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ONCOFERTILITY BEST PRACTICES:
OPTIMIZING REPRODUCTIVE OUTCOMES IN CANCER
Leslie Coker Appiah MDAssociate ProfessorChief, Division of Obstetrics and GynecologyDirector, Fertility Preservation and Reproductive Late Effects ProgramThe University of Colorado Denver | Anschutz Medical CampusChildren’s Hospital Colorado
Vail, ColoradoFebruary 16, 2020
Objectives
• Explain the effects of cancer treatments on fertility and limits of risk stratification.
• Discuss standard and novel fertility preservation therapies for patients with cancer.
• Identify and manage reproductive late effects in survivorship.
Hum Reprod. 2018 Jul 1;33(7):1281-1290.
• Young adult survivors ages 18 – 39 years 38% less likely to conceive compared to controls
• Chance of achieving pregnancy greater than 5 years after diagnosis HR 0.57
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How is Risk Quantified?
Estimating Risk
Green et al. Pediatr Blood Cancer. 2014;61:53‐67
Subfertility/Infertility RiskHigh risk > 80%
Conditioning for BMT
Hodgkin: w/ alkylators
Soft‐tissue sarcoma: metastatic
Ewing sarcoma
Localized pelvic radiation
Total body irradiation
Medium Risk 30 – 70 %AML
Breast
Osteosarcoma
Soft‐tissue sarcoma: stage II/III
Non‐Hodgkin lymphoma
Hodgkin: alternating alkylators
Craniospinal radiation > 24Gy
Low Risk < 20%ALL
Wilms tumor
Soft‐tissue sarcoma: stage I
Retinoblastoma
Germ‐cell tumors (fertility sparing)
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Gonadotoxicity of Newer Agents
•Oxaliplatin
• Irinotecan
•Bevacizumab – 30% rate of primary ovarian insufficiency
•Cetuximab
• Trastuzumab
• Erlotinib
• Imatinib
Loren et al. J Clin Oncol 2013;31:2500-2510
ALA4
• American Society of Clinical Oncology (ASCO) 2006, 2013
• American Society for Reproductive Medicine (ASRM) 2010
• Association of Pediatric Hematology/Oncology Nurses (APHON)
– “Physicians should inform cancer patients about options for fertility preservation and future reproduction prior to treatment…”
– “…regardless of the patient’s age, gender, culture, socioeconomic status, or healthcare team bias…”
– “…and continue throughout treatment and survivorship in a manner appropriate to the patient’s developmental stage at that time.”
Statements supported by American College of Obstetricians and Gynecologists (ACOG) and
American Academy of Pediatrics (AAP).
Expert Consensus Position Statements
GapLess than 30% receive fertility
preservation therapies
Gwede CK et al. Pract Radiat Oncol. 2012;2:242‐247. Quinn GP et al. J Clin Oncol. 2009; 27:5952–5957
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Slide 7
ALA4 Diane, I want to find a more descriptive slide on these newer agents regarding what we know about toxicity.Appiah, Leslie A, 3/18/2018
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Which Fertility Preservation Options are Available?
Fertility Preservation MethodsStandard Methods Success rates Partner Considerations
Mature oocyte cryopreservation
35 ‐ 50% No 10 – 14 days stimulation; surgical procedure; no ovarian function preserved; stimulation may occur at any phase of the cycle
Sperm cryopreservation 57% No At least two samples recommended prior to exposure
Embryo cryopreservation
60‐70% Yes or donor
10 – 14 days stimulation; surgical procedure; no preservation of ovarian function; embryo ownership concerns
Ovarian transposition 60‐90% N/A Underutilized
Ovarian shielding 75‐80% N/A Scatter effect; consider concomitant chemotherapy
Fertility Preservation Methods
Investigational Methods Partner Considerations
Immature oocyte cryopreservation
No No stimulation; surgical procedure; costs; no ovarian function preserved
Ovarian tissue freezing ‐ no longer investigational
No Surgical procedure; costs; transplantation not suitable with high gonadal involvement or hormone sensitive tumor; preservation of gonadal function
Testicular tissue freezing No Similar to OTC
GnRHa ovarian suppression No Conflicting data; recent Cochrane study clearer evidence
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Ovarian Tissue Cryopreservation
Matthews SJ et al. Minerva Ginecol. 2018; 70(4):432–435Poirot C. et al Lancet 2012;379:588
Ernst E et al. Eur J Cancer 2013;49:911–4
Donnez et al. NEJM; 2017;377(17):1657-1665 Shenfield et al. Hum Reprod Open. 2017 Jensen et al. J Assist Reprod Genet (2017) 34: 325 Gellert et al. J Assist Reprod Genet. 2018
• 130 children born worldwide
• 4700+ cryopreserved tissues with 360 transplantations
• Age range pre-pubertal* to mid 30’s
• 29 - 32% delivery rate with half of singletons conceived naturally
• Recommend no longer consider experimental for post-pubertal patients
• Hormone function up to 10 years
Donnez J et al. Hum. Reprod. Update 2006;12:519‐535
OTC and Orthotopic Transplantation
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In Vitro Growth of Primordial Follicles
Methodologies to Optimize the Potential of Cryopreserved Tissue
AMH
VEGFS1P
Anti-oxidants
Stem Cells
Additives
Telfer and Zelinski. Fertil Steril. 2013 May;99(6):1523-33
Artificial Ovary
Salama and Woodruff 2019. Takae and Suzuki.. 2019
In Vitro Maturation
•21 yo s/p interval bilateral oophorectomy for ovarian carcinomas
•OTC at second surgery followed by aspiration of all visible follicles
• ICSI followed by 2 embryo transfer and delivery of healthy
infant
•20‐35% live birth rate after IVM of growing folliclesPrasath et al. 2014 Hum Reprod
•Potentially higher gonadotropin doses in early puberty
• Transabdominal monitoring with sedated transvaginal retrieval
• Efficiency in adolescents needs to be confirmed Cil and Oktay
•28.1% live‐birth at age 25 for 2 oocytes thawed after vitrification
•Probability increased to 31.3% with 6 oocytesReichman et al. Fertil Steril 2012;98:1225–8. 2012 Cil and Oktay et al. Fertil Steril 2013;100:492-9
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Fertility Preservation Methods
Investigational Methods Partner Considerations
Immature oocyte cryopreservation
No No stimulation; surgical procedure; costs; no ovarian function preserved
Ovarian tissue freezing N/A Surgical procedure; costs; transplantation not suitable with high gonadal involvement; preservation of gonadal function
Testicular tissue freezing No Similar to OTC
GnRHa ovarian suppression N/A Conflicting data; recent Cochrane study supports use
GnRHa and Ovarian Protection
Hickman, Falcone et al. J Reprod Gen. 2017
Cochrane Review 2019
GnRHa Control Relative Effect p value Level of Evidence
Menstruationrecovery
12 months
178 of 239(74.5%)
110 of 221(50%)
RR 1.60(1.14 to 2.24)
0.006 Low - certainty
> 12 months
326 of 447(72.9%)
276 of 422(65.4%)
RR 1.08(0.05 to 1.2)
0.24 Low - certainty
Premature ovarian failure
43 of 401(10.7%)
96 of 379(25.3%)
RR 0.44(0.31 to 0.61)
< 0.00001 Moderate
Ovulation 29 of 47(61.7%)
12 of 28 (25%)
RR 2.47(1.43 to 4.26)
0.001 Low-certainty
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Cochrane Review 2019
“GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, treatment‐related premature ovarian failure and ovulation. Evidence for protection of fertility was insufficient and
needs further investigation.”
GnRHa Control Relative Effect p value Level of Evidence
Pregnancy 32 of 356(9%)
22 of 347(6.3%)
RR 1.49 (0.93 to 2.7)
0.09 Low-certainty
How to Screen for Reproductive Late Effects?
Cancer Care Paradigm Shift
Quality of Life• Screening• Prevention• Treatment
Survival• Clinical trials• Aggressive
therapy
Eradicate• Targeted therapy• Gene therapy
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Decreased libidoDiminished self esteem
Dyspareunia/Lost intimacy
Decreased libidoDiminished self esteem
Dyspareunia/Lost intimacy
Vaginal stenosisHematocolposVaginal stenosisHematocolpos
Diminished uterine volumeFetal loss
Low birthweightVaginal stenosis
Diminished uterine volumeFetal loss
Low birthweightVaginal stenosis
HypoestrogenismVasomotor/GSM/bone lossDelayed pubertyInfertility
HypoestrogenismVasomotor/GSM/bone lossDelayed pubertyInfertility
Hormonal Insufficiency
Uterine and Vaginal
Radiation Injury
Genital Graft Versus Host
Disease
Sexual Dysfunction
Reproductive Late Effects
• Growth span from primordial to pre-ovulatory follicle: 6 months
• Risk of mutagenesis maximal during this maturation phase
• Recommendation: delay conception for 6 months after completion of treatment
Gougeon et al., Endocr Rev. 1996 Apr;17(2):121-55Meirow et al., J Natl Cancer Inst Monogr. 2005;34:21–5Chung et al., Fertil Steril 2013;99:1534-42Mahajan. J Human Reprod Sci. 2015 Jan-Mar; 8(1): 3–13
Monitoring Ovarian Reserve
• AMH not yet considered standard of care for ovarian monitoring
Guzy and Demeestere. Minerva Gineocologica 2017 Feb;69(1):57‐67
Baseline AMH and FSH
Post‐treatment AMH and FSH*
AMH nl reference range for age
FSH < 10 mIU/ml
Continue yearly monitoring**
AMH < reference range
FSH ≥ 10 mIU/ml
Refer to REI
Image created from text by Appiah, L.
* Perform one year post-treatment completion** Consider every six months depending on the value
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Epidemiology. March 2000, Vol. 11 No. 2
Female Genital Tract Graft‐Versus‐Host‐ Disease
Stratton et al., 2017; Majhail 2012
GVHD Genital Atrophy
Redness of vulva
Pale pinkvaginal walls
Erosions, sores, fissures
Vaginal tissue bleeds easily withcontact
Tenderness of vulvarglands
Labia thinner,sometimes fuseScarringFunke VAM. Rev. Assoc. Med. Bra. 2016; 62 (suppl. 1):44-50
Treatment Strength
1. Reduce mechanical or chemical irritation Avoid perfumed emollients and soaps
AIIIb
2. Topical class IV corticosteroids to rapidly control inflammation Clobetasol proprionate qhs x 4 weeks
BIb
3. Topical calcineurin inhibitors for long-term treatment Tacrolimus or pimecrolimus
CIb
4. Topical estrogen as supportive therapy to increase epithelial thickness and improve resilience
BIb
5. Regular intercourse or use of dilators to prevent narrowing and stenosis CIIIa
6. Manual lysis of adhesions under anesthesia if refractory to therapy CIIIa
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Hormone Replacement Therapy:Estrogen Effects on Physiology
Estrogen Oral Transdermal
Bioavailability Lower Higher
First pass through liver + --
Estrogen delivery to tissues
High to liver Similar in all tissues
Dosing Supra-physiologic Physiologic
Mimics normal physiology -- +
Hepatic protein alterations + --
Risk of VTE Higher Lower
Increased TG + --
Increased HDL/LDL ratio + --
Uterine growth + +++
IGF-1 Decreases No effect
Lobo, R. Obstetrics and Gynecology Clinics of North America 1987; 14,1:143-167
Transdermal 17b-estradiol no increased VTE risk (OR 0.9)Canonico M et al. Circulation. 2007 Feb 20;115(7):840-5
WHI findings cannot be extrapolated to pediatric and adult population less than age 60 years
Kmietowicz et al. BMJ 2019;364:l157Liliberte F et al. Menopause. 2011;18(10):1052–9
GUSM: Non‐Estrogen Therapies
•Hyaluronic acid – biopolymer that releases water molecules
•Compared to estrogen ‐ 84% and 89% response respectively
•DHEA 6.5 mg vaginal suppository x 12 weeks for dyspareunia
•Ospemifine (SERM): (FDA) menopause related dyspareunia
•CO2 laser – need comparison studies and long‐term safety data
• Intravaginal oxytocin 400 IU qhs x 7 weeks; inhibits cancer cells
Chen 2013; NAMS 2013; Markowska 2011; Al‐Saqi 2015; Goetsch 2015
• Adolescent survivors engage in risky health behaviors at rates generally equivalent to their siblings Klosky et al. J Pediatr Psychol. 2012 Jul;37(6):634-46
• 77% of adult survivors of childhood cancer reported sexual dysfunction irrespective of gender or age Frederick et al. Pediatr Blood Cancer 2016;63:1622–1628
Existing paradigm Emerging paradigm
Sexual Dysfunction
Coady 2016; Masters et al., 1996; Basson 2000
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Practice Pearls
•Acute ovarian and testicular gamete failure 12% and 66%
•Pregnancy rates decreased to 38% for young adults
•OTC is clinical care and combined with IVM when feasible
•Ovarian stimulation may be offered in post‐pubertal adolescents
•Evaluation of reproductive late effects is more than just fertility
•Contraception and sexual function management vitally important
Future Directions
• Identify targeted agents that minimize gonadal injury
• Improve risk stratification to better identify candidates for fertility preservation pre‐treatment
• Standardize assessment and management of reproductive late effects in survivorship
• Optimize ovarian tissue transplantation procedures
Patient Experiences“75% of cancer survivors without children stated they wanted to have
children in the future. “
Moffat et al. Arch Gynecol Obstet. 2012;286(6):1521‐1527.Letourneau. Cancer. 2012;118(6):1710‐1717.Partridge et al. Clin Breast Cancer. 2008;8(1):65‐69Chandra et al. Fertil Steril.2010;93(3):725‐736
“Patients experience less regret and have improved quality of life when counseled about fertility preservation options even if no option is
pursued.”
“Women counseled about their risk of infertility by an oncologist and a fertility specialist had significantly less regret about their decision to preserve fertility that those counseled only by an oncology team.”
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,
Fertility Preservation and Reproductive Late Effects Conference
Save the Date!
Friday May 21st and Saturday May 22nd, 2021
Denver, Colorado, USA
Chair: Leslie Coker Appiah, MD and Co-chair Anna Franklin, MD
University of Colorado Cancer Center Children’s Hospital Colorado
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