Fertility Preservation: Has the Time Come? - Adam S. Howe, MD Pediatric Urology - 18th Annual Current Concepts in Men's ...

Fertility Preservation:
 Has the Time Come?
Friday August 9, 2019
Current Concepts in Men's Health, Saratoga, NY

                       Adam S. Howe, MD
                       Pediatric Urology
                       Albany Medical College
                       Albany, NY

Objectives
1. Assess the risk of infertility in patients undergoing iatrogenic
gonadotoxic therapies

2. Understand the importance of onco-fertility and fertility
preservation to patients and families undergoing cancer therapies

3. Explore different management options for fertility preservation
(FP), including established, novel, and future therapies

4. Learn how to start up a fertility preservation program at your
institution

Disclosures

 None

“No patient should be excluded for consideration
   of discussion of fertility preservation for any
 reason including age, prognosis, socioeconomic
                 status or parity”

  American Society of Clinical Oncology, 2013

Iatrogenic Infertility

   Cancer patients are surviving longer
   Certain patients are at increased risk of infertility due
    to side effects or complications of therapies treating
    other conditions.
   It is our duty as healthcare providers to discuss these
    risks and offer management, if possible, to increase
    the chance of fertility for these patients.

Conditions with increased risk of infertility

   Oncology
   Immunosuppression
    – Hematologic
    – Autoimmune / Rheumatologic / Nephrotic
    – Transplant
   Disorders of sex development and transgender
   Trauma (eg, testicular/ovarian torsion)
   Urological / Gynecologic

Estimation of Infertility Risk in Cancer
   Challenging due to several factors:
          the disease
          stage
          site
          cumulative treatment dose (chemo + rad + sx)
          age
          gender

Chemotherapy that causes sub-fertility
     in males (azoospermia)

  - Chlorambucil*       - Carmustine*
  - Cyclophosphamide*   - Lomustine*
  - Procarbazine        - Busulfan
  - Melphan*            - Ifosphamide*
  - Cisplatin*          - Nitrogen Mustard*
                        - Bleomycin
  *Alkylating Agents!

Chemotherapy: Females (amenorrhea)
  High Risk:            Intermediate Risk:   Low Risk:

  - Busulfan*           - Adriamycin         - Actinomycin D
  - Chlorambucil*       - Carboplatin*       - Bleomycin
  - Cyclophosphamide* - Cisplatin*           - 5-Fluorouracil
  - Ifosphamide*                             - Methotrexate
  - Melphalan*                               - Vincristine
  - Nitrogen mustard*
  - Procarbazine            *Alkylating Agents!

Novel agents
 Note:
    Tyrosine kinase inhibitors, mTOR inhibitors,
      and monoclonal antibodies have an unknown
      risk to fertility

Radiation: Males
- Testicular radiation > 1.2 Gy
- Total body radiation > 12 Gy
- Cranial radiation > 40 Gy

Radiation: Females
- Total body irradiation for bone marrow or stem cell txp
- Craniospinal radiation dose >25 Gy
- Pelvic or whole abdominal radiation dose:
       –   Pre-pubertal: >10-15 Gy
       –   Post-pubertal: >5-10 Gy
- Oocyte median lethal dose

Risk of Sub-Fertility in Females
   Acute Ovarian Failure
           Occurs immediately following treatment
           Associated with full abdominal or pelvic radiation or
            hematopoietic stem cell transplant
           Should counsel prior to starting therapy

   Premature Ovarian Failure
            Ovarian failure before 35 yo
            Associated with alkylating agents
            Should counsel survivors in late adolescence

Patient Concerns

    Discussions about fertility and preservation of this are of
     great importance to patients
     – Cancer survivors place great importance on having
       children later in life and report psychological distress
       related to fertility loss
    Patients may make treatment decisions based on fertility
     concerns
    Parental influence in children and adolescents

Fertility Preservation
   All newly diagnosed cancer patients should be
    informed of potential risk of compromised fertility
    from the proposed treatment plan, along with being
    informed of fertility preservation (FP) options
   Fertility preservation procedures ideally should be
    performed before the start of therapy
   The decision to pursue FP is up to the patient and
    family, declining to pursue FP is acceptable.

Fertility Preservation Interventions

Options for Males

   Sperm banking
   Testicular biopsy for cryopreservation

Sperm banking

   Suitable for boys Tanner stage 3 and above
   60-86% success rates (pregnancy)
   Referral to reproductive endocrinologist
   Can be given a private room to produce a sample when
    inpatient which will be immediately transported to storage
    center
   Can be collected via electro-ejaculation if required

Sperm banking
   Botchan 2013
     – Low usage rates (10%)
     – Normal concentration but low motility
     – Testicular cancer with worst semen qualities
     – 66% conception rate
   Kamischke 2004
     – Low ejaculate volumes for pts

Testicular tissue for cryopreservation
   Option for pre-pubertal boys and post-
    pubertal boys who are unable to produce
    a semen sample via ejaculation
   Simple scrotal surgery under general
    anesthesia with coordination of other
    procedures
    Contraindicated in patients with acute
    leukemia not in remission

Testicular tissue for cryopreservation
   Wu 2012
     – Successful ICSI or natural mating in mice
   Pietzak 2015
     – 81% boys over 6mo had adult spermatogonia
     – 44% over 6 yrs had primary spermatocytes
   Sandri-Ardekani 2011
     – Successful xenotransplantation from humans to mice

Hormonal therapy
Gonadoprotection through hormone manipulation for FP has
  not been shown to improve recovery of spermatogenesis in
  men and is not recommended.

Options for Females
   Oocyte Preservation
   Ovarian Tissue Cryopreservation
   Ovarian Transposition

Oocyte preservation

   Suitable only for post-pubertal females and considered established FP
    method
   60-87% live birth rates
   Referral to reproductive endocrinologist
   Ovarian stimulation (10-12 days, 4 different protocols)
             GnRH antagonist-based protocols
             May not be suitable for patients with conditions that preclude a delay
              in starting therapy
   Transvaginal ultrasound for retrieval of oocytes

Oocyte preservation
   Wald 2019
     – Oocytes yield doubled after back-to-back random-start
       ovarian stimulation prior to chemo
     – Mean time to complete 33 days
   Relchman 2012
     – Successful cryo of 18 mature oocytes in 13 year old
       premenarchal female with myelodysplastic syndrome
       prior to chemo

Ovarian tissue for cryopreservation
                 For pre-pubertal girls and post-pubertal girls
                  who are unable to cryopreserve oocytes for
                  any reason
                 More than 60 cases of live births reported
                 Ovarian tissue biopsy or oophorectomy via
                  laparoscopic surgery under general anesthesia,
                  cryopreservation, and future reimplantation
                  (autotransplantation) or in vitro procedures
                 Future reimplantation contraindicated in
                  patients with leukemia

  Vide
  o

Ovarian tissue for cryopreservation
   Donnez 2013
     – 30% pregnancy and 20% live birth rate (natural and
       IVF) after orthotopic reimplantation
   Poirot 2019
     – Better pregnancy and live birth rates (32% vs 0%) in
       patients treated with chemo vs no chemo at 3 yrs
       after orthotopic/heterotopic reimplantation
     – Prior chemotherapy should no longer be a limitation to
       ovarian tissue cryo

Ovarian transposition (oophoropexy)

   Treatment strategy when pelvic
    radiation is performed for cancer
    treatment
   Laparoscopic surgery under
    general anesthesia placing the
    ovaries outside of the pelvis
   Preservation of ovarian function
    in 90%

Ovarian suppression therapy

Gonadoprotection with GnRH analogs for FP in women show
  conflicting results and there is a lack of pediatric data. The
  ASCO does not support their use, therefore it is not
  recommended.

Conservative surgery
    Strategy utilized to retain fertility by performing less radical
    surgeries with the intent of sparing as much of the
    reproductive organs as possible.
   Examples:
             Partial orchiectomy for mass in a solitary testis
             Robotic trachelectomy for localized cervical cancer

Costs of FP
                            1st year          Annually thereafter

   Sperm banking:       ~$500         $400
   Testicular tissue:     ~$1,500            $400
   Oocyte banking:      ~$5,000         $400
   Ovarian tissue:      ~$2,000         $400
   Oophoropexy:           ~$1,000

Costs
   Currently, all costs are the responsibility of the patient/family
   The LiveStrong fertility program is available for patients to apply online to
    offset costs of coverage
                 www.livestrong.org/what-we-do/program/fertility

   In 2017, Rhode Island and Connecticut became the first states to start
    covering FP procedures for patients undergoing cancer treatment

Legislation

   Recently, the Fertility Preservation Bill (formerly FAFTA
    [Fair Access to Fertility Treatment Act), S719 and A2817,
    has passed in New York state to add coverage for standard
    fertility treatments for those facing iatrogenic infertility

Albany Medical Center
Fertility Preservation Program

Team members

   Urology
   Pediatric Hematology/Oncology
   Central NY Fertility (local site in Latham, NY)

Process
1. Hematology/Oncology initiates discussion of FP with patients before starting therapy
2. If patient desires and is a candidate for FP, referral to Urology for education with the
    family and consent to FP intervention
3. Blood screen for transmittable disease markers (syphilis screen, Hep C virus serology,
    Hep B antigen and antibody, HIV1/HIV2)
4. Referral to CNY (consent and arrangements for sperm banking, ovarian stimulation,
    cryopreservation of samples)
5. Coordination of FP procedure with other surgeries (eg, mediport placement, bone
    marrow biopsy)
6. Day of procedure: CNY brings transport media to AMC, urology notifies CNY when
   biopsy or sample is finished and available for pickup
7. CNY sends report of biopsy to AMC (Urology & Heme/Onc)

Potential

   There are about 60 newly diagnosed pediatric
    cancer patients that present to Albany Med per
    year:
       – 32 Male (20 prepubertal, 12 postpubertal)
       – 28 Female (16 prepubertal, 12 postpubertal)

Case
   13 yo female with pelvic rhabdomyosarcoma and no
    menses undergoing chemotherapy (vincristine,
    dactinomycin, cyclophosphamide, and irinotecan)
   Schedule to undergo pelvic radiation (total dose >50 Gy)
   Underwent successful laparoscopic left ovarian
    transposition and right ovarian cortex harvest for
    cryopreservation

Building a FP program
  at your institution

1. Strong connection between
       oncologists and fertility specialists

   Strong collaboration
   Support and opinion of oncologist's “primary
    care” can have significant impact on patient
    decision making
   Open communication crucial
     – Especially with modification of treatment plans

2. Building a FP team

   Reproductive endocrinologist
   Oncologist
   Anesthesia (experience with coordination)
   Pathologist (ovarian and testicular tissue)
   Lab personnel (experience with handling tissue banking)
   Genetic counselors
   Mental health professionals (help discuss ethical and legal issues)
   ***FP patient navigator (initial counseling and referrals)***

3. Design of FP consultation

   Use of patient decision aids, brochures, and
    websites
   Follow-up visits (can be by phone or email too)
   Additional contact with fertility specialist

oncofertility.northwestern.edu

References
   Ameri A, Novin K, Sourati A, Rshidi P. Awareness of female cancer patients about the risk of impaired
    fertility. J Adolesc Young Adult Oncol, 2019 Jun;8(3):342-8.

   Cakmak H and Rosen MP. Ovarian stimulation in cancer patients. Fertility and Sterility, 2013.

   Cardozo ER, Huber WJ, Stuckey AR, Alvero RJ. Mandating Coverage for Fertility Preservation – A Step in
    the Right Direction. NEJM, 2017.

   Donnez J and Dolmans MM. Fertility Preservation in Women. NEJM, 2017.

   Fallat ME and Hutter J. Preservation of Fertility in Pediatric and Adolescent Patients with Cancer.
    Pediatrics, 2008.

   Johnson EK, Finlayson C, Rowell EE, et al. Fertility Preservation for Pediatric Patients: Current State and
    Future Possibilities. Pediatric Urology, 2017.

   Loren AW, Mangu PB, Beck LN, et al. Fertility Preservation for Patients With Cancer: American Society of
    Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology, 2013.

   Moawad NS, Santamaria E, Rhoton-Vlasak A, Lightsey JL. Laparoscopic Ovarian Transposition before
    Pelvic Cancer Treatment: Ovarian Function and Fertility Preservtation. JMIG, 2017.

Resources
   www.allianceforfertilitypreservation.org
   www.cms.gov
   www.livestrong.org
   www.nysenate.gov
   Lisa Campo-Engelstein, PhD (Alden March Bioethics Institute at AMC)
   SickKids Fertility Preservation Program (The Hospital for Sick Children, Toronto,
    ON, Canada): Anne Marie Maloney, MSN, NP, CPHON (Pediatric
    Hematology/Oncology) and Armando Lorenzo, MD, FRCSC (Pediatric Urology)
   Southern California Reproductive Center (Los Angeles, CA, USA): Lina Akopians,
    MD, PhD, FACOG (Reproductive Endocrinology)

Thank You