e-learning module fertility preservation in girls and women with cancer … · 2017-03-07 ·...

Cancer in Adolescents and Young Adults (AYA)Working Group

FERTILITY PRESERVATION IN GIRLS AND WOMEN WITH CANCER

Richard A Anderson

Elsie Inglis Professor of Clinical Reproductive ScienceUniversity of Edinburgh

Cancer in Adolescents and Young Adults (AYA) Working Group

LEARNING OBJECTIVES

Effects of cancer treatment on female fertility

Options for fertility preservation in girls and women


Early Breast Cancer Trialists' Collaborative Group. Lancet 2005;365:1687-1717

Polychemotherapy reduces the annual breast cancer death rate by about 38%

IMPROVING SURVIVAL


5 YEAR UK SURVIVORS BY CURRENT AGE

Long-term survival rate from childhood cancer is 80%1 in 700 adults is a childhood cancer survivor

Skinner R, et al. Lancet Oncology 2006;7:489-498


CHEMOTHERAPY: IMMEDIATE AND LATE EFFECTS ON THE OVARY

Depletion of growing folliclesHimelstein-Braw R, Peters H and Faber M (1978)Morphological study of the ovaries of leukaemic children.Br J Cancer 38, 82-87

Premature ovarian insufficiency (POI)Chapman RM, Sutcliffe SB and Malpas JS (1979)Cytotoxic-induced ovarian failure in women with Hodgkin's disease. I. Hormone function. JAMA 242, 1877-1881


PRIMORDIAL FOLLICLES: THE GUARDIANS OF FEMALE FERTILITY AND FEMININITY

Human ovary, 17 weeks


ACUTE OVARIAN FAILURE AFTER CHEMOTHERAPY

Letourneau JM, et al. Cancer 2012;118:1710-1717


Prop

ortio

n of

wom

en

INFERTILITY DESPITE MENSES RESUMING AFTER CHEMOTHERAPY

Letourneau JM, et al. Cancer 2012;118:1710-1717


RISK OF INFERTILITY BY DISEASE/TREATMENT

Low (<20%) Medium High (>80%)Acute lymphoblastic leukaemia Acute myeloid leukaemia Total Body Irradiation

Wilms’ tumour Osteosarcoma Pelvic/testes RTEwing’s sarcoma Chemo pre BMT

Soft tissue sarcoma (stage1) STS: stage II/III Metastatic Ewing’sBrain tumour

(Surgery, RT <24Gy)Neuroblastoma

Hodgkin Lymphoma(low stage)

Hodgkin Lymphoma (high stage) Hodgkin Lymphoma (pelvic RT)

Non-Hodgkin Lymphoma

( g y y)Hodgkin Lymphoma

(low stage) Hodgkin Lymphoma (high stage) Hodgkin Lymphoma (pelvic RT)

Anderson R, et al. Fertil Steril 2013;99:1469-1475


HAZARD RATIO FOR MENOPAUSE <40 YEARS IN TREATMENT OF HODGKIN LYMPHOMA

0 5 10 15 20 25 30 35 40

No alkylating, no pelvic RT

Pelvic RT

Alkylating, no pelvic RT

Alkylating, pelvic RT

ABVD

ABVD with pelvic RT

All adjusted for age, overall n=2127Swerdlow AJ, et al. J Natl Cancer Inst 2014;106(9):dju207


PARENTHOOD IN FEMALE SURVIVORS OF CHILDHOOD HODGKIN LYMPHOMA

Brämswig JH, et al. Lancet Oncol 2015;16:557-675


TREATMENT-RELATED ASPECTS

Brämswig JH, et al. Lancet Oncol 2015;16:557-675

Non significant / minor effects of:• Procarbazine (to 11 400 mg/m2)• Cyclophosphamide (to 6000 mg/m2)• Alkylating agent dose scores

of 1–5• Treatment protocol• Abdominal/supradiaphragmatic

radiation• Age at treatment

Radiotherapy location


OVARIAN FAILURE AND RADIATION TO THE OVARY

Chemaitilly W, et al. J Clin Endocrinol Metab 2006;91:1723-1728


STERILISING RADIATION DOSE (50% RISK) AND AGE

Anderson RA, et al. Lancet Diabetes and Endocrinol 2015;3:556-567


THE UTERUS


ADVERSE EFFECT OF RADIOTHERAPY TO UTERUS

0

10

20

30

40

50

60

TBI Cyclophos Expected

6/16

4/56

0

20

40

60

80

TBI Cyclophos Expected

5/8

8/44

Perc

ent

Miscarriage Premature delivery

Sanders JE, et al. Blood 1996;87:3045-3052


HOW TO DETECT UTERINE DAMAGE?


Consider:• Diagnosis / treatment plan• Expected outcome of fertility treatment• Prognosis of the cancer treatment

NICE, 2013


Offer to all‘Insurance policy’

Offer to those with clear need

WHO GETS FERTILITY PRESERVATION?

Issues of costs, equality of access, informed decision making at a time of extreme stress etc.


RISK ASSESSMENT FOR FERTILITY PRESERVATION

Intrinsic factorsHealth status of patientConsent (patient/parent)AgeAssessment of ovarian reserve

Extrinsic factorsNature of predicted treatment

(high/medium/low/uncertain risk)Expertise/funding available

Wallace WH, et al. J Clin Oncol 2012;30:3-5


CHEMOTHERAPY-RELATED AMENORRHOEA: BREAST CANCER

Petrek JA, et al. J Clin Oncol 2006;24:1045-1051


PREMATURE LOSS OF OVARIAN FUNCTION:INFERTILITY AND POI

Can we individualise based on ovarian reserve?

Wallace WH, et al. PLoS One 2010;5:e8772


AMH REFLECTS THE NUMBER OF SMALL GROWING FOLLICLES

Inhibin B, estradiolAMH

Anderson RA, Clin Endocrinol 2012;77:652-655


THE AMH NORMAL RANGE FROM BIRTH TO MENOPAUSE

0 10 403020 50

AMHng/ml

Key featuresDetectable in girls of all agesRise through childhoodPeak at 24 yearsDecline to menopause

Kelsey TW, et al. PLoS One 2011;6:e22024


REDUCED OVARIAN RESERVE IN CHILDHOOD CANCER SURVIVORS WITH REGULAR CYCLES

ControlsCancer survivors

Inhibin B

0

100

200pg/ml

FSH

0

4

8

12IU/L

E2

0

100

200pmol/L pmol/L

AMH

0

10

20

30

*

Bath LE, et al. Human Reprod 2003;18:2368-2374


AMH DIFFERENTIATES HIGH AND LOW RISK CHEMOTHERAPY

N=26, HL and NHL

Months after chemo

Decanter C, et al. RBM Online 2010;20:280-285


60 women recruited

59 women included

1 woman excluded: ineligible

55 women at 1 year

46 women at 2 years

4 women withdrew before 1 year:

disease recurrence (n=1)oophorectomy (1)choice (2)

9 woman withdrew before 2 years:

disease recurrence (2) hyst/oophorectomy (3)choice (4)

Chemotherapy (table 1)

Endocrine therapyTamoxifen (44)

Tamoxifen +Goserelin (6)Tamoxifen+anastrozole (1)

Goserelin (1)

Breast cancer prospective cohorts

Prediction of post chemo ovarian function

Analyse ovarian activity here

In relation to predictive markers here

Anderson R, et al. Eur J Cancer 2013;49:3404-3411


CLINICAL APPLICATION:PREDICTIVE MOSAIC CHART IN EBC

Sensitivity 98.2% specificity 80.0% for correct classification of amenorrhoea

n=75

Anderson R, et al. Eur J Cancer 2013;49:3404-3411


PREDICTION OF LONG-TERM OVARIAN FUNCTION: PRETREATMENT ASSESSMENT

*

Inhibin B

0

20

40

60

80

100

CRA Menses

AMH

0.0

1.0

2.0

3.0

4.0

CRA Menses

E2

0

100

200

300

CRA Menses

FSH

0

5

10

15

CRA Menses

*At diagnosis of early breast cancer AMH is higher in those women who will still be having menses 5 years later

Anderson R, et al. JCE&M 2011;96:1336-1343


AMH AND PREDICTION OF MENOPAUSE

257 ovulatory women, 21-46yrReassessed after 11 years (19% menopausal)

AMH at baseline Menopause by AMH centileLow age specific AMH

Shift towards younger age at menopause

High age specific AMH

Shift towards higher age at menopause

a

Broer SL, et al. JCE&M 2011;96:2532-2539


AMH IN 3 GIRLS WITH CANCER

0 50 100 150 2000.0

1.0

2.0

3.0

Age 2.4; rhabdomyosarcoma

0 50 100 1500.0

0.5

1.0

1.5

2.0

Weeks

Age 14.6: Hodgkin’s lymphoma

Can this predict their reproductive lifespan?

0 25 50 750.0

0.2

0.4

0.6

0.8

1.0

Weeks

AMH

(ng/

ml)

Age 1.2; neuroblastomaTreatment

Brougham MFH, et al. JCE&M 2012;97:2059-2067


AMH: APPLICATION IN CHILDHOOD CANCER

PreCyc

le 1

Cycle

2Cyc

le 3

Cycle

4Cyc

le 5

Cycle

6

0.0

0.5

1.0

1.5

2.0

2.5

**** *** ***

AMH

(ng/

ml)

Pre End Recovery0

1

2

3

* **AM

H (n

g/m

l)

High riskPre End Recovery

0

1

2

3 **

AMH

(ng/

ml)

Medium/low risk

22 girls age 0.3-15 yr17 prepubertal

Brougham MFH, et al. JCE&M 2012;97:2059-2067


FERTILITY RISK ASSESSMENT(Includes Intrinsic and Extrinsic factors)

Pre-pubertal

Testisbiopsy

Pubertal

Able to produce a suitablesemen sample

Post-pubertal

Testis TissueCryopreservation

Experimental Established

SpermCryopreservation

Ovarian TissueCryopreservation

EmbryoCryo

Pre-pubertal

FEMALEMALE

PatientAssessment

Intervention

Storage

NO

Testis biopsy/Gamete extraction

YES

Post-pubertal

Ovarianstimulation

Partner/Donorsperm

OocyteCryo

Ovarian biopsy

Anderson RA, et al. Lancet Diabetes Endocrinol 2015;3:556-567


COMPARISON OF FRESH AND VITRIFIED OOCYTES

Perc

ent

Survival: 96.7%Implantation: 40.8%

Cobo A, et al. Fertil Steril 2008;89:1657-1664


EMBRYO CRYOPRESERVATIONestablished optionBut….


HOW DO CANCER PATIENTS RESPOND IN IVF CYCLES?

Cancer (n=227) Controls (n=1258) PNo of mature oocytes 9.0±6.5 10.8±6.7 0.003Fertilisation 7.98±5.2% 8.08±5.1% nsPoor responders 7.8% 5.9% ns

Meta-analysis of 7 studies

Friedler S, at al. Fertil Steril 2012;97:125-133


REDUCED AMH IN LYMPHOMA

Controls, n=38 Hodgkin lymphoma, n=31 Non-Hodgkin lymphoma, n=7

0

1

2

3

4

Controls HL and NHL

*

Age

Lawrenz B, et al. Fertil Steril 2012;98;141-144


WHAT STIMULATION REGIMEN TO USE?Time and safety

Urgency of starting: when in cycle?Short protocol needed

Minimise risk of ovarian hyperstimulation (OHSS)Avoid high oestrogen exposure in breast cancer?


NON-CONVENTIONAL OPTIONS

Conventional(n = 87; 101 cycles)

Random start(n = 24; 24 cycles) P

Age (y) 33.9 ± 5.2 34.6 ± 5.0 NSAFC 13 (9-19) 11.5 (6-16) NSDays of stimulation 9 (8-10) 11 (10-12) <.0

01

FSH dose (IU) 3,386 ± 1,085 4,201 ± 1,147 0.001

Mature oocytes 11 (6-16) 9 (5-14.5) NSMature oocyte/AFC ratio

0.8 (0.5-1.1) 0.8 (0.6-1.2) NS

Fertilization 0.77 ± 0.22 0.87 ± 0.15 NS

No data on birth rateCakmak H, et al. Fertil Steril 2013;99:1476-1484


FERTILITY PRESERVATION IN 1035 WOMEN OVER 5 YEARS

Oncology475 womenAge 31.9 5.1MII oocytes: 8.2

Non-oncology560 womenAge 36.7 4.2MII oocytes: 9.8

Garcia-Velasco JA, et al. Fertil Steril 2013:99:1994-1999


HOW MANY HAVE RETURNED?

26 non-oncology women have attempted pregnancyMean interval 20.5 months84% oocyte survival rate1 women no embryo transferPregnancy rate 30.7% (cumulative 70.9%)

Garcia-Velasco JA, et al. Fertil Steril 2013;99:1994-1999


OVARIAN STRIP AUTOTRANSPLANTATION

Strip reimplantation on ovarian pedicle

Oophorectomy

Gosden RG, et al. Hum Reprod 1994;9:597-603


RESTORATION OF FERTILITY AFTER AUTOTRANSPLANTATION OF CRYOPRESERVED OVARIAN BIOPSIES


OVARIAN TRANSPLANT MODEL

OophorectomyCryopreservation of cortical stripsReimplantation

High basal FSH60-70% of follicles lost

Gosden RG, et al. Hum Reprod 1994;9:597-603


TEAMWORK REQUIRED!

IVF unitOocyte/embryo

storageRepro Med specialist

Operation:Theatre/Anaesthetic

Oncology

PaediatricOncology

Haematology (sickle cell disease)

Regulatory aspects: HFEA vs HTA, IRAS, Hospital R&D

Tissue ServicesResearch

lab

Others e.g.Rheumatology


"Our findings suggest that cryopreservation of ovarian tissue should be offered to all young women diagnosed with cancer."

New mother Quarda Touirat, speaking at a press conference on Friday, said:"I'm very happy, it's what I've always wanted. It was a dream."

FIRST BABY AFTER OVARIAN CRYOPRESERVATION

Donnez J, et al. Lancet 2004;364:1405-1410


SUMMARY OF 60 REPLACEMENTS

Team PatientsPregnancy Live birth

Total Natural IVF No. of patients

No. of live births

Belgium 13 6 4 2 3 6Denmark 25 8 6 2 2 4Spain 22 4 3 1 1 2 (twins)Total 60 11 women 13 5 6 12

93% achieved ovarian activity after a median of 4 months18% of women achieved a pregnancy

Donnez J, et al. Fertil Steril 2013;99:1503-1513


T/A USS of anterior wall graft follicles during IVF cycle

8-cell and 5-cell embryosTwin pregnancy at 8 weeks of gestation

PREGNANCY AFTER HETEROTOPIC TRANSPLANTATION

Stern C, et al. Hum. Reprod 2013;28:2996-2999


Sickle cell disease, unilateral oophorectomy for cryopreservation age 13(thelarche age 10, premenarchal)Prior to HSCT

Tissue replaced age 25, menses after 5 months; normalised FSH, AMH undetectableNatural conception 2 years later


REPLACEMENT FOR PUBERTY?

BUTRapid onset of oestrogenisationEarly progesterone exposureWaste of oocytesMalignant contamination?

Anderson, Hindmarsh and WallaceEur J Cancer 2013

Poirot C, et al. Lancet 2012;379:588


OVARIAN CONTAMINATION:VERTEBRAL EWING’S SARCOMA

CD99


THE NEED FOR PATIENT SELECTION

0

20

40

60

80

100

Breastcancer

Lymphoma Leukaemia Sarcoma Autoimmune Aplasticanaemia

Other

Percent of women with POI after pre-chemo unilat oophorectomy

Overall n=143, mean 58 months follow up

BMT

Schmidt KT, et al. RBM Online 2013;26:272-279


PREGNANCY AFTER TREATMENT(AND UNILAT OOPHORECTOMY)

57 women had tried to conceive41 succeeded (72%)

68 pregnancies overall45 babies5 ongoing15 miscarriages1 ectopic1 termination

Schmidt KT, et al. 2013 RBM Online 26, 272


CAN WE DEVELOP USEFUL CRITERIA?

Development of ‘Edinburgh criteria’ since 1996Age <35 yearsNo previous chemotherapy (or low risk if young)High (>50%) risk of ovarian failure

High dose alkylating agentsRadiotherapy to pelvis

Good (>50%) chance of survivalNo previous children

Anderson R, et al. Reproduction 2008;131:681-689Wallace WHB, et al. Lancet Oncology 2014;15:1129-1136


15 YEAR, POPULATION-BASED ANALYSIS OF CRITERIA FOR OVARIAN CRYOPRESERVATION

Female cancer patientsage <18 at diagnosis

01/01/1996 - 30/6/2012n = 410

Offered cryopreservationn = 34

Tissue cryopreservedn = 20

Proceduredeclinedn = 13

Procedureunsuccessful

n = 1

Deceased

n = 1

Not offered cryopreservationn = 376

Deceasedn = 81

Deceased

= cryopreservation offered.

= reasons for not having tissue cryopreserved.

= patients in study eligible for ovarian function evaluation.

n = 1

n = 4

Poorcommunication

n = 1

Uterinefactorn = 1

Parentalchoicen = 2

Too unwell

n = 9

<12 years oldn = 91

<12 years oldn = 1

Deceasedn = 3

<12 years oldn = 2

Lost to follow-upn = 1

<12 years old

n = 14 n = 6 n = 141

On COCP

n = 1

Still ontreatment

n = 4

On COCP

n = 17

Insufficientinformation on

follow-upn = 42

Do the ‘Offered’ group have a higher prevalence of POI?(robust criteria of amen >4 mo +high FSH x2/low E2)

Wallace WHB, et al. Lancet Oncology 2014;15:1129-1136


CUMULATIVE INCIDENCE OF POI

Not offered

Offered

15-year probability 35% [95% CI 10–53] vs 1% [0–2] p<0.0001Hazard ratio 56.8 [95% CI 6.2–521.6] at 10 years

Wallace WHB, et al. Lancet Oncology 2014;15:1129-1136


OTHER OPTIONS: OVARIAN PROTECTION

GnRH agonist administration during chemoIncreasing evidence for efficacy (reduced risk of POI) in breast cancerNo evidence in other cancersLimited evidence of preservation of fertility

Ovarian transpositionMay be an option where radiotherapy field is well definedRisk of vascular compromise to ovaryNo high-quality evidence of effectiveness

Lambertini M, et al. Ann Onc 2015;26:2408-2419Gubbala K, et al. J Ovarian Res 2014;7:69


CONCLUSIONS

Fertility preservation is becoming ‘main stream’Need for accurate, patient-specific risk to fertility and ovarian function

Extrinsic issues: proposed treatmentIntrinsic issues: ovarian reserve

Development of evidence-based algorithms to enable truly informed patient choice

Options:Oocyte and embryo vitrification: established, for postpubertal womanOvarian tissue cryo: remains experimental, especially in girlsOvarian protection: limited evidence of efficacy

Contacts ESMO

European Society for Medical Oncology Via L. Taddei 4, CH-6962 Viganello – LuganoT. +41 (0)91 973 19 00F. +41 (0)91 973 19 [email protected]

esmo.org

Cancer in Adolescents and Young Adults (AYA)Working Group

Contacts SIOPE

European Society for Paediatric Oncology Av. Mounier 83, B-1200 Brussels, BelgiumT. +32 (2)775 02 01F: +32 (2)775 02 [email protected]

siope.eu

e-learning module fertility preservation in girls and women with cancer … · 2017-03-07 ·...

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