or nurse who can help reproductive age women with cancer explore their fertility preserving options should they be interested prior to therapy.
  • (PowerPoint)

    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: http://www.infertility.wustl.edu/ </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 @ http://www.infertility.wustl.edu/ </li></ul><ul><li>Myoncofertility.org </li></ul>
    23. 23. Thank you!