1. Oncofertility Abdulrahman Alserri MD, FRCSC. Assistant Professor
Reproductive Endocrinology and Infertility
Department of Obstetrics and Gynecology
Kuwait University

2. Disclosure
I have no conflicts of interest.

3. Oncofertility consortium 2006
What is Oncofertility
“A subfield that bridges oncology and reproductive research to explore and expand options for the reproductive future of cancer survivors.”
Oncofertility consortium 2006

4. NIH –National cancer institute - Cancer.gov
Why?
NIH –National cancer institute - Cancer.gov

5. Why? Improved survival due to advancements in cancer therapy.
Cancer therapy can be gonadotoxic.
Fertility preservation (FP) enhances quality of life of survivors.

6. ‘‘As part of education and informed consent before cancer therapy, oncologists should address the possibility of infertility with patients treated during their reproductive years and be prepared to discuss possible fertility-preservation options or refer patients to reproductive specialists.’’
Lee SJ et al. J Clin Oncol 2006

7. Despite this … FP services are under utilized.
Nearly half of oncologist never refer to a fertility specialist.
Lack of knowledge of options and resources.
Perception that ART are costly and of limited efficacy.
Concern regarding delay of cancer treatment. *
No delay in treatment
Fertility treatment does not diminish the chance of successful cancer treatment ASCO 2013
Forman EJ et al fertility and sterility Blumenfield Z et al journal of the society of gynecologic investigation Goodwin T et al pediatric blood and cancer Quin GP et al, Journal of cancer survivorship Woodruff TK Nature reviews clinical oncology Quin GP et al, Social science and medicine 2009, Vadaparamil S et al, Patient education and counseling Schover LR et al, Journal of clinical oncology 2002.

8. Requirements for a successful program
Rapid access.
Multidisciplinary.
Oncologists
REI
Surgeons
Pediatricians
Counselors
Experienced ART lab.
ASRM practice committee guideline, fertility and sterility

9. Oncofertility
Male
Female

10. Outline – informed consent
Risk of cancer treatments on future fertility.
FP options.
Risk of delaying cancer treatment.
Investigational FP.
Success of FP.
Risks of FP.
Disposition of tissue and post humous reproduction.
Alternative options and prevention.
CFAS- CPG

11. Risk of cancer treatment on future fertility.

12. Risk of cancer treatment on future fertility.
Risk of POF
High: > 70%
Intermediate: 30-70%
Low risk: <30%
Very low/No risk: negligible
ASCO- CPG update 2014 supplement

13. Risk of cancer treatment on future fertility.
Depends on..
Age
Fertility potential
Type of cancer
Type of treatment *
Dose of treatment
Chemo, radio or even surgery

14. Roness et al fertility and sterility 2016
Chemotherapy
Alkylating agents
Cyclophosphamide, Busulphan, Dacarbazine.
Platinum complexes
Cisplatin, Carboplatin.
Taxanes
Paclitaxel.
Alkylating agents and Platinum complexes are DNA damaging
Taxanes are microtubule stabilizing drugs
All eventually lead to apoptosis
Roness et al fertility and sterility 2016

15. Goodwin PJ et al, Journal of clinical oncology
Chemotherapy
Cyclophosphamide containing protocols cause ovarian failure in 80% of treated women within 1 year.
Goodwin PJ et al, Journal of clinical oncology

16. Roness H et al, Fertility and sterility 2016
Chemotherapy
Activation
Apoptosis
Vascular damage
Roness H et al, Fertility and sterility 2016

17. Radiation therapy Site: Abdomino-pelvic Cranial
2 Gy - loss of > 50% of primordial follicle pool.
50 Gy Gyne malignancies.
Vascular, endometrial and myometrial damage.
Cranial
Central hypogonadism > Gy.
Wallace WH et al, human reproduction 2003.
Sklar CA et al, Journal of national cancer institute 2006.
Green DM et al, Journal of clinical oncology 2009.
Green DM et al, Fertility and sterility 2011.
Critchley HO et al, Journal of the national cancer institute monographs 2005

18. Fertility preservation options
Established
Male:
Sperm Cryopreservation.
Female:
Embryo cryopreservation.
Oocyte cryopreservation.
Conservative gyn surgery.
Investigational
Male:
Testicular tissue cryo.
Female:
Ovarian tissue cryo.
ASCO- CPG update 2014

19. Which to choose? Age Diagnosis Type of treatment Fertility potential
Availability of a male partner or banked sperm.
Time available
Likelihood of ovarian metastasis
ASCO- CPG update 2014

20. FP – Established options

21. Embryo cryopreservation
COS needed:
Time.
Hormone sensitive cancers.
Risks:
OHSS
OPU
Sperm needed.
Success:
Number and quality of stored embryos.
ASCO – CPG 2014, CFAS – CPG 2014, ASRM practice committee guideline, fertility and sterility

22. Oocyte cryopreservation
COS needed:
Time.
Hormone sensitive cancers.
Risks:
OHSS
OPU
No sperm needed.
Success:
Number and quality of stored oocytes.
ASCO – CPG 2014, CFAS – CPG 2014, ASRM practice committee guideline, fertility and sterility

23. Embryo vs. Oocyte cryopreservation success
When an average of 1-2 embryos were transferred following: *
Embryo cryopreservation: CPR 52-53%
Oocyte cryopreservation: CPR 36-61% (55.4%)
Extrapolated from data on infertility patients
SART – 2014
ASRM practice committee guideline, fertility and sterility

24. Fertility sparing surgery
Ovarian transposition. *
Others:
Conization
Trachelectomy
USO
Cystectomy
* And shielding
CFAS – CPG 2014

25. FP – Investigational options

26. Ovarian tissue cryopreservation
No time.
Hormone sensitive cancers.
Pre-pubertal girls.
Surgery.
Cryopreservation expertise.
Low risk for ovarian mets / future ovarian cancer.
Risk of cancer cells re-introduction.
ASRM practice committee guideline, fertility and sterility
ASCO – CPG 2014, CFAS – CPG 2014, ASRM practice committee guideline, fertility and sterility

27. ASRM practice committee guideline, fertility and sterility 2013.
Techniques
Ovarian cortical tissue:
Cut into 0.3 – 2 mm thick pieces.
Risk of ischemia.
Whole ovary cryopreservation:
Vascular pedicle left. *
Less ischemia.
Fracture of pedicle or ovarian surface.
More difficult to freeze.
* For cryoprotection introduction and facilitate transplantation
ASRM practice committee guideline, fertility and sterility
ASCO – CPG 2014, CFAS – CPG 2014, ASRM practice committee guideline, fertility and sterility

28. Cortical tissue transplantation
Orthotopic
Ovarian medulla or ovarian fossa. *
Normal menses 4-9 months.
> 60 live births. **
Heterotopic
forearm, Abdominal wall or chest wall. ***
Restoration of ovarian function.
IVF required. ****
More ischemia.
* Allows for spontaneous pregnancy
**Data confounded by that most procedures did not involve removal of both ovaries initially and the site of ovulation (transplanted vs native ovary) not confirmed.
One center 60 transplants 11 pregnancies (18%) – all of which except one had native ovarian tissue as well.
*** accessible but not cosmetically appealing.
**** no live births
ASRM practice committee guideline, fertility and sterility
ASCO – CPG 2014, CFAS – CPG 2014, ASRM practice committee guideline, fertility and sterility
Donnez J et al, JARG 2015

29. Whole ovary transplantation
No successful transplant of a whole cryopreserved ovary.
Successful transplant of a fresh whole ovary from a living-related donor.
Live birth.
Silber SJ et al, NEJM 2008

30. ASRM practice committee guideline, fertility and sterility 2014.
Alternative options
In vitro maturation
Directly from the ovary. *
Or from recovered ovarian tissue. **
Where available and permitted:
Egg/sperm/embryo donation.
Adoption.
* Time restriction or hormone sensitive cancers
** no live births to date from IVM from recovered ovarian tissue
ASRM practice committee guideline, fertility and sterility

31. Prevention of ovarian damage

32. Prevention of ovarian damage by chemotherapy
GnRH agonist:
Hypothesis
Down-regulation of the pituitary gonadal axis.
Ovarian senescence.
Conflicting data *
Large trials showed  POF, small trials didn’t.
No studies comparing ovarian reserve and pregnancy rates.
Probably carry some protective effect. Safe.
Roness H et al, Fertility and sterility 2016

33. Prevention of ovarian damage by chemotherapy
Activation
AS101
AMH
Apoptosis
Imatinib
S1P
Vascular damage
G-CSF
Targeted transport
Encapsulation
Roness H et al, Fertility and sterility 2016

34. Summary
Patients diagnosed with cancer have the right to be informed about the impact treatment will have on their fertility and what fertility preservation options are available to them.
Early referral to a multidisciplinary team is essential.
If investigational FP is used then the patient should be informed about the investigational nature and REB approval is necessary.
Prevention of treatment induced damage should be the focus for the future.

35. References
1. Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. Journal of assisted reproduction and genetics. 2015;32(8):
2. Donnez J, Dolmans MM, Diaz C, Pellicer A. Ovarian cortex transplantation: time to move on from experimental studies to open clinical application. Fertility and sterility. 2015;104(5):
3. Frydman R, Grynberg M. Introduction: Female fertility preservation: innovations and questions. Fertility and sterility. 2016;105(1):4-5.
4. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(19):
5. Practice Committee of American Society for Reproductive M. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertility and sterility. 2013;100(5):
6. Practice Committee of American Society for Reproductive M. Ovarian tissue cryopreservation: a committee opinion. Fertility and sterility. 2014;101(5):
7. Roberts J, Ronn R, Tallon N, Holzer H. Fertility preservation in reproductive-age women facing gonadotoxic treatments. Current oncology. 2015;22(4):e
8. Roness H, Kashi O, Meirow D. Prevention of chemotherapy-induced ovarian damage. Fertility and sterility. 2016;105(1):20-29.
9. Silber SJ, Grudzinskas G, Gosden RG. Successful pregnancy after microsurgical transplantation of an intact ovary. The New England journal of medicine. 2008;359(24):
10. Wallace WH, Kelsey TW, Anderson RA. Fertility preservation in pre-pubertal girls with cancer: the role of ovarian tissue cryopreservation. Fertility and sterility. 2016;105(1):6-12.

36. Thank you