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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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