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Fertility In Cancer Patients Treatment

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MedicYatra provides the safe & best Fertility In Cancer Patients Treatment and procedure at its affiliate & trusted hospitals & clinics in various metro cities of India, like Mumbai, Delhi, Bangalore, Chennai, Pune etc.Our Associate Board certified doctors are extensively trained and vastly experienced and have performed hundreds of such cases at our state of the art JCI accredited hospitals & Clinics. Our aim is to provide you the best of the services at the most affordable costs. Don't forget to say hi at info@medicyatra.com

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Fertility In Cancer Patients Treatment

  1. 1. Email: enquiry@medicyatra.comFertility In Cancer Patients 22-06 2012 Copyright @ Forever Medic
  2. 2. Email: enquiry@medicyatra.comThe 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 researchin this area only and limitations of it Copyright @ Forever Medic
  3. 3. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  4. 4. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  5. 5. Email: enquiry@medicyatra.com 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) Copyright @ Forever Medic
  6. 6. Email: enquiry@medicyatra.com 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) Copyright @ Forever Medic
  7. 7. American Society of Clinical Oncology Email: enquiry@medicyatra.com Recommendations on Fertility Preservation in People Treated for Cancer • Assessment of risk for infertility •Communication with patient • Patient at risk for treatment induced infertility - • Patient interested in fertility preservation options Refer to specialist with expertise in fertility preservation methods Eligible for proven fertility preservation method Investigational fertility preservation technique*Male: Female: • ryopreservation of Cspermcryopreservation embryocryopreservation testicular or ovarian tissue conservative gynecologic surgery • ryopreservation ofoocytes C oophoropexy • Ovarian suppression *Clinical trial participation encouraged Copyright @ Forever Medic www.asco.org (Lee et al., J Clin Onc; 2006)
  8. 8. American Society of Clinical Oncology Email: enquiry@medicyatra.com Recommendations on Fertility Preservation in People Treated for Cancer • Assessment of risk for infertility •Communication with patient • Patient at risk for treatment induced infertility - • Patient interested in fertility preservation options Refer to specialist with expertise in fertility preservation methods Eligible for proven fertility preservation method Investigational fertility preservation technique*Male: Female: • ryopreservation of Cspermcryopreservation embryocryopreservation testicular or ovarian tissue conservative gynecologic surgery • ryopreservation ofoocytes C oophoropexy • Ovarian suppression *Clinical trial participation encouraged Copyright @ Forever Medic www.asco.org (Lee et al., J Clin Onc; 2006)
  9. 9. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  10. 10. Email: enquiry@medicyatra.comAll 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 Copyright @ Forever Medic
  11. 11. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  12. 12. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic – Testis grafting with maturation in SCID mice
  13. 13. Email: enquiry@medicyatra.com 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. Copyright @ Forever Medic
  14. 14. Email: enquiry@medicyatra.comNatural Decline of Oocytes with Age Copyright @ Forever Medic (Lobo, NEJM 2005)
  15. 15. Email: enquiry@medicyatra.comChemotherapy-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 Copyright Forever Medic Online Pvt. Ltd
  16. 16. Email: enquiry@medicyatra.comRisk of amenorrhea is related to age and treatment Copyright @ Forever(Goodwin et al., J Clin Oncol 1999) Medic
  17. 17. Email: enquiry@medicyatra.com 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, Copyright @ Forever Medic Tyrosine kinase inhibitors (Sonmezer and Oktay, Hum Reprod Update, 2004)
  18. 18. Email: enquiry@medicyatra.com Risk of Chemotherapy-Related Amenorrhea with Common Breast Cancer Regimens Treatment Age <30 Age 30-40 Age>40 None ~0 <5 20-25 AC x 4 -- 13 57-63 CMF x 6 19 31-38 76-96 CAF/CEF x 6 23-47 80-89 TAC x 6 51 AC x 4, T x 4 38 (15% age <40)(Goodwin et al., JCO 1999; Burstein, H. J. et al. NEJM 2000; Nabholtz et al., ASCO 2002; Copyright @ Forever MedicParulekar et al., JCO 2005; Fornier et al., Cancer 2005; Petrek et al, JCO 2006)
  19. 19. Email: enquiry@medicyatra.com Effects of Newer Treatments: Paclitaxel, Dose Density, and Trastuzumab on CRA• 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) Copyright @ Foreveret al., Breast Cancer Res Treat 2006) (Abusief Medic
  20. 20. Email: enquiry@medicyatra.com Effects of Paclitaxel, Dose Density, and Trastuzumab on CRA Variable Odds 95% CI p-value ratio*Chemotherapy AC-T 1.27 0.70-2.32 0.61 AC 1.00 Referent --Regimen DD 1.30 0.66-2.57 0.56 q3wk 1.00 Referent --Trastuzumab AC-TH 0.49 0.21-1.17 0.11 AC 1.00 Referent --Tamoxifen yes 2.14 1.16-3.97 0.02 no 1.00 Referent --Age at diagnosis 1.39 1.30-1.49 <0.0001 Copyright @ Forever Medic (Abusief et al., Breast Cancer Res Treat 2006)
  21. 21. Email: enquiry@medicyatra.com 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”) Copyright @ Forever Medic
  22. 22. Email: enquiry@medicyatra.comOvarian Reserve in Women Who RemainPremenopausal 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@ Forever Medicand Sterility, In Press) Copyright al., Fertility
  23. 23. Email: enquiry@medicyatra.com Ovarian Reserve in Survivors Compared to Controls Survivors (n=20) Controls (n=20) P-valueAntral Follicle 5.2 11.3 0.0042Count (AFC)Anti-Mullerian 0.57 1.77 0.0004Hormone(AMH)Follicle 11.56 8.04 0.02StimulatingHormoneInhibin B (InB) 24.3 46.6 0.02Estradiol (E2) 126.0 38.8 0.14 Prospective studies are needed to determine the predictive value of these tests for pregnancy after Copyright @ Forever Medic chemotherapy (Ruddy et al., Fertility and Sterility, In Press)
  24. 24. Age of Menopause Among Women Who Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic (Partridge et al, Eur J Ca 2007)
  25. 25. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  26. 26. Email: enquiry@medicyatra.comFertility Preservation Considerations for Women with Cancer The obvious: weigh the “necessity” of systemic therapy Copyright @ Forever Medic
  27. 27. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  28. 28. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  29. 29. Email: enquiry@medicyatra.com Ovarian Sensitivity to Chemotherapy Normal premenopausal ovaryLow level recruitment of primordial follicles Cytotoxic chemotherapy Oocyte toxicity Decreased estradiol Increased FSH Increased follicular recruitment More oocytes at risk Copyright @ Forever Medic
  30. 30. Email: enquiry@medicyatra.com Ovarian Sensitivity to Chemotherapy Normal premenopausal ovaryLow level recruitment of primordial follicles Cytotoxic chemotherapy Oocyte toxicity Decreased estradiol Increased FSH GnRHa Increased follicular recruitment More oocytes at risk Copyright @ Forever Medic
  31. 31. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  32. 32. A randomized trial using the GnRH agonist Email: enquiry@medicyatra.com (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 respectivegroups as follows: triptorelin vs control 6 months: 44% vs 60%, 12 months 83% vs 79% Copyright @ Forever Medic (R. Ismail-Khan et al. ASCO 2008)
  33. 33. Gonadotropin-releasing hormone agonists for Email: enquiry@medicyatra.com 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 Medic in control group Copyright @ Forever vs. 10 (Badawy et al., Fertility and Sterility, in Press)
  34. 34. Email: enquiry@medicyatra.com Ongoing Study: SWOG 0230 “POEMS”II, IIIA Premenopausal Stage I, ER-/PR- Breast Cancer Under age 50 CALGB 40401 Randomization Stratification: ECOG S0230 n=416 Age IBCSG 34-05 ChemotherapyStandard cyclophosphamide Standard cyclophosphamideContaining (neo)adjuvant Containing (neo)adjuvantchemotherapy chemotherapy Plus monthly goserelin Copyright @ Forever Medic
  35. 35. Email: enquiry@medicyatra.comIVF/Embryo Cryo Copyright @ Forever Medic
  36. 36. Email: enquiry@medicyatra.com• 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) Copyright @ Forever Medic
  37. 37. Comparison of Cycle Characteristics and Embryo Yield Among Tam- Email: enquiry@medicyatra.com IVF (12 patients) TamFSH-IVF (seven patients), and Letrozole-IVF (11 patients) Patients (Oktay et al, JCO, 2005) Tam-IVF TamFSH-IVF Letrozole-IVF av bv Variable (a) (b) (c) b avc cAge, years 36.6 ± 1.6 38.3 ± 1.9 38.5 ± 1 NS NS NSBaseline FSH, mU/ 9.4 ± 1.5 9.4 ± 1.5 6.2 ± 1.1 NS NS NSmLPeakE2, pg/mL 419 ± 39 1,182 ± 271 380 ± 57 <. > .05 <. 05 05Total follicles, No. 2 ± 0.3 6±1 7.8 ± 0.9 <. <. >. 01 001 05Follicle > 17 mm, 1.2 ± 0.1 2.6 ± 0.4 3.2 ± 0.4 <. <. >.No. 05 001 05Total oocytes, No. 1.7 ± 0.3 6.9 ± 1.1 12.3 ± 2.5 <. <. >. 05 001 05Mature oocytes, 1.5 ± 0.3 5.1 ± 1.1 8.5 ± 1.6 <. <. >.No. 05 001 05Total embryos, No. 1.3 ± 0.2 Copyright @ Forever Medic ± 0.8 3.8 ± 0.8 5.3 <. <. >. 05 001 05
  38. 38. Tamoxifen or aromataseEmail: enquiry@medicyatra.com 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) Copyright @ Forever Medic
  39. 39. Email: enquiry@medicyatra.com Oocyte Cryopreservation• Requires time and stimulation prior to treatment• No requirement for sperm, less ethical concern• Experimental- approximately 2% pregnancy rate per thawed oocyte Copyright @ Forever Medic
  40. 40. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  41. 41. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  42. 42. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  43. 43. Email: enquiry@medicyatra.com 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 Copyright Forever Medic
  44. 44. Email: enquiry@medicyatra.com 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)@ Forever Medic Copyright
  45. 45. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic
  46. 46. Email: enquiry@medicyatra.com 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) Copyright @ Forever Medic
  47. 47. Email: enquiry@medicyatra.com 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 Copyright @ Forever Medic al, Nat Med 1997;3:1228-32) (Perez G, et
  48. 48. Email: enquiry@medicyatra.comSafety 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 Copyright @ Forever Medic
  49. 49. Conclusions: Fertility Concerns in Email: enquiry@medicyatra.com Cancer Survivors• Very complex and difficult issues• Limited available data• Patient preferences critical in some settings• Managing expectations often necessary Copyright @ Forever Medic
  50. 50. Email: enquiry@medicyatra.comConclusions: Fertility Concerns in Cancer Survivors (cont.)• Address fertility issues up front; include fertility concerns in the risk-benefit analysis – Refer to fertility specialists early• In the event of pregnancy, consider “high risk” obstetrics management Copyright @ Forever Medic

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