Fertility Preservation in Adults with Cancer Agenda Background information The effects of cancer treatments on fertility Fertility preservation options Referral and patient experience Study conducted to explore attitudes, knowledge & referring behaviors in Oncofertility among Ontario physicians providing adult cancer care Survey sent to 641 physicians in Ontario (medical oncologists, radiation oncologists, gynecologic oncologists & urologists) 152 physicians returned the survey - response rate of 23.7% Results: 1. Majority of oncologists had positive attitudes but many did not have current knowledge of cryopreservation 2. Great majority did not have educational materials or patient resources to facilitate discussion 3. ~25% did not know where to refer male cancer patients for sperm banking; almost 50% rarely made a referral 4. ~ 45% did not know where to refer female cancer patients for fertility preservation consultation; 70% rarely made a referral Results: • Study conducted to survey sperm banking facilities and fertility clinics of the provision of Oncofertility services (commissioned by Canadian National Task Force on Adolescent and Young Adult Cancer) • Response rates: • 59% (46/78) for oncology sperm banking services • 59% (45/76) for female fertility preservation services Results: Results: • Volume of oncofertility referrals was very low: i. For oncology sperm banking, only two responding facilities had high referral volume (14-18/month); remaining received 1-6 referrals or rarely received any ii. For female pre-cancer treatment fertility consultation, only two responding facilities had high monthly referral volume (approx. 15); the remaining received 1-7 referrals or rarely received any Fertility Preservation The detrimental impact of cancer on fertility can be severe Having a history of cancer does not necessarily reduce the desire to be a parent Cancer survivorship rates are high and fertility as an indicator of quality of life should not be overlooked (Holzer, 2013; Schover et al., 1999; Yee et al., 2012) Fertility Preservation Diagnosis of cancer Treatment plan Assess fertility risk based on treatment plan R I S K Yes Offer Fertility Preservation Referral Inform of Risk (Adapted from Fertile Hope, 2008) Document Discussion R I S K R I S K ? No Chemotherapy Germinal epithelial cell damage Depletion of spermatogonia Leydig cell impairment Testicular dysfunction Testicular failure (Adapted from Howell & Shalet, 2001 ; Jahnukainen et al., 2011) Chemotherapy Germinal epithelium of the testicle occlusive junctions mature spermatid spermatid spermatocyte 2nd order spermatocyte 1st order spermatogonia basal lamina Sertoli cells (Wikimedia Commons, 2006) Chemotherapy (Meistrich, 2009) Chemotherapy Destruction of growing follicles Loss of primordial follicles Loss of ovarian reserve Ovarian atrophy Ovarian failure (Adapted from Holzer, 2013) The human ovary, and potential targets of chemotherapeutic agents (Morgan et al., 2012) © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected] Table 4: Chemotherapy agents with high, intermediate and low gonadotoxic impact in females and males Prolonged azoospermia in males or amenorrhea in females High risk • Cyclophosphamide • Ifosphamide • Melphalan • Busulfan • Nitrogen mustard • Procarbazine • Chlorambucil Intermediate risk • Cisplastin with low cumulative dose • Carboplatin with low cumulative dose • Adriamycin (Rodriguez-Wallberg & Oktay, 2014) Low risk • Treatment protocols for treatment protocols without alkylating agents • Bleomycin • Actinomycin D • Vincristine • Methotrexate • 5-Fluorouracil (5FU) NB: FDA warning - Bevacizumab is associated with ovarian failure Radiotherapy Direct damage to testicles Dose dependent; total dose and fractionation schedule (Adapted from Holzer, 2013) Damage to hypothalamicpituitary axis Age dependent Radiation field dependent Radiotherapy Direct damage to ovaries Dose dependent; total dose and fractionation schedule Damage to hypothalamicpituitary axis Age dependent; size of primordial follicle pool (Adapted from Ogilvy-Stuart & Shalet, 1993; Holzer, 2013) Radiation field dependent Radiotherapy Could also affect uterine function: Impaired blood flow (Adapted from Green et al., 2002; Holzer, 2013) Endometrial damage Small uterine volume Miscarriage, low birth weight, premature delivery (Wallace, 2011) (* 100 × Gy = cGy) * (* 100 × Gy = cGy) (Fertile Hope, 2008) * (* 100 × Gy = cGy) (Fertile Hope, 2008) * (* 100 × Gy = cGy) (Fertile Hope, 2008) * (Fertile Hope, 2008) (* 100 × Gy = cGy) (Fertile Hope, 2008) * *NB: FDA warning - Bevacizumab is associated with ovarian failure (Fertile Hope, 2008) (Retrieved from http://oncofertility.northwestern.edu/assessing-ovarian-reserve-after-cancer-treatments) Determining Risk • Pretreatment fertility potential • Proposed treatment (Ronn & Holzer, 2013) Males & Females “The impact of cancer on fertility The quantitative impact of any given cancer on a young patient’s fertility may be difficult to define, but detrimental effects have consistently been demonstrated”. Recovery Men: Some degree of spermatogenesis may recover postchemo/ radiation but this may take up to 5–10 years Often advised to wait 1 to 3 years post-treatment for semen analysis Women: Amenorrhoea may last 6-12 months or more postchemo/ radiation Often advised to wait at least that long for ovarian function assessment (Howell & Shalet, 2001) Pregnancy after Cancer When? Most patients are advised to wait 2 years and this is related to recurrence risk and possible risk of genetic damage to sperm or eggs Recurrence risk: Pregnancy itself it not known to cause or increase the risk of recurrence, even after breast cancer Pregnancy and ovarian failure: Women who have experienced iatrogenic ovarian failure can still carry a pregnancy (Green et al., 2002; Meistrich & Byrne, 2002) Pregnancy after Cancer Obstetrical risks: Pregnancy will be higher risk if pelvis radiated or posttrachelectomy Risk to offspring: Birth defect rates or genetic diseases no higher in children born to survivors No increased cancer risk in offspring of survivors unless heritable caner (Meistrich & Byrne, 2002) Fertility Preservation Options should be tailored to: Patient’s age Type of disease Spread of the disease Planned treatment Time available Single or partnered (Adapted from Holzer, 2013) Fertility Preservation Gonadal protection: Shielding Ovarian transposition prior to local radiotherapy: Reduces dose to 5-15% Patients <40 Laparoscopy Location depends on the planned radiation Does not protect against chemotherapy (Holzer, 2013; Stroud et al., 2009; Wallace et al., 2005; Wo & Viswanathan, 2009) Fertility Preservation Suppression with GnRHa: Hormonal therapy for testicular suppression not successful in preserving fertility and therefore not recommended Ovarian suppression is possibly helpful but there is insufficient evidence to recommend (Bedaiwy et al., 2011; Holzer, 2013) Fertility Preservation Cryopreservation: Testicular and ovarian tissue Cryopreservation and reimplantation or grafting of human testicular or ovarian tissue is recommended to be performed only as part of clinical trials or approved experimental protocols Surgical Only (Loren et al.,2013) option for prepubescents Fertility Preservation Cryopreservation: Sperm banking Most established technique for fertility preservation in men Obtained through masturbated sample May also be obtained through extraction procedures Ideally performed prior to cancer treatment but as long as there is sperm, can be done any time Number of visits required varies (Loren et al.,2013) (Retrieved from savemyfertility.org) Fertility Preservation Cryopreservation: Oocyte banking Option if not partnered, ethical concerns re: embryo banking No longer experimental, PR dependent on age, approx 6-7% per egg Ovarian stimulation required Ovarian stimulation associated with high E2 aromatase inhibitor 2-6 weeks required (Loren et al.,2013); Oktay, Cil & Bang, 2006; Oktay et al., 2006) Fertility Preservation Cryopreservation: Embryo banking Option if partnered Ovarian stimulation required stimulation associated with high E2 aromatase inhibitor Ovarian 2-6 weeks required (Loren et al.,2013; Oktay et al., 2006) In Vitro Fertilization (IVF) Cryobiology Cryobiology • Removal of water • Additions of Cryoprotectants (PROH, glycerol, DMSO) • Slow cooling vs. Vitrification • Storage periods of more than 40 years (J Assist Repro Genet Sept 2013) for sperm and 11 years for embryos prior to pregnancies established have been documented, but these records will be broken. • Cost to freeze = $250 – 750 • Annual Storage = $200 - 600 AssistedConception Conception Options Assisted Options Embyro Adoption Donor Sperm Donor Oocytes No Oocytes No Sperm After Biopsy No Banked Sperm Sperm Recovered Testicular Biopsy Azospermic Pre-treatment Cryopreserved Sperm Frozen Oocytes (Frozen Pre-treatment) ART IUI, IVF, ICSI IVM, FET Abnormal Sperm Parameters Frozen Embryos (Created Pre-treatment) Normal Ovarian Function Spermic Normal Sperm Function No Ovarian Function No conception (12 mths) Spontaneous Conception Female Cancer Survivor Male Cancer Survivor Ovarian Tissue Transplant Age Related Fertility Rates (In: Heffner, 2004) IVF Success Rates IVF/ICSI Cycles 40 Pregnancy Live birth % per cycle started 35 30 25 20 15 10 5 0 <35 6444 35-37 3530 38-40 3546 41-42 1844 43-44 623 >44 75 CARTR 2012 Barriers Safety concerns Hormones used for ovarian hyperstimulation Treatment delay Ethical concerns Treatment of minors; experimental Logistical issues Lack of access to appropriate fertility centres Financial issues Disease often strains patient / family finances Fertility preservation is very expensive (Oncofertility in Ontario: A Presentation to Cancer Care Ontario, October 2013 Initial contact secretary Information Schedule Appointment at the Centre for Fertility and Reproductive Health Consultation (NP/ Fellow /MD) TV Ultrasound (AFC, cycle stage) Consultation review of all options, tailored options C O U N S E L L I N G GnRHa Do nothing 3rd party Oocyte Embryo Nursing consultation prn Discuss and teach planned treatment Treatment Oocyte CP Embryo CP GnRH-a Follow up 2nd collection Luteal collection US (AFC) (Adapted from Holzer, 2013) Additional cycle Long term follow up FSH AMH Consultation Counselling T R E A T I N G P H Y S I C I A N Fertility Preservation Costs Time Frame Immediate Procedure Sperm banking - subsequent samples $150 Surgical Sperm recovery – cost set by Urology and Average Cost ($) 300.00 1600.00 subject to change Future Annual Sperm Storage 240.00 Sperm prep - Intra-uterine Insemination (IUI) 300.00 COH medications for in vitro fertilization (IVF) 3000.00 Monitoring; egg retrieval; lab procedures for IVF 7000.00 Intracytoplasmic sperm injection (ICSI) 1500.00 Fertility Preservation Costs Time Frame Immediate Procedure Average Cost ($) Controlled ovarian Stimulation (COH) meds 3000.00 Oocyte pick up (OPU) procedure and egg freezing 4800.00 Oocyte pick up (OPU) procedure and embryo freezing - includes intracytoplasmic sperm injection (ICSI) and first 5700.00 year of storage Annual Egg / Embyro Storage Future 360.00 Monitoring; egg / embryo thaw and transfer 1500.00 Intracytoplasmic sperm injection (ICSI) 1500.00 Embryo Freezing 650.00 Annual Embryo Storage 360.00 Power of Hope Requirements Income Female Male <$100,000/year (single) <$50,000/year (single) <$125,000/year (married/Common Law) <$75,000/year (married/common law) Age 40 years old and younger Treatment Ca tx presents risk to fertility and has not begun prior to completion of fertility treatment* Identification Valid Ontario Health Card (Canadian Citizen/Permanent Resident) Reimbursement 1 time offer, must apply within 1 year of fertility preservation procedure Fertility Clinic Power of Hope program member *Requirements are taken into consideration upon contacting the Power of Hope Coordinator at Fertile Future. www.fertilefuture.ca Wish List 1) Better education of oncology health care providers re: importance of fertility discussion with all individuals of childbearing age 2) Universal access for young patients with cancer to fertility preservation 3) Funding of fertility preservation by MOHLTC (analogous to, for example, post-mastectomy reconstruction) (Oncofertility in Ontario: A Presentation to Cancer Care Ontario, October 2013 Resources American Society of Clinical Oncology: clinical tools and resources - http://www.asco.org/quality-guidelines/fertility-preservationpatients-cancer-american-society-clinical-oncology Canadian Fertility & Andrology Society: Clinical Practice Guideline - Fertility Preservation In Reproductive Age Woman Facing Gonadotoxic Treatments Cancer Knowledge network - cancerkn.com Fertile Future: information and support for cancer patients and oncology professionals - www.fertilefuture.ca Fertile Hope: fertilehope.org risk Network: calculator, information, print referral materials - Take Home Messages • Cancer survivorship rates are high • Cancer and its treatment can lead to infertility or sterility • Fertility is an important aspect of quality of life for many people • Resources for patients do exist and should be utilized Questions/Comments? 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