infertility risk reduction in female oncology patients … risk... · infertility risk reduction in...

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


• 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)


• 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


• Cryopreservation

• Protecting native ovarian function

• Alternatives

• Safety Concerns

• Practical Information (i.e. cost, contact info)




• 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




• Alternatives

• Safety Concerns


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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



• Alternatives

• Safety Concerns


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




• 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



• 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


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)




• Alternatives

• Safety Concerns


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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


• 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


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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http://fertilefuture.ca/patients/power-of-hope/

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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