Fertility In Cancer Patients

1. Fertility In Cancer Patients Ann H. Partridge, M.D., M.P.H., Dana-Farber Cancer Institute, Harvard Medical School Boston, MA April 21, 2009

2. The speaker declares no conflict of interest with the topic presented in the lecture.

3. The speaker declares that specific brand-name medications and/or off-label, non-FDA-approved uses are discussed in the lecture. Letrozole or tamoxifen for ovarian stimulation I will attempt to avoid bias by discussing the published research in this area only and limitations of it

4. Cancer and Future Fertility • Patients of reproductive age often find prospect of infertility one of the most difficult components of their disease and treatment • Oncology providers focus on survival • Can be difficult to assess who is interested in future fertility

5. Fertility after cancer poses challenging medical issues and emotional consequences • Surveys of cancer survivors have identified an increased risk of emotional distress in those who become infertile because of their treatment • Long-term quality of life is affected by unresolved grief and depression

6. Fertility Concerns Common • 57% of women age 40 and younger at diagnosis of breast cancer recalled concerns about fertility • 29% reported that infertility concerns influenced treatment decisions (Partridge et al., JCO 2004)

7. Providers May Neglect to Discuss Fertility • Only 68% of women age 50 or younger at diagnosis of breast cancer recalled physician discussion of early menopause • 34% of women recalled discussion of infertility risk (Duffy et al., JCO 2005)

8. American Society of Clinical Oncology Recommendations on Fertility Preservation in People Treated for Cancer Assessment of risk for infertility • • Communication with patient • • • • Patient at risk for treatment Patient at risk for treatment - - induced infertility induced infertility • • Patient interested in fertility preservation options Patient interested in fertility preservation options Refer to specialist with expertise in fertility preservation Refer to specialist with expertise in fertility preservation methods Eligible for proven fertility preservation method Eligible for proven fertility preservation method Investigational fertility Investigational fertility preservation technique* preservation technique* Male: Male: Female: Female: • • Cryopreservation Cryopreservation of of sperm sperm cryopreservation cryopreservation embryo embryo cryopreservation cryopreservation testicular or ovarian tissue testicular or ovarian tissue conservative gynecologic surgery conservative gynecologic surgery • • Cryopreservation Cryopreservation of of oocytes oocytes oophoropexy oophoropexy • • Ovarian suppression Ovarian suppression *Clinical trial participation *Clinical trial participation encouraged encouraged www.asco.org (Lee et al., J Clin Onc; 2006)

9. American Society of Clinical Oncology Recommendations on Fertility Preservation in People Treated for Cancer Assessment of risk for infertility • • Communication with patient • • • • Patient at risk for treatment Patient at risk for treatment - - induced infertility induced infertility • • Patient interested in fertility preservation options Patient interested in fertility preservation options Refer to specialist with expertise in fertility preservation methods Eligible for proven fertility preservation method Eligible for proven fertility preservation method Investigational fertility Investigational fertility preservation technique* preservation technique* Male: Male: Female: Female: • • Cryopreservation Cryopreservation of of sperm sperm cryopreservation cryopreservation embryo embryo cryopreservation cryopreservation testicular or ovarian tissue testicular or ovarian tissue conservative gynecologic surgery conservative gynecologic surgery • • Cryopreservation Cryopreservation of of oocytes oocytes oophoropexy oophoropexy • • Ovarian suppression Ovarian suppression *Clinical trial participation *Clinical trial participation encouraged encouraged www.asco.org (Lee et al., J Clin Onc; 2006)

10. Risk of Infertility in Men • Male infertility can result from: • Disease • Anatomic problems • Primary or secondary hormonal insufficiency • Damage or depletion of the germinal stem cells • The effects of chemotherapy or radiotherapy include compromised sperm number, motility, morphology, and DNA integrity • Azospermia typically surrogate for infertility

11. All Cancer Treatments Are not Equal • Alkylating agents appear to be most gonadotoxic; cis-platin • cumulative dose important • Radiation is very damaging: • >=2.5 Gy to testis area results in prolonged azospermia • External beam to field that includes ovaries

12. Men Have Sperm Banking! • Sperm cryopreservation • involves freezing and banking sperm collected through masturbation, rectal electroejacualtion, testicular aspiration or post-masturbation urine • If patient sick or with certain cancers (e.g., testicular cancer and Hodgkins)- sperm quality may be poor prior to treatment • Many patients have to start chemotherapy soon enough to limit the number of ejaculates • Still reasonable to make every effort to bank sperm- intracytoplasmic sperm injection (ICSI) allows the successful freezing and future use of small sample

13. Other “Options” for Men • Hormonal Gonadoprotection (e.g. GnRH analogs) • The efficacy of gonadoprotection through hormonal manipulations has only been evaluated in very small studies in male cancer patients • Evidence suggests hormonal therapy in men is not successful in preserving fertility when highly sterilizing chemotherapy is given • Potential future options (not tested in humans yet) • Testicular tissue cryopreservation or reimplantation • Testis grafting with maturation in SCID mice

14. Risk of Infertility in Women • Female fertility can be compromised by any treatment that: • Decreases the number of primordial follicles • Affects hormonal balance • Interferes with the functioning of the ovaries, fallopian tubes, uterus or cervix.

15. Natural Decline of Oocytes with Age (Lobo, NEJM 2005)

16. Chemotherapy-related Amenorrhea • CRA may be permanent or temporary • CRA is an imperfect surrogate for menopause and infertility • Accurate assessment of ovarian function has implications for • family planning, contraception • treatment in hormone sensitive tumors • other survivorship concerns

17. Risk of amenorrhea is related to age and treatment (Goodwin et al., J Clin Oncol 1999)

18. Ovarian Failure Risk with Cancer Treatments • High risk: • Total body irradiation, high dose cyclophosphamide, chlorambucil, melphalan, busulfan, nitrogen mustard, procarbazine • Intermediate risk: • Cisplatin, carboplatin, doxorubicin • Low or no risk: • Methotrexate, 5-fluorouracil, vincristine, vinblastine, bleomycin, actinomycin • Unknown risk: • Taxanes, oxaliplatin, irinotecan, monoclonal antibodies, Tyrosine kinase inhibitors (Sonmezer and Oktay, Hum Reprod Update, 2004)

19. Risk of Chemotherapy-Related Amenorrhea with Common Breast Cancer Regimens % women with amenorrhea (Goodwin et al., JCO 1999; Burstein, H. J. et al. NEJM 2000; Nabholtz et al., ASCO 2002; Parulekar et al., JCO 2005; Fornier et al., Cancer 2005; Petrek et al, JCO 2006)

20. Premenopausal women who received adjuvant chemotherapy N=451 Age at diagnosis, mean: 42 years (range 25-55) Follow-up, mean: 34 months (range 6-93) Effects of Newer Treatments: Paclitaxel, Dose Density, and Trastuzumab on CRA (Abusief et al., Breast Cancer Res Treat 2006)

21. Effects of Paclitaxel, Dose Density, andTrastuzumab on CRA (Abusief et al., Breast Cancer Res Treat 2006)

22. Issues for Women Who Remain Premenopausal • Will a woman be less fertile, even if she continues to menstruate? • Will a woman go through menopause earlier (“delayed, premature menopause”)

23. Ovarian Reserve in Women Who Remain Premenopausal After Chemotherapy For Early Stage Breast Cancer • 20 breast cancer survivors who remained premenopausal after chemotherapy • 20 age, gravidity-matched controls • Day 2-4 of cycle, measured ovarian reserve (Ruddy et al., Fertility and Sterility, In Press)

24. Ovarian Reserve in Survivors Compared to Controls • Prospective studies are needed to determine the predictive value of these tests for pregnancy after chemotherapy (Ruddy et al., Fertility and Sterility, In Press)

25. Age of Menopause Among Women Who Remain Premenopausal Following Treatment for Early Breast Cancer • Long-term data from the International Breast Cancer Study Group (IBCSG) Trials V and VI • Included women who had reported menses in months 12-24 after diagnosis • N= 767 women • 540 women randomized to PeCT (1 cycle CMF) or No CT • 227 randomized to CMF x 6 or 7 (Partridge et al, Eur J Ca 2007)

26. Age at Menopause by Age at Treatment and Treatment Group Not clear that these data apply to women treated with more modern regimens (Partridge et al, Eur J Ca 2007)

27. Effects of Endocrine Therapy • Adjuvant endocrine therapy for breast cancer (tamoxifen or ovarian suppression) does not appear to cause permanent amenorrhea or infertility • BUT… endocrine therapy usually entails years of treatment when pregnancy contraindicated, and aging during that time compromises fertility

28. Fertility Preservation Considerations for Women with Cancer The obvious: weigh the “necessity” of systemic therapy

29. Options for Fertility Preservation in Women- Anatomic Fixes • Pelvic shielding during radiation • Ovarian Transposition • surgical repositioning of ovaries away from the radiation field • Conservative Gynecologic Surgery (Radical Trachelectomy) • surgical removal of the cervix while preserving the uterus

30. Other Options for Preserving Fertility for Women with Cancer • Ovarian suppression (LHRH agonists) during treatment • Cryopreservation of embryos • Cryopreservation of ovarian tissue • Cryopreservation of oocytes • Pharmaceutical protection with anti-apoptotic agents (eg. Sphingosine-1-phosphate) • Oocyte donation and gestational surrogacy

31. Ovarian Sensitivity to Chemotherapy Normal premenopausal ovary Low level recruitment of primordial follicles Cytotoxic chemotherapy Oocyte toxicity Decreased estradiol Increased FSH Increased follicular recruitment More oocytes at risk

32. Ovarian Sensitivity to Chemotherapy Normal premenopausal ovary Low level recruitment of primordial follicles Cytotoxic chemotherapy Oocyte toxicity Decreased estradiol Increased FSH Increased follicular recruitment GnRHa More oocytes at risk

33. Summary of Phase II Trials and Case Series • GnRH agonist coadministration with chemotherapy is associated with high rates of resumption of menses after chemotherapy • Successful pregnancies have occurred following chemotherapy with GnRHa • Lack of randomized data • Uncontrolled studies tended to have young patient populations

34. A randomized trial using the GnRH agonist (triptorelin) during chemotherapy N=49 (12-month f/u on 42 patients, and 18 month on 34 patients) Median age 39 years, range 21–43 Median time to return of menses Triptorelin arm: 6.1 months (range 1–19) Control arm: 4.7 months (range 0–22) (p=0.79) Menstruation resumed post chemotherapy in the respective groups as follows: triptorelin vs control 6 months: 44% vs 60%, 12 months 83% vs 79% 18 months 88% vs 84% (R. Ismail-Khan et al. ASCO 2008)

35. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study N=80 Age range 18-40 Menstruation resumed post chemotherapy (3-8 months) in the respective groups as follows: GnRHa group Control group 35/39 resumed menses 13/39 resumed menses 27 resumed spontaneous ovulation vs. 10 in control group (Badawy et al., Fertility and Sterility, in Press)

36. Ongoing Study: SWOG 0230 “POEMS” Premenopausal Stage I, II, IIIA ER-/PR- Breast Cancer Under age 50 Randomization n=416 CALGB 40401ECOG S0230 IBCSG 34-05 Stratification: Age Chemotherapy Standard cyclophosphamide Containing (neo)adjuvant chemotherapy Plus monthly goserelin Standard cyclophosphamide Containing (neo)adjuvant chemotherapy

37. IVF/Embryo Cryo

38. Cryopreservation of Embryos • Standardly available: 20-30% pregnancy rate per transfer of 2-3 embryos • Requires medical stability, time, and partner/sperm, adequate ovarian reserve • Expensive, ethically problematic if patient dies • Requires ovarian stimulation prior to systemic breast cancer treatment- concerning in patients with hormone-sensitive cancer • Natural cycle IVF has low yield (Oktay et al, JCO, 2005; Partridge & Winer, JCO 2005)

39. Variable Tam-IVF (a) TamFSH-IVF (b) Letrozole-IVF (c) a v b a v c b v c Age, years 36.6 ± 1.6 38.3 ± 1.9 38.5 ± 1 NS NS NS Baseline FSH, mU/mL 9.4 ± 1.5 9.4 ± 1.5 6.2 ± 1.1 NS NS NS PeakE2, pg/mL 419 ± 39 1,182 ± 271 380 ± 57 < .05 > .05 < .05 Total follicles, No. 2 ± 0.3 6 ± 1 7.8 ± 0.9 < .01 < .001 > .05 Follicle > 17 mm, No. 1.2 ± 0.1 2.6 ± 0.4 3.2 ± 0.4 < .05 < .001 > .05 Total oocytes, No. 1.7 ± 0.3 6.9 ± 1.1 12.3 ± 2.5 < .05 < .001 > .05 Mature oocytes, No. 1.5 ± 0.3 5.1 ± 1.1 8.5 ± 1.6 < .05 < .001 > .05 Total embryos, No. 1.3 ± 0.2 3.8 ± 0.8 5.3 ± 0.8 < .05 < .001 > .05 Comparison of Cycle Characteristics and Embryo Yield Among Tam-IVF (12 patients) TamFSH-IVF (seven patients), and Letrozole-IVF (11 patients) Patients(Oktay et al, JCO, 2005)

40. Tamoxifen or aromatase inhibitor stimulation protocols for IVF • Increase embryo yield, lower E2 levels with Letrozole, blockage of receptors with Tamoxifen • Unclear if mitigates potential risk • Preliminary safety data available • Number of babies resulting from such strategies that would have not been born otherwise remains unclear (Oktay et al, JCO 2005; Partridge & Winer, JCO 2005; Oktay et al., JCO 2008)

41. Oocyte Cryopreservation • Requires time and stimulation prior to treatment • No requirement for sperm, less ethical concern • Experimental- approximately 2% pregnancy rate per thawed oocyte

42. Oocyte Cryopreservation Technically difficult MII oocytes: extremely sensitive to temperature changes Crystal formation can cause cytoplasmic damage Cryoprotectants depolymerize meiotic spindle cause aneuploidy Hardening of zona pellucida barrier to fertilization

43. Cryopreservation of Ovarian Tissue • Requires surgical procedure to remove ovary or piece of ovary • May increase risk of infertility in low risk situation • Potential for reintroduction of malignant cells at reimplantation • Highly experimental- few babies born to date

44. Ovarian Cryopreservation Ovarian cortex is frozen in thin slices Primordial follicles are less sensitive to cryodamage because of low metabolic rate absence of zona pellucida high surface-volume ratio

45. Ovarian Cryopreservation Resumption of endocrine function has been reported after orthotopic and heterotopic transplantation Embryo was generated from oocytes retrieved from sc transplanted ovarian tissue Two live births reported after orthotopic transplantation of frozen-banked ovarian tissue in lymphoma survivors

46. Ovarian Cryopreservation Heterotopic tranplantation technique: Optimal site unknown Most have been to arm or forearm (or suprapubic area) - No need for abdominal surgery - Easy monitoring of follicular dvelopment - Easy removal if necessary (Oktay K, et al, JAMA,2001;286:1490-3)

47. Ovarian Cryopreservation Xenotransplantation: Has been shown feasible in several animal models into immunodeficient mice Concerns: Retroviruses, prions Abnormal oocyte development Abnormal chromatin patterns Benefits: Easier to repeat grafting if needed Easier access for IVF

48. Ovarian Cryopreservation Transplanting complete, intact ovary: Has been demonstrated in rats and sheep Recently demonstrated in human, but high risk for ischemia-reperfusion injury No pregnancy demonstrated (Bedaiwy M, et al, Hum Reprod, 2006)

49. Sphingosine-1-Phosphate Apoptotic inhibitor blocks pro-apoptotic messenger: ceramide (early messenger that signals apoptosis in response to stress) shown to be beneficial in mice when injected into ovarian bursa sac prior to radiation has not been evaluated in humans (Perez G, et al, Nat Med 1997;3:1228-32)

50. Safety and Timing of Pregnancy after Cancer • Conventional wisdom is to wait until patient gets through the period of highest risk recurrence • Receive optimal therapy (endocrine therapy may be prolonged) • No data to suggest harm in pregnancy sooner • No evidence for increased risk of disease recurrence associated with most fertility preservation methods and pregnancy- little data! • Aside from hereditary genetic syndromes and in-utero exposure to chemotherapy, no evidence for increased risk of cancer or abnormality in progeny