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Best Treatmen for Fertility In Cancer Patients

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Fertility In Cancer Patients

           22-06 2012




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The speaker declares that specific brand-name medications and/or
  off-label, non-FDA-approved uses are discussed in the lecture.


1) Letrozole or tamoxifen for ovarian stimulation

2) I will attempt to avoid bias by discussing the published research
in this area only and limitations of it




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     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


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          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

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    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)
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 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)
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        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:                                        •Cryopreservation of
sperm cryopreservation               embryo cryopreservation                        testicular or ovarian tissue
                                     conservative gynecologic surgery               •Cryopreservation of oocytes
                                     oophoropexy                                    •Ovarian suppression
                                                                                    *Clinical trial participation
                                                                                    encouraged
                                     Copyright @ Forever Medic
       www.asco.org                                        (Lee et al., J Clin Onc; 2006)
        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:                                        •Cryopreservation of
sperm cryopreservation               embryo cryopreservation                        testicular or ovarian tissue
                                     conservative gynecologic surgery               •Cryopreservation of oocytes
                                     oophoropexy                                    •Ovarian suppression
                                                                                    *Clinical trial participation
                                                                                    encouraged
                                     Copyright @ Forever Medic
       www.asco.org                                        (Lee et al., J Clin Onc; 2006)
                                               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

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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



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         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
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            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
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   – Testis grafting with maturation in SCID mice
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      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.


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Natural Decline of Oocytes with Age




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                                          (Lobo, NEJM 2005)
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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
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Risk of amenorrhea is related to
       age and treatment




         Copyright @ Forever(Goodwin et al., J Clin Oncol 1999)
                             Medic
                                             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 @
    Tyrosine kinase inhibitorsForever Medic Hum Reprod Update, 2004)
                             (Sonmezer and Oktay,
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    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;
Parulekar et al., JCO 2005; Fornier et al., Cancer 2005; Petrek et al, JCO 2006)
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    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)
                            (Abusief Medic
                  Copyright @ Foreveret al., Breast Cancer Res Treat 2006)
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  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
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                                    (Abusief et al., Breast Cancer Res Treat 2006)
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       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”)




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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
               Copyright al., Fertility
             (Ruddy et@ Forever Medicand Sterility, In Press)
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              Ovarian Reserve in Survivors
                 Compared to Controls
                  Survivors (n=20) Controls (n=20) P-value
Antral Follicle   5.2                      11.3                           0.0042
Count (AFC)
Anti-Mullerian    0.57                     1.77                           0.0004
Hormone
(AMH)
Follicle          11.56                    8.04                           0.02
Stimulating
Hormone
Inhibin B (InB) 24.3                       46.6                           0.02
Estradiol (E2)    126.0                    38.8                           0.14
  Prospective studies are needed to determine the predictive value of these
  tests for pregnancy after chemotherapy
                            Copyright @ Forever Medic
                                           (Ruddy et al., Fertility and Sterility, In Press)
Age of Menopause Among Email: enquiry@medicyatra.com
                         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

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                                  (Partridge et al, Eur J Ca 2007)
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      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
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Fertility Preservation Considerations
       for Women with Cancer


 The obvious: weigh the “necessity” of
           systemic therapy




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   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




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     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
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 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

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 Ovarian Sensitivity to Chemotherapy
      Normal premenopausal ovary
Low level recruitment of primordial follicles

        Cytotoxic chemotherapy

                 Oocyte toxicity

                   Decreased estradiol
                     Increased FSH

         GnRHa          Increased follicular recruitment
                                        More oocytes at risk

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      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



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   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%
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   18 months                  88% vs 84% (R. Ismail-Khan et al. ASCO 2008)
  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


                    Copyright @ Forever vs. 10
   27 resumed spontaneous ovulation Medic in control group
                       (Badawy et al., Fertility and Sterility, in Press)
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      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                                            Chemotherapy



Standard cyclophosphamide          Standard cyclophosphamide
Containing (neo)adjuvant           Containing (neo)adjuvant
chemotherapy                       chemotherapy
                                   Plus monthly goserelin

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IVF/Embryo Cryo




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•
    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)
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Comparison of Cycle Characteristics and Embryo Yield Among Tam-
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 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      c
Age, years             36.6 ± 1.6    38.3 ± 1.9      38.5 ± 1      NS    NS      NS
Baseline FSH,          9.4 ± 1.5      9.4 ± 1.5      6.2 ± 1.1     NS    NS      NS
mU/mL
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,      1.2 ± 0.1     2.6 ± 0.4       3.2 ± 0.4      <      <      >
No.                                                                .05   .001    .05
Total oocytes, No.     1.7 ± 0.3     6.9 ± 1.1       12.3 ± 2.5     <      <      >
                                                                   .05   .001    .05
Mature oocytes,        1.5 ± 0.3     5.1 ± 1.1       8.5 ± 1.6      <      <      >
No.                                                                .05   .001    .05
Total embryos, No.             Copyright @ Forever Medic ± 0.8
                       1.3 ± 0.2      3.8 ± 0.8        5.3          <      <      >
                                                                   .05   .001    .05
                          inhibitor
 Tamoxifen or aromataseEmail: enquiry@medicyatra.com
   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)
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        Oocyte Cryopreservation

• Requires time and stimulation prior to treatment

• No requirement for sperm, less ethical concern

• Experimental- approximately 2% pregnancy rate
  per thawed oocyte




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             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

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            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
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     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

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     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
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              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




                                 Copyright
    (Oktay K, et al, JAMA, 2001;286:1490-3)@ Forever Medic
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        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

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     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)
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     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
               Copyright @ Forever Medic al, Nat Med 1997;3:1228-32)
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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
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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
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Conclusions: 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


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