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Oncofertility: State of the art for young people with cancer
Professor W Hamish Wallace
Consultant Paediatric Oncologist,
Edinburgh
Scotland, UK
Swedish Society for Paediatric Oncologists, Stockholm 28 January 2015
Improved Five Year Survival (1966-2000)
Increasing numbers of five year UK survivors by current age
Skinner, Wallace & Levitt , Lancet Oncology, 2006
Risk assessment for Fertility preservation
• Intrinsic factors – Heath status of patient – Consent (Patient/Parent) – Assessment of ovarian reserve
• Extrinsic factors – Nature of predicted treatment
• High/Medium/Low/Uncertain Risk
– Time available – Expertise available
Wallace WH, Critchley HOD & Anderson RA. JCO, 2012
Risk assessment for Fertility preservation
• Intrinsic factors – Heath status of patient – Consent (Patient/Parent) – Assessment of ovarian reserve
• Extrinsic factors – Nature of predicted treatment
• High/Medium/Low/Uncertain Risk
– Time available – Expertise available
Wallace WH, Critchley HOD & Anderson RA. JCO, 2012
Infertility - Risk Factors
Ü RT to HPA or a field that includes testes/ovaries
Ü Busulphan
Ü BCNU
Ü CCNU
Ü Cyclophosphamide
Ü Ifosfamide
Ü Melphalan
Ü Mustine
Ü Nitrogen mustard
Ü Procarbazine
Ü Thiotepa
Ü Chlorambucil
Ü Cytarabine
The pre-pubertal gonad is not protected
Radiation-induced ovarian damage
Human oocyte (Primordial follicle)
Ü LD50 < 2 Gy
Wallace, Thomson, Kelsey. (2003)
Hum Reprod.
Risk of infertility Low risk (<20%) Medium risk High risk (>80%)
ALL Wilms’ tumour Brain tumour Sx, RT < 24Gy Soft tissue sarcoma (stage1) Hodgkin’s Lymphoma HL(Low stage)
AML Osteosarcoma Ewing’s sarcoma STS: stage II/III Neuroblastoma NHL Brain tumour RT>24Gy HL (High Stage)
Total Body Irradiation Pelvic/testes RT Chemo pre BMT Metastatic Ewing's HL (Pelvic RT)
Wallace, Anderson, Irvine. Lancet Oncology 2005
Risk assessment for Fertility preservation
• Intrinsic factors – Heath status of patient – Consent (Patient/Parent) – Assessment of ovarian reserve
• Extrinsic factors – Nature of predicted treatment
• High/Medium/Low/Uncertain Risk
– Time available – Expertise available
Wallace WH, Critchley HOD & Anderson RA. JCO, 2012
The Wallace-Kelsey Model (Five parameter asymmetric double-Gaussian cumulative curve)
Wallace &Kelsey (2010) PloS ONE ESHRE, Lille, 2012
Ovarian reserve: Conception to Menopause
Wallace &Kelsey (2010) PloS ONE
Ovarian reserve: Conception to Menopause
Anna
Bella
Wallace &Kelsey (2010) PloS ONE
Effective ovarian sterilizing doses of radiotherapy with increasing age
Prediction of Ovarian Reserve (AMH)
Ü Anti Mullerian Hormone (AMH) is an important product of the adult ovary, produced by the granulosa cells of small growing follicles
Ü AMH has little variation across and between menstrual cycles
Ü AMH is the best currently available marker of the number of small-growing follicles in the ovary
Ü But there was no validated reference model for AMH available
Anderson, Nelson, Wallace (2011) Maturitas
A validated model of serum anti-Mullerian hormone (AMH) from conception to
menopause
Kelsey et al. PLoS ONE 2011
Pre
Cycle
1
Cycle
2
Cycle
3
Cycle
4
Cycle
5
Cycle
60.0
0.5
1.0
1.5
2.0
2.5
**** *** ***
AMH
(ng/
ml)
AMH in childhood cancer
Pre End Recovery0
1
2
3
* **
AMH
(ng/
ml)
High risk
Pre End Recovery0
1
2
3 **
AMH
(ng/
ml)
Medium/low risk
22 girls age 0.3-15yr 17 prepubertal
Brougham et al 2012 JCE&M
AMH in 3 girls with cancer
0 50 100 150 2000.0
1.0
2.0
3.0
Age 2.4; rhabdomyosarcoma 0 25 50 75
0.0
0.2
0.4
0.6
0.8
1.0
Weeks
AMH
(ng/
ml) Age 1.2; neuroblastoma
0 50 100 1500.0
0.5
1.0
1.5
2.0
Weeks
Age 14.6: Hodgkin’s lymphoma
Brougham et al 2012 JCE&M
Summary
Ü AMH is detectable before puberty
Ü AMH falls rapidly during cancer treatment in both pre-pubertal and pubertal girls
Ü AMH levels recover in those patients at low/medium risk of gonadotoxicity
Ü AMH fails to recover in those at high risk. This could be indicative of future reproductive impairment
Brougham et al 2012 JCE&M
Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer.
Anderson and Cameron 2011 JCE&M Anderson et al 2013 Eur J Cancer
sensitivity 98.2% specificity 80.0% for correct classification of amenorrhoea n=75
Fertility preservation options: established and experimental
FERTILITY RISK ASSESSMENT(Includes Intrinsic and Extrinsic factors)
Pre-pubertal
Testis
biopsy
Pubertal
Able to produce a suitable
semen sample
Post-pubertal
Testis Tissue
Cryopreservation
Experimental Established
Sperm
Cryopreservation
Ovarian Tissue
Cryopreservation
Embryo
Cryo
Pre-pubertal
FEMALEMALE
PatientAssessment
Intervention
Storage
NO
Testis biopsy/
Gamete extraction
YES
Post-pubertal
Ovarian
stimulation
Partner/
Donor
sperm
Oocyte
Cryo
Ovarian biopsy
Key features of the 3 options for fertility preservation for women
Ü Embryo cryopreservation Ü Established but require time and a partner
Ü Oocyte cryopreservation Ü Established but require time and hormone
stimulation (success rate per oocyte low)
Ü Ovarian tissue cryopreservation Ü Minimal delay Ü No lower age limit Ü Surgical procedure Ü Allows for future developments
Ovarian tissue cryopreservation: World-‐wide experience
* At least 39 pregnancies worldwide after othotopic reimplantation of frozen–thawed ovarian cortex * Success rate is unclear as the denominator is unknown * No pregnancies reported following the reimplantation of ovarian tissue harvested pre-‐pubertally * Young children are potentially ideal candidates
Donnez, J. & Dolmans, M.‐M. Nat. Rev. Endocrinol. 9, 735–749 (2013)
8
5 3
3 3
8 2 1
Children born from transplanta7on of frozen/thawed ovarian 7ssue
All Normal Babies weight and dura7on
Orthotopic >> heterotopic
All except for one is a result of a slow-‐freezing protocol
An es7mated excess of 150 transplanta7ons have been performed
1 3 1 1
Cryopreservation: European experience
Ü Three centres ( Denmark, Spain and Belgium)
Ü 60 cases of orthotopic reimplantation.
Ü Of these women, 11 (21%) became pregnant
Ü Six have delivered 12 healthy babies.
Ü Restoration of ovarian activity was observed in 93% of the patients between 3.5 months and 6.5 months after grafting
Ü The mean duration of ovarian function after trans- plantation is ~4–5 years but can persist for up to 7 years.
Donnez, J. et al. Fertil. Steril. 99, 1503–1513 (2013).
Reduc7on in FSH and LH following transplanta7on of frozen/thawed ovarian 7ssue in Danish pa7ents
0
10
20
30
40
50
60
70
80
90
100
0 4 8 12 16 20 24 28 32
IU/L
Weeks a5er transplanta;on
FSH LH
Edinburgh experience in children (< 18 yrs)
1996-‐2012
Ovarian Cryopreservation & Ovarian Function
Cryopreservation of ovarian cortical tissue – Edinburgh criteria
Selection criteria (1995, modified 2000) Ü Age < 35 years Ü No previous chemotherapy/radiotherapy if age >15 years
Ü Mild, non gonadotoxic chemotherapy if < 15 years Ü A realistic chance of surviving five years Ü A high risk of ovarian failure Ü Informed consent (parent and where possible patient)
Ü Negative HIV and Hepatitis serology Ü No existing children
The normative validated model of ovarian volume throughout life
Kelsey TW, Dodwell SK, Wilkinson AG, Greve T, Andersen CY, et al. (2013) Ovarian Volume throughout Life: A Validated Normative Model. PLoS ONE 8(9): e71465. doi:10.1371/journal.pone.0071465
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
Walllace WH et al. 2014 Lancet Oncology
Do the ‘Offered’ group have a higher prevalence of POI?
Not offered
Offered
Cumulative incidence of POI
Walllace…..and Anderson 2014 Lancet Oncology
15-year probability 35% [95% CI 10–53] vs 1% [0–2] p<0.0001 Hazard ratio 56.8 [95% CI 6.2–521.6] at 10 years
Conclusion
• Ovarian cryopreservation was offered to 9% of our patients, and performed in 5%
• The procedure was safe and without complications • No patients have asked for re-‐implantation of their tissue – to date
• All patients who have thus far developed premature ovarian insufficiency were identified except one patient
• The Edinburgh Selection Criteria have proved to be helpful in selecting those patients at highest risk of POI
Wallace WH…..and Anderson 2014 Lancet Oncology
Reimplantation?
Ü It is important to be aware that reimplantation of ovarian cortical tissue is a separate procedure at a time distant from the treatment of the original cancer
Ü Consent for harvesting ovarian tissue from children often will have been obtained from their parents
Ü Informed consent for reimplantation can be obtained from the patients at a much later date when they are competent to assess the complex issues themselves.
Ewings sarcoma localised T 7 Vertebrae (Age 12) – unexpected contamination of ovarian biopsy
CD99
Re-‐implantation or IVG and maturation?
Ü Contamination of the cryopreserved tissue with malignant cells, particularly in haematological malignant disease – shown in a rodent lymphoma model – to cause recrudescence of the original disease
Ü Oocyte maturation in vitro, followed by IVF, would eliminate this risk
Antral development from in vitro grown human primordial follicles within 10 days
Telfer et al., 2008: A two step serum free culture system supports development of human oocytes from primordial follicles in the presence of activin. Human Reproduction 23: 1151-1158
Telfer et al. (2008) Human Reproduction
The Uterus
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
2.2
2.4
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Uterine Volume (cm3log- adjusted)
Age (years)
Observed Uterine Volume Predicted Uterine Volume 95% Conf Lim for Model 95% Prediction Limit
Normative model for uterine volume from birth to 40 years. The r2 is 0.859.
Kelsey et al. unpublished
30
25
20
15
10
5
0 2 4 6 8 10 12 14
Uterine volume and age at irradiation (TBI)
Bath et al. BJOG (1999) Age at Irradiation (years)
Uterine function after cancer treatment
Ü No reports of uterine damage due to chemotherapy
Ü Radiotherapy: Ü Uterine damage, manifest by impaired growth and
blood flow. Ü Uterine volume correlates with age at irradiation. Ü Exposure of the pelvis to radiation is associated with
an increased risk of miscarriage, mid-trimester pregnancy loss, PPH, pre-term birth and low birth weight.
Vitruvian man
Leonardo da Vinci 1490
Sertoli Cell
Hormone levels and semen concentration in relation to the number of MOPP cycles in male long-term survivors of childhood Hodgkin’s.
van Beek R D et al. Hum. Reprod. 2007;22:3215-3222
Radia7on-‐induced tes7cular damage
Germinal epithelium
>1.2Gy azoospermia
Radia7on-‐induced tes7cular damage
Leydig cell function
Ü Dose received by testis P <0.05
Ü Time Interval after radiotherapy P <0.05
Ü Age at treatment NS
Li, Kelsey, Wallace (unpublished data)
FERTILITY RISK ASSESSMENT(Includes Intrinsic and Extrinsic factors)
Pre-pubertal
Testis
biopsy
Pubertal
Able to produce a suitable
semen sample
Post-pubertal
Testis Tissue
Cryopreservation
Experimental Established
Sperm
Cryopreservation
Ovarian Tissue
Cryopreservation
Embryo
Cryo
Pre-pubertal
FEMALEMALE
PatientAssessment
Intervention
Storage
NO
Testis biopsy/
Gamete extraction
YES
Post-pubertal
Ovarian
stimulation
Partner/
Donor
sperm
Oocyte
Cryo
Ovarian biopsy
Males: Fer7lity preserva7on
Ü Young men who can produce semen should have the opportunity of sperm banking before treatment begins
Ü Sperm retrieval should be considered if the chances of infer7lity are high and the testes are >10mls Ü Storage of gametes is governed by the HFE act 1990 Ü WriWen informed consent from a competent male is required
Ü There is currently no established op7on to preserve fer7lity in the pre-‐pubertal boy….
Isolated human sperm cells (1500x) Albert Tousson – Nikon Small world
Cryopreservation of pre-pubertal testis tissue prior to cancer treatment
Ü Boys undergoing cancer treatment with >80% risk of infertility
Ü Biopsy to be taken with routine procedure
Ü Storage by Tissue Services according to ‘mature’ or ‘immature’ protocol
Ü Small piece of tissue to be used for research
Ethical Approval Granted – September 2013
Human Testis Xenografting
Ü Provide fertility counseling to all young patients with cancer
Ü Cryopreserve ovarian and pre-‐pubertal testicular tissue from the right (high risk) patients
Ü Define the success rate of the procedures
Ü Develop IVG/M as a safe alternative to re-‐implantation through basic research
Challenges
Acknowledgements
• Richard Anderson • David T Baird • Tom Kelsey • Evelyn Telfer • Marie McLaughlan • Alice Grove Smith • Lucy Li • Phoebe Wright • Sarah Dodwell
• Rod Mitchell • Louise Bath • Chris Kelnar • Angela Edgar • Mark Brougham • Fraser Munro • Merrill McHoney
Ü [1] R. Skinner, W. H. Wallace, G. A. Levitt, and U. K. C. s. C. S. G. L. E. Group, "Long-term follow-up of people who have survived cancer during childhood," Lancet Oncol, vol. 7, pp. 489-98, Jun 2006.
Ü [2] W. H. Wallace, R. A. Anderson, and D. S. Irvine, "Fertility preservation for young patients with cancer: who is at risk and what can be offered?," Lancet Oncol, vol. 6, pp. 209-18, Apr 2005.
Ü [3] W. H. Wallace, H. O. Critchley, and R. A. Anderson, "Optimizing reproductive outcome in children and young people with cancer," J Clin Oncol, vol. 30, pp. 3-5, Jan 1 2012.
Ü [4] W. H. Wallace and T. W. Kelsey, "Human ovarian reserve from conception to the menopause," PLoS One, vol. 5, p. e8772, 2010.
Ü [5] W. H. Wallace, A. B. Thomson, and T. W. Kelsey, "The radiosensitivity of the human oocyte," Hum Reprod, vol. 18, pp. 117-21, Jan 2003.
Ü [6] R. A. Anderson, S. M. Nelson, and W. H. Wallace, "Measuring anti-Mullerian hormone for the assessment of ovarian reserve: when and for whom is it indicated?," Maturitas, vol. 71, pp. 28-33, Jan 2012.
References
Ü [7] R. A. Anderson and D. A. Cameron, "Pretreatment serum anti-mullerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer," J Clin Endocrinol Metab, vol. 96, pp. 1336-43, May 2011.
Ü [8] R. A. Anderson, M. Rosendahl, T. W. Kelsey, and D. A. Cameron, "Pretreatment anti-Mullerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer," Eur J Cancer, vol. 49, pp. 3404-11, Nov 2013.
Ü [9] M. F. Brougham, P. M. Crofton, E. J. Johnson, N. Evans, R. A. Anderson, and W. H. Wallace, "Anti-Mullerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study," J Clin Endocrinol Metab, vol. 97, pp. 2059-67, Jun 2012.
Ü [10] J. Donnez and M. M. Dolmans, "Fertility preservation in women," Nat Rev Endocrinol, vol. 9, pp. 735-49, Dec 2013.
Ü [11] T. W. Kelsey, P. Wright, S. M. Nelson, R. A. Anderson, and W. H. Wallace, "A validated model of serum anti-mullerian hormone from conception to menopause," PLoS One, vol. 6, p. e22024, 2011.
Ü [12] J. Donnez, M. M. Dolmans, A. Pellicer, C. Diaz-Garcia, M. Sanchez Serrano, K. T. Schmidt, et al., "Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation," Fertil Steril, vol. 99, pp. 1503-13, May 2013.
References
Ü [13] T. W. Kelsey, S. K. Dodwell, A. G. Wilkinson, T. Greve, C. Y. Andersen, R. A. Anderson, et al., "Ovarian volume throughout life: a validated normative model," PLoS One, vol. 8, p. e71465, 2013.
Ü [14] W. H. Wallace, A. G. Smith, T. W. Kelsey, A. E. Edgar, and R. A. Anderson, "Fertility preservation for girls and young women with cancer: population-based validation of criteria for ovarian tissue cryopreservation," Lancet Oncol, vol. 15, pp. 1129-36, Sep 2014.
Ü [15] E. E. Telfer, M. McLaughlin, C. Ding, and K. J. Thong, "A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin," Hum Reprod, vol. 23, pp. 1151-8, May 2008.
Ü [16] R. D. van Beek, M. Smit, M. M. van den Heuvel-Eibrink, F. H. de Jong, F. G. Hakvoort-Cammel, C. van den Bos, et al., "Inhibin B is superior to FSH as a serum marker for spermatogenesis in men treated for Hodgkin's lymphoma with chemotherapy during childhood," Hum Reprod, vol. 22, pp. 3215-22, Dec 2007.
Ü [17] R A Anderson, R T Mitchell, T W Kelsey, N Spears, E E Telfer, W H B Wallace; “Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults”,The Lancet Diabetes and Endocrinology, 2015.
Ü [18] W. H. Wallace, T. W. Kelsey, and R. A. Anderson, "Ovarian cryopreservation: experimental or established and a cure for the menopause?," Reprod Biomed Online, vol. 25, pp. 93-5, Aug 2012.
References
Thank You