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Infertility Risk Reduction in Female Oncology Patients
Dr. Mike Ripley
Atlantic Assisted Reproductive Technologies
Division of Reproductive Endocrinology and Infertility
Dalhousie University
Canadian Association of Pharmacy in Oncology - April 27th, 2019
Overview
• Fertility impacting diseases
• Chemotherapy and Radiation
• Fertility Preservation• Pre-treatment counseling
• Fertility preservation methods
• IVF safety
• Practical Information
Introduction
• Women have a 42% lifetime risk (1 in 2.4) of cancer• 5.7% under age 40
• 0.7% under age 20
• ASMR declined 30-40% in women of reproductive age 1986-2010
Byrne et al. (1989)
Risk of infertility among cancer survivors
• Depends on:• Type of stage of cancer
• Drug class and cumulative dose
• Radiation field, number of treatments, and cumulative dose
• Extent of surgical therapy
• Age (eg, prepubertal, postpubertal, near menopause)
• Gender
• Genetic Factors
• Development of post-treatment hypothyroidism
Fertility-impacting diseases
Introduction
• Malignancy, precancerous and benign conditions
• Treatment• Surgical resection of reproductive organs
• Gonadotoxic chemotherapy
• Gonadotoxic radiation therapy
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Up To Date (2018): Fertility Preservation in Patients Undergoing Gonadotoxic Treatment or Gonadal Resection Up To Date (2018): Fertility Preservation in Patients Undergoing Gonadotoxic Treatment or Gonadal Resection
Up To Date (2018): Fertility Preservation in Patients Undergoing Gonadotoxic Treatment or Gonadal Resection
Chemotherapy and Radiation
https://diagramchartspedia.com/female-reproductive-system-ovaries/female-reproductive-system-ovaries-anatomy-of-ovaries-gallery-human-anatomy-learning/
Chemo and Fertility
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Multiple drug regimens
• Hodgkin lymphoma• ABVD
• Low incidence of chemo-induced ovarian failure• 90% normal spermatogenesis at 1 year
• BEACOPP• Approx. 50% ovarian failure
• 3+ cycle of MOPP• Azoospermia in ~90% at 1 year (likely from procarbazine)
• Early stage breast cancer• Two commonly used adjuvant chemo regimens:
• CMF (cyclophosphamide, MTX, and 5-FU) • AC (doxorubicin plus cyclophosphamide)
• Ovarian failure CMF>AC
Radiation Therapy
• XRT more damaging to ovarian tissue than chemo
• Transient amenorrhea • resolves after 6-18 months
• Wallace et al. (2005) estimated radiosensitivity of oocyte to be <2 Gy• Calculated dose = immediate/permanent ovarian failure
• Birth: 20.3 Gy
• 10 yo: 18.4 Gy
• 20 yo: 16.5 Gy
• 30 yo 14.3 Gy
• 40 yo 6.0 Gy
Assessment of fertility potential after cancer therapy
• Females:• Amenorrhea/oligomenorrhea
• Evaluate for POI
• Diagnosis problematic: ovarian dysfunction may not be permanent
• Regular menstrual cycles• Assessment of ovarian reserve: AMH or AFC
• Males:• Semen analysis
• If repeated analyses demonstrate severe oligozoospermia/azoospermia -> FSH/LH and testosterone
Pretreatment Counseling
Pretreatment Counseling
• Risk of treatment-induced infertility
• Possible interventions to preserve fertility
• Only 26% of women 40 years and younger with breast cancer had a documented fertility discussion with their physician• 90% of these women pursued further consultation for fertility preservation
• Initiate conversation early - fertility interventions can take time and delay start of treatment
McCray et al. (2016)
Pretreatment Counseling
• Fertility preservation = individualization
• Things to consider:• Type of gonadotoxic treatment (XRT vs chemo)
• Time available
• Patient age
• Specific disease
• Relationship Status
• Costs
• Long-term issues (storage and use of frozen gametes or embryos)
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Disclosure
• No large RCTs evaluating majority of the following interventions
• No long-term follow-up studies assessing the possible impacts of fertility treatment on cancer survivors
• Oncologists remain cautious about use of traditional assisted reproductive technology (ART) in women with estrogen-dependent malignancies
Fertility Preservation Infertility Risk Reduction
• Preservation:
• Fertility “Preservation”:
Fertility Preservation Methods
Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost, contact info)
Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost)
Cryopreservation
• Embryo
• Oocyte• Mature
• Immature
• Ovarian tissue
• Whole ovary
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What is in vitro fertilization (IVF)? IVF Protocols
• Ovarian stimulation with gonadotropins (FSH +/- LH) takes advantage that month’s developing follicular pool
• ovulation must be prevented (GnRH agonists or antagonists) during ovarian stimulation
• Letrozole to keep estrogen levels low in breast cancer patients
• At the end of stimulation, final stage of oocyte maturation with injection of HCG
• Egg retrieval
• Embryos cultured (“grown”) in lab
• Freezing of embryos
IVF - Stimulation Phase
• Daily subcutaneous injections of FSH +/- LH
• Monitoring with transvaginal U/S and bloodwork q 2-3 days (follicle growth, estradiol level)
• Stimulation phase typically lasts 9-12 days
• When oocytes are “ready” patient stopsgonadotropins and GnRHa, takes HCG 36 hours before egg retrieval
IVF – Egg Retrieval (OPU)
IVF - Fertilization
Intracytoplasmic Sperm Injection
Standard IVF
IVF – Embryo Culture
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Embryo Cryopreservation
• Fresh eggs fertilized with sperm +/- ICSI then frozen• No known time limit for the duration of embryo storage
• Live birth from 20 year old embryo!
• Live birth rates from frozen-thawed embryos depends on the age of the woman at the time of egg-retrieval
• Obstetrical outcomes equal for fresh vs frozen embryos
Up to Date: Fertility preserving options for women of advancing age
Embryo Cryoprservation
• Well established technique for storing surplus of embryos
• May not be feasible for patients planning gonadotoxic therapy• Time constraints
• No partner
• Prepubertal
• Legal and ethical issues
• Estrogen sensitive tumors
IVF Success Rates IVF Success Rates
Oocytes – Mature Oocytes
• 1986: First human birth after oocyte cryopreservation
• 2012: ASRM lifted ‘experimental’ label
• Limitations• Lower survival, fertilization rate, pregnancy rate
• Mature oocyte fragile during thaw
• Large size
• High water content
• Ice formation, chilling injury and osmotic damage all detrimental to mitotic spindle
• May delay start of cancer treatment
• High estradiol levels
• Not an option for prepubertal patients
Oocytes – Mature Oocytes
• Good option for patients:• No long-term partner
• Religious or ethical objection to embryo freezing
• Young age/good ovarian reserve
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Oocyte cryopreservation - outcomes Oocyte cryopreservation - outcomes
Elective oocyte freezingOvarian tissue cryopreservation
Donnez, J., et al (2011)
Posthumous use of reproductive tissue
• Consent form, advance directive to be completed at time of cryopreservation
• Consent could allow use of the gametes by a partner, donation to others, research, or destruction/discarding of the tissue
• Children born after posthumous conception are the legal children of the deceased
Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost)
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Protecting Native Ovarian Function
• Radiation Therapy• Transposition (oophoropexy)
• Shielding
• Auto-transplantation
• Chemotherapy• GnRH agonist treatment
Women receiving radiation
• Transposition (oophoropexy)• Once radiation field is planned, move ovary to position to best protect it from
exposure• Non-pelvic tumors and narrow midline radiation field
• Simple oophoropexy
• Broad pelvic radiation (absence of chemo)• Consider transposing ovaries out of radiation field
Ovarian transposition Ovarian transposition
Women receiving radiation
• Shielding• Externally shielding ovaries to reduce effects of scatter radiation
• Auto-transplantation• If XRT to pelvis is planned, consider transplant of fresh ovary to upper
extremity with creation of vascular anastomosis
• Practicality of this approach is in question
Women receiving chemotherapy
• Option #1: proven cryopreservation techniques!!
• GnRH agonist treatment: not recommended as primary treatment fertility preservation• Not shown to be equivalent or superior to embryo or oocyte cryopreservation
• Ideally: fertility preservation AND restoration of cycles
• Should be considered if cryopreservation is not an option
• Alternative use: reduction of HMB in women at risk for severe chemo-induced thrombocytopenia.
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GnRH agonist suppression
CFAS, ASCO differ on their support for this method of FP
GnRH agonist suppression
GnRH agonist suppression Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost)
Egg donation
• No fresh/frozen oocytes/ovarian tissue available
• Intact uterus
• Consider fresh/frozen donor oocytes and partner’s sperm for IVF
• Success rates >50-60% per embryo transfer
Embryo Donation
• Couples in IVF programs sometimes donate excess cryopreserved embryos
• Can implant these embryos in a woman with a uterus, even if no ovarian function is present
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Adoption
• Another option for parenthood
Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost, contact info)
IVF and Safety in Cancer Patients
Women with Breast Cancer
• Ovarian stimulation• 4-6 week hiatus between breast ca surgery and initiation of chemo
• Natural cycle
• Yield = extremely low
• IVF
• Estradiol levels 10 x natural cycle
• Concern: breast tumors contain estrogen receptor-positive cells
• Even ER-negative can be estrogen responsive
• Approach: minimize estrogen exposure during fertility preservation procedures• Letrozole
• Tamoxifen
Women with Breast Cancer
• Letrozole (aromatase inhibitor)• Advantage: peak estradiol levels are close to those observed in natural cycles
• Recommended: letrozole-FSH protocol• Low estradiol exposure
• High oocyte recovery
• Additional concern: • BRCA1 mutation carriers: lower ovarian response rate to letrozole-FSH than BRCA
mutation-negative patients, and produce fewer eggs
• These patients may be more vulnerable to gonadotoxic effects of cancer treatments.
Women who cannot undergo ovarian stimulation
• Large/locally advanced (inflammatory) breast ca• Neoadjuvant chemo is begun immediately after diagnosis and before surgical
treatment
• Consider harvesting immature oocytes
• BRCA carriers and other women with hereditary breast-ovarian cancer syndromes• Risk of developing ovarian cancer
• Relatively high incidence of occult ovarian cancer
• Future avenues: possible to culture frozen-thawed ovarian tissue strips to achieve oocyte maturation and perform IVF
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IVF – treatment delay
• 7501 Danish patients with early stage breast cancer between 1977-99• Three different chemotherapy regimens, as treatment changed during
the study period• Chemo treatment start after surgery divided into 4 groups – weeks 1-3,
week 4, week 5, or week 6-12
IVF – treatment delay
IVF – treatment delay
• 2594 Canadian patients with stage I or II breast cancer between 1989-98.
• Chemo treatment start after surgery divided into 4 groups – < 4 weeks, 5-8 weeks, 8-12 weeks, and > 12 weeks
IVF – treatment delay
Safety of IVF in breast cancer
Kim J et al J Clin Endocrinol Metab. 2016 Jan 11
• Prospective study of 337 women with stage 1-3 breast CA, all saw FP specialist• 120 underwent FP (gonadotropins + letrozole), 217 didn’t (controls)
• Followed for avg of 5 years
• No difference in recurrence or survival
• No effect of BRCA status, ER status of tumor, or timing of ovarian stim (pre- or post-surgery)
Fertility Preservation Methods
• Cryopreservation
• Protecting native ovarian function
• Alternatives
• Safety Concerns
• Practical Information (i.e. cost)
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Components of Fertility Preservation Program
• Rapid access
• Multidisciplinary team – physicians, nurses, pharmacists, embryologists, administration
• Experienced lab – embryo, oocyte, sperm cryopreservation protocols, +/-IRB-approved protocols for testicular/ovarian tissue cryo
• Counsellors – mental health, genetic, financial
• Interdisciplinary collaboration
Current Status of IVF Funding in CanadaQuebec:
• Funding started August 2010 but cancelled in 2014, now income-based assistance sliding scale
Ontario:
• One lifetime IVF cycle funded for patients since January 2016
• Cap on number of provincially funded cycles/year, each clinic has a maximum number of funded cycles/year based on clinic size and volume
Manitoba:
• Fertility Treatment Tax Credit - 40% of up to $20000 fertility treatment fees + drug expenses (max $8000 per year)
New Brunswick:
• The Special Assistance Fund for Infertility Treatment
• One-time grant for 50% of fertility treatment fees + drugs, up to maximum of $5000
Financial Assistance
• Partnership with Fertile Future helps reduce cost of FP treatments for patients
• Fertile Future is a Canadian non-profit organization that provides fertility preservation information and support services to cancer patients and oncology professionals
• Power of Hope is a financial assistance program for Canadian cancer patients wishing to pursue fertility preservation prior to beginning fertility threatening treatment
Financial Assistance
• Fertile Future’s Power of Hope program will assist eligible patients in financial need (http://fertilefuture.ca/patients/power-of-hope/)
• Female patients will receive cost reimbursement of $1000
• Male patients can undergo sperm cryopreservation at no cost
• Fertility medications will be supplied under compassion care programs through the manufacturers (Merck and AMD Serono)
• Participating clinics reduce their IVF fees by 1/3
Financial Assistance
SERVICE AART
FEE
AART
DISCOUNT
AART FEE
ELIGLBLE
PTS
MEDICATIONS
POWER
OF HOPE
COST TO
PATIENT
Oocyte
Freezing
$8500 $2833 $5667 Compassionate $1000 $4667
Embryo
Freezing
(IVF)
$6900 $2300 $4600 Compassionate $1000 $3600
Embryo
Freezing
(ICSI)
$6900
+
$1500
$2800 $5600 Compassionate $1000 $4600
Sperm
Freezing
$500 $150 $350 N/A $350 $0
Financial Information
Cost of treatments:
• IVF: • Embryo cryopreservation: $4600 (ISCI) or $3600 (standard IVF) • Oocyte cryopreservation: $4667
• Sperm cryopreservation: $0
• Storage of embryos/oocytes: $900, then $300/yr
• Leuprolide acetate 3.75mg: $500/month
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Ethical Considerations
• Risk to future fertility of cancer treatments
• Fertility preservation treatment options
• Any investigational/experimental aspects of fertility treatments
• Risks of delaying cancer treatments
• Likelihood of success of FP options
• Potential risks of FP treatments
• Treatment costs
• Disposition of human reproductive material / posthumous use
• Alternative fertility options (oocyte donation, gestational carriers, surrogacy, adoption)
Roberts J et al. Curr Oncol. 2015 Aug; 22(4): e294–e304.
Conclusions
• Embryo or oocyte cryopreservation are good options for female oncology patients who wish to preserve fertility prior to cancer treatments
• Cryopreservation does not guarantee that patients will be able to have children after their treatment
• Cryopreservation is unaffordable or impractical for some patients
• Futher studies are need to gather better long-term data on outcomes and safety, although current research is reassuring
References
• Bedaiwy MA, El-Nashar SA, El Saman AM, et al. Reproductive outcome after transplantation of ovarian tissue: a systematic review. Hum Reprod 2008; 23:2709.
• Borini A, Levi Setti PE, Anserini P, et al. Multicenter observational study on slow-cooling oocyte cryopreservation: clinical outcome. Fertil Steril 2010; 94:1662.
• Byrne J, Lewis S, Halamek L, et al. Childhood cancer survivors' knowledge of their diagnosis and treatment. Ann Intern Med 1989; 110:400.
• Cardonick, Elyce. Overview of infertility and pregnancy outcome in cancer survivors Up To Date: Literature review current through: Jul 2018. | This topic last
updated: May 24, 2018
• Chow EJ, Stratton KL, Leisenring WM, et al. Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a
report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016; 17:567.
• Cobo A, Meseguer M, Remohí J, Pellicer A. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Hum
Reprod 2010; 25:2239.
• Cobo A, Kuwayama M, Pérez S, et al. Comparison of concomitant outcome achieved with fresh and cryopreserved donor oocytes vitrified by the Cryotop method.
Fertil Steril 2008; 89:1657.
• Cold, S., During, M., Ewertz, M., Knoop A., Moller S. Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish
Breast Cancer Cooperative Group (DBCG).
• Goldman KN, Noyes NL, Knopman JM, et al. Oocyte efficiency: does live birth rate differ when analyzing cryopreserved and fresh oocytes on a per-oocyte basis?
Fertil Steril 2013; 100:712.
References
• McCray DK, Simpson AB, Flyckt R, Liu Y, O'Rourke C, Crowe JP, Grobmyer SR, Moore HC, Valente SA Fertility in Women of Reproductive Age After Breast Cancer Treatment: Practice Patterns and Outcomes. Surg Oncol. 2016;23(10):3175.
• Oktay K, Buyuk E, Libertella N, et al. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005; 23:4347.
• Oktay K, Hourvitz A, Sahin G, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006; 91:3885.
• Pacheco F, Oktay K. Current Success and Efficiency of Autologous Ovarian Transplantation: A Meta-Analysis. Reprod Sci 2017; 24:1111
• Parmegiani L, Cognigni GE, Bernardi S, et al. Efficiency of aseptic open vitrification and hermetical cryostorage of human oocytes. Reprod Biomed Online 2011; 23:505
• Rienzi L, Romano S, Albricci L, et al. Embryo development of fresh 'versus' vitrified metaphase II oocytes after ICSI: a prospective randomized sibling-oocyte study. Hum Reprod 2010; 25:66.
• Scaravelli G, Vigiliano V, Mayorga JM, et al. Analysis of oocyte cryopreservation in assisted reproduction: the Italian National Register data from 2005 to 2007. Reprod Biomed Online 2010; 21:496
• Srikanthan et al. Mol Clin Oncol. 2018 Jan;8(1):153-158
• Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat OncolBiol Phys 2005; 62:738.
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