1. S L I D E 0 Updates on Fertility Preservation: Concepts, Considerations & Strategies Cindy M. P. Duke, M.D., Ph.D. Clinical Instructor Division of Reproductive Endocrinology & Infertility Department of Obstetrics, Gynecology & Reproductive Sciences

2. S L I D E 1 Disclosure and Accreditation This Lecture is accredited for CME by the Yale School of Medicine. Acknowledgement is made on behalf of the CMPPA that: ~ There is no commercial support for this lecture. Confirmation is also made that today’s lecture and disclosure have been peer reviewed and there are No conflicts of interest

3. S L I D E 2 Overview  Relevance?  Burden  Feasibility  Options  Status of FP utilization in the Caribbean  Barriers in the Caribbean?  Strategic approaches to improving patient autonomy & patient access to FP options  Enhancing awareness amongst providers – a multidisciplinary approach  Lectures  Online webinars/education  Advertising need for and access to FP options in the Caribbean  Personal Goal  Ongoing efforts

4. S L I D E 3 Cancer Burden in the Caribbean  Leading causes of Cancer death amongst women in the Caribbean  Breast  Cervical  Uterine  Ovarian  Colon  Leading causes of Cancer Death amongst men in the Caribbean  Prostate  Gastrointestinal: esophageal, gastric (stomach), colorectal  Liver  Lung  Childhood cancers

5. S L I D E 4 2002-2008 Combined pediatric cancers83% Retinoblastoma98% Hodgkin Lymphoma96% Wilms Tumor89% Non-Hodgkin Lymphoma86% Leukemia84% Neuroblastoma75% Ewings Tumors75% CNS tumors71% Osteosarcoma71% Rhabdomyosarcoma68% Malignancy 5-year Survival American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013. 20081970 90%75% 20081970 83%68%

6. S L I D E 5 Underpinnings to Gonadotoxicity Quantitative & Qualitative Concerns 20 to 30 follicles are growing at the start of the cycle Only 1 selected and becomes dominant

7. S L I D E 6 Considerations Common Chemotherapeutic Gonadotoxic Regimens Alkylating agents Platinum Derivatives Antibiotics Plant Alkaloids Taxanes

8. S L I D E 7 Long-Term Biologic Effects of Cancer Therapies Women  Early Menopause  Vaginal dryness  Diminished Body image  Diminished sexual function  Psychological, emotional and social concerns  Osteoporosis  Bone Fractures  Shortened Fertility  Loss of Fertility Men  Loss of Fertility  Diminished sexual function  Depression

9. S L I D E 8 Statement%agree Childless cancer survivors who want a child in the future76% Believe their experience with cancer will make them a better parent78% See themselves as healthy enough to be a good parent94% Would want to be a parent even if they died60% Worry a fair amount that cancer will effect fertility26% Discussed their children’s risk of inheriting cancer with a health professional 22% Discussed FP with a specialist25% Had undergone fertility treatment6% Patient/Societal Perspectives Schover, LR, Rybicki, LA, Martin BA, Bringelsen, KA. (1999), Having children after cancer. Cancer, 86: 697-709. Schover, LR. Rates of post-cancer parenthood. J Clin Oncol. 2009; 27:321-322 - Questionnaire completed by 283 patients ages 18-35 from Cleveland Clinic Foundation tumor registry. Female survivors may have up to a 50% decrease in successful pregnancies compared to controls

10. S L I D E 9 American Society of Clinical Oncologists –“As part of education and informed consent before cancer therapy, oncologists should address the possibility of infertility with patients treated during their reproductive years and be prepared to discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists.” where possible American Society of Reproductive Medicine –“Cancer specialists should inform patients about these options and refer them to fertility specialists, who can offer further counseling and management.” American Cancer Society –“For younger survivors, the loss of fertility can be a life-changing, long-term effect of cancer with irreversible consequences that can affect quality of life.” Medical Opinion Lee SJ, Schover LR, Partidge AH, et al, American Society of Clinical Oncology Recommendations in Fertility Preservation in Cancer Patients. J Clin Oncol 2006;24(18):2917-2931 Ethics Committee. American Society for Reproductive Medicine. Fertil Steril 2005;83:1622– 8 American Cancer Society. Cancer Treatment and Survivorship Facts & Figures 2012-2013. Atlanta: American Cancer Society; 2012.

11. S L I D E 10 Available Options for Fertility Preservation OptionDescriptionExperimentalComments Ovarian SuppressionWith GnRH agonist cotreatment with chemotherapy YesEvidence from RCTs suggests a potential benefit of GnRH co treatment with chemotherapy in premenopausal women, producing higher rates of spontaneous resumption of menses. Embryo CryopreservationRequires ovarian stimulation; can take a minimum of 9-11 days from initiation of fertility drugs to egg collection NoEmbryo cryopreservation requires availability of a partner or use of donor sperm. Oocyte CryopreservationRequires ovarian stimulation, egg collection; can take 7-11 days from initiation of treatment to egg collection NoPreferred option for post pubertal women without a partner. Immature Oocyte Retrieval, In Vitro Maturation (IVM) & Oocyte Cryopreservation With minimal or no ovarian stimulation options, time to egg retrieval can be as little as 1-5 days and can be undertaken regardless of timing in menstrual cycle YesOnly a few reported pregnancies Ovarian Tissue Cryopreservation Surgical procedure, involves freezing ovarian tissue YesPotential risk of metastasis, particularly in patients with Leukemia Immature Oocyte Retrieval from Ovarian T, IVM & Oocyte Cryopreservation Ex vivo oocyte retrieval from ovarian tissue followed by IVM and oocyte cryopreservation YesPreferred to tissue cryopreservation for patients with Leukemia to reduce risk of metastasis Ovarian TranspositionSurgical procedure performed before radiation treatment NoOvaries may migrate, may also need to be repositioned Radical TrachelectomySurgical procedure which spares the uterus, cerclage placed at time of surgery NoLimited to early stage cervical cancer. May have pregnancy complications 1.Lee SJ et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006; 24:2917 2.Fertility Preservation for women Diagnosed with Cancer. SaveMyFertility.org (2011) 3.Grynberg M et al. In vitro maturation of oocytes: uncommon indications. Fertil Steril. 2013;99(5):1182-8. 4.Wang C et al. Gonadotropin-Releasing Hormone Analog Cotreatment for the Preservation of Ovarian Function during Gonadotoxic Chemotherapy for Breast Cancer: A Meta-Analysis. PLoS One. 2013 21;8(6):e66360.

12. S L I D E 11 Fertility Preservation Through Medical Management PLoS One.PLoS One. 2013 Jun 21;8(6):e66360 The pooled ORs for the incidence of women with spontaneous menstruation.

13. S L I D E 12 Algorithm for Fertility Preservation (Females) Age of Patient Prepubescent Postpubescent Is there time for ovarian stimulation? Ovarian tissue Cryopreservation** Yes No In vitro maturation (IVM)* Ovarian tissue cryopreservation* GnRH analogues In vitro maturation (IVM)* Ovarian tissue cryopreservation* GnRH analogues Sperm source? (Tissue or Donor) Sperm source? (Tissue or Donor) Yes No Embryo Cryopreservation Oocyte Cryopreservation Contemporary Ob/Gyn. DEC 01, 2013. Wang,E MD, Pisarka,M MD.

14. S L I D E 13 Embryo Cryopreservation Gold Standard IVF Timeline Egg Retrieval Embryo Freezing

15. S L I D E 14 Oocyte Cryopreservation (Egg Freezing) - Now is a standard of clinical care

16. S L I D E 15 Additional Surgical Options Anticipating Pelvic Radiation Therapy For Patients with Early Stage Cervical Cancer

17. S L I D E 16 Cryopreservation of Sperm –Via ejaculation –Via testicular sperm extraction (TESE) Gonadal Shielding Testicular Tissue Cryopreservation An adequate number of sperm can be collected within a period of 1-3 days. Pre-treatment collection is strongly encouraged Preservation Fertility Preservation for Men Chan PT, Palermo GD, Veeck LL, Rosenwaks Z, Schlegel PN. Testicular sperm extraction combined with intracytoplasmic sperm injection in the treatment of men with persistent azoospermia postchemotherapy. Cancer. 2001;92(6):1632.

18. S L I D E 17 Current State of Affairs …. Reality Barriers to Access Lack of awareness amongst providers & patients Provider bias –“Patient has already had children (completed family building)” Is this what patient said or is that the provider’s assumption? –“Patient cannot afford it” Based on what information? provider’s assumption vs. patient perspective? “There just is not enough time.” –There is always time for counseling “Definitive FP strategies will worsen patient’s prognosis” –Depends. Lets review the evidence… “The patient is already stressed as it is. No need to burden them with this.” –What if this were your family member? Availability of and access to services in the Caribbean? –Not exactly true! Feasibility Bedoschi & Oktay, Fertil Steril. May 2013; 99(6): 1496–1502Fertil Steril. May 2013; 99(6): 1496–1502

19. S L I D E 18 Step 1: Evaluation of resources and educational materials available for patients and providers Step 2: Conduct needs assessment to determine patient volume, available staff, potential barriers and to gain the interest & support of staff Step 3: Establish formal relationship between fertility specialists and cancer care providers Step 4: Initiate the Onco-Fertility Program Step 5: Fertility Preservation and On-Going Cancer Care Step 6: Ongoing Program Assessment Inventory existing & assess updated patient directed educational resources Provide Staff with empirically supported continuing education on Fertility Preservation Assess the current system & how to implement or grow Fertility Preservation services Important to understand the views of both providers, staff & cancer patients Develop real-time patient referral system including transfer of health information and timely appointments Utilize navigators, survivorship clinics & identified staff to direct basic patient education & referrals Cancer care providers: Discuss interest, provide education & highlight potential options for fertility preservation with young women newly diagnosed or post treatment Collaboration between cancer care providers & fertility specialists for young women interested in fertility preservation Interested & eligible patients undergo fertility preservation followed by recommended treatment plan Patients not interested in fertility preservation will proceed with treatment plan Ongoing modification of the system to address barriers, changes in practice, other issues Establish a system for regular assessment of patient and provider outcomes, time to appointment satisfaction, number of referrals J Assist Reprod Genet (2012) 29:469–472 Practical Considerations

20. S L I D E 19 Call to Action Strategic approach to improving patient autonomy & patient access to FP options  Enhancing awareness amongst providers  A multidisciplinary approach  Continue to sensitize providers to the Gonadotoxic implications of therapy  Familiarize providers with available options and FP related timeline  Familiarize community to the concept of FP strategies to facilitate patient driven dialogue initiation  Improving and Advertising access to FP options for the Caribbean

21. S L I D E 20 Fertility Preservation Paradigm Pre Gonadotoxic Rx Post Gonadotoxic Rx At Diagnosis Before Gonadotoxic Rx is Initiated Counsel ALL reproductive age women/men regarding implications of disease & of Rx on gonadal function & fertility prognosis Interest in Fertility Preservation Consultation? **Offer Consultation with Fertility Specialist Regardless of Disease Severity Consult scheduling Fertility Preservation Options For Women: Oocyte/embryo cryopreservation Ovarian tissue cryopreservation Medical suppression BEFORE chemotherapy – continued for the duration of planned Gonadotoxic therapy. For Men: Semen cryopreservation Gonadotoxic Rx Already Initiated Counsel ALL reproductive age women and men regarding implications of disease & of Rx on gonadal function & fertility prognosis Interest in Fertility Preservation Consultation? **Offer consultation with fertility specialist regardless of disease severity Consult scheduling within 24 hours Fertility Preservation Options For Women: Medical suppression for the duration of planned chemotherapy Counseling regarding future fertility options - Donor Egg? For Men Semen cryopreservation

22. S L I D E 21 Female Fertility Preservation Options  Cryopreservation of cells/tissues  eventual IVF –Embryo cryopreservation –Oocyte cryopreservation ◦ Mature or immature Oocyte Cryopreservation –Ovarian tissue cryopreservation  Surgical intervention –Radical trachelectomy, ovarian transposition  Medical  GnRH analogs

23. S L I D E 22 Call to Action – Looking to the Future  Implementation of a Multidisciplinary linked best practice advisory or BPA (an alert system)  Strategy for “guided counseling”  Fires when specific diagnoses are entered into the problem list  Aimed at initiating counseling at time of diagnosis  Fires again at time of pharmacy order for Gonadotoxic therapy  Brief neither burdensome nor hurdle  Implementation of fertility preservation if needed  Investigate further possibilities for assisting qualified patients “in need” with costs $$$$

24. S L I D E 23 Barriers to Fertility Preservation Who should be counseled on FP/possible loss of future fertility? –EVERYONE of Reproductive Age (birth to 45) “Patient has already had children (completed family building)” –Is this what patient said or is that provider’s assumption? “Patient cannot afford it” –Based on what information? i.e is this provider’s assumption? “There just is not enough time.” –Counseling = discussion. “Definitive FP strategies will worsen patient’s prognosis” –Depends. Is this based on most recent evidence?  Do not forget about Patient Autonomy  Current committee statements by the American Society of Clinical Oncologists (ASCO), American Society of Reproductive Medicine (ASRM) and American Cancer Society (ACS) recommend that:  “providers should address the possibility of treatment induced infertility with patients treated during their reproductive years and be prepared to discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists.” Who should be counseled on possible loss of future fertility/FP? EVERYONE of Reproductive Age (birth to 45)

25. S L I D E 24 THANK YOU!!! Any Questions?