Fertility Preservation for People with Cancer

Bo Hyon Yun, M.D. Department of Obstetrics &

Gynecology, Severance Hospital, Yonsei University College of Medicine

Contents

► General principals

► Specially, in female patients with GYN cancers

► Fertility preservation in female cancer patients

Introduction• “Loss of Fertility”

− Immense concern that may cause great distress.− 임신할수있는능력일뿐아니라, 여성으로서의정체성그리고삶의문제.− Affects reproductive health: pubertal development, hormone production, sexual function,

and menopause.

Indications of fertility preservation• Cancer

− Impaired semen quality or ovarian function associated with the cancer itself.− Chemotherapy: Alkylating agents.− Pelvic radiation.

Male Female

Spermatogonia: very sensitive to CTx & RTx. CTx & RTx may induce premature ovarian insufficiency (POI).

Dose-dependent: may not be permanent if the spermatogonial stem cell is not fully depleted.

Ovarian damage: dose-, drug-dependent & increases as ages.

Surgical pelvic interventions may affect the anatomy or function.

RTx may affect uterus: leading to reduced vascularity, myometrium damage (fibrosis), hormone dependent insufficiency. Biological or targeted cancer treatment: Limited, but except for Bevacizumab-34% rate of POI reported.

Options for fertility preservation

Ovarian transposition

Anderson RA et al., Lancet Diabetes Endocrinol 2015

Hickman et al., Am J Obstet Gynecol 2016

Patient assessmentIntrinsic factors Extrinsic factors

Health status of patient Risk of predicted treatment (High, medium, low or uncertain risk)

Psychosocial factors Time availableConsent (patient or parent) Expertise & technical options available Assessment of pubertal statusAssessment of ovarian reserve

• Assessment of Ovarian reserve: ovarian reserve markers ►

• Influence of cancer types on existing ovarian reserve Hodgkin’s lymphoma, leukemia, non-Hodgkin’s

lymphoma, Nephroblastoma, sarcoma and neuroblastoma

Side effects of Cancer Tx on fertility• How Cancer Tx harms the ovary

Anderson RA et al., Lancet Diabetes Endocrinol 2015

Side effects of CTx on fertilityBedoschi G. et al., Future Oncol 2016

• CTx harms the ovary by…. − Follicular maturation arrest − Stromal fibrosis − Depleted oocyte population− Injury to blood vessels − Focal ovarian cortical fibrosis− Direct apoptotic effect of CTx on follicles

Side effects of RTx on fertility• Ovaries

− Depletion of the non-growing follicle pool in a dose-dependent manner: Less than 2Gy may deplete the NGF pool by 50%.

• Uterus − Smaller uterine volume− Endometrial damage: interfere with the development of the lining, implantation, placentation.− Damage of uterine blood supply: impair trophoblast invasion & placenta development.− Alterations of the myometrium tissue: myometrial atrophy, fibrosis, scar tissue.− Miscarriage, premature delivery, stillbirth

• Hypothalamus & Pituitary− Subtle development of ovulatory dysfunction.

Risk of Tx-related infertility with main anticancer therapiesDegree of risk Type of anticancer TxHigh risk

>80% risk of permanent amenorrhea HSC transplantation with cyclophosphamide/TBI or

cyclophosphamide/busulfan External beam radiation to a field that includes the ovaries CMF, CEF, CAF, TAC x 6 cycles in women ≥ 40 years

Intermediate risk40-60% risk of permanent amenorrhea

BEACOPP CMF, CEF, CAF, TAC x 6 cycles in women age 30–39 AC x 4 cycles in women ≥ 40 years AC or EC x 4 → Taxanes

Low risk <20% risk of permanent amenorrhea

ABVD in women ≥ 32 years CHOP x 4–6 cycles CVP AML therapy (anthracycline/cytarabine) ALL therapy (multi-agent) CMF, CEF, CAF, TAC x 6 cycles in women ≤ 30 years AC x 4 cycles in women ≤ 40 years

Very low risk ABVD in women < 32 years Methotrexate Fluorouracil Vincristine Tamoxifen Lambertini et al., BMC Medicine 2016

Degree of risk Type of anticancer TxUnknown risk Taxanes

Irinotecan Oxaliplatin Monoclonal Ab: except Bevacizumab (Intermediate risk for POI) Tyrosine kinase inhibitors

Abbreviations: C, cyclophosphamide 600-1200mg/m2; A, Adriamycin 25-60mg/m2; F, fluorouracil 600mg/m2; E, epiruvicin 60mg/m2; D, dacarbazine 375mg/m2; B, bleomycin 10U/m2; V, vinblastine 6mg/m2; D, dacarbazine 375mg/m2; V(O), vincristine 1.2-2mg/m2; P, prednisolone 40mg/m2; H, hydroxydaunorubicin 50mg/m2.

Fertility preservation methods• Embryo/Oocyte cryopreservation: Established approaches

− Random start protocol: 생리주기와상관없이시작~!− As soon as possible : 약 14일정도의기간이소요되므로암치료지연이되지않게. − As many as we can, but should avoid OHSS: 암치료지연이되지않게.

• Ovarian tissue cryopreservation: Experimental approaches− Surgical removal of ovarian tissue (either ovarian cortical biopsies or sometimes

oophorectomy) & a further surgical procedure to replace the tissue later on.

− Minimum delay of cancer treatment.

− The chance of livebirth after replacement of ovarian tissue: about 20%.

− Concerns Potential for reimplantation of malignant cells or tissue when the cryopreserved ovarian

tissue is replaced (ex. Leukemia, ovarian cancer). Ability of the prepubertal ovary to support later fertility: unknown yet.

• The Edinburgh selection criteria for gonadal tissue cryopreservation These criteria were established with ethics committee review and approval because they refer to experimental procedures, and should be regarded as a starting point for future discussion, research, and refinement.

− Age younger than 35 years− No previous chemotherapy or radiotherapy if aged 15 years or older at diagnosis, but mild,

non-gonadotoxic chemotherapy is acceptable if younger than 15 years− A realistic chance of 5-year survival− A high risk of premature ovarian insuffi ciency (>50%)− Informed consent (parent and, when possible, patient)− Negative HIV, syphilis, and hepatitis serology− Not pregnant and no existing children

Female patients

Wallace WH et al., Lancet Oncol 2014

• GnRH agonist− Controversial− Improves chances of ovarian recovery (PostCTx)Decreasing ovarian & uterine perfusionIncreasing anti-apoptotic mechanisms within the ovaryProtecting germline stem cells

− Large RCTs (GnRH a. vs. control)POEMS: ovarian failure rate 8% vs. 22% Pregnancy outcome: 21% vs. 11%

PROMISE trial: ovarian failure rate 8.9% vs. 25.9% Long term follow up (median 7.3years): Higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate.

JAMA 2015;314(24):2632-40N Eng J Med 2015;372:923-32

JAMA 2011;306(3):269-276

N Eng J Med 2015;372:436-46N Eng J Med 2014;371:107-18

• Efficacy of GnRHagonist

• Future Perspectives − Activation of ovarian follicles − In vitro follicle culture − Artificial ovaries

Fertility preservation techinques in women. International Society for Fertility Preservation-ESHRE-ASRM Expert Working Group. 2015 Expert meeting

Thyroidectomy, Radioiodine Tx

CTx, surgery, RTx, Endocrine Tx

CTx, surgery, CCRT (pelvis)

CTx, surgery (possible BSO)CTx, surgery, monoclonal Ab

Surgery, CCRT (pelvis)

Surgery, CTx

Fertility preservation & gynecologic cancer• Effect to the fertility

− GYN cancer is able to affect capability from an anatomical point of view, to the extent that a definitive damage is caused by the surgical approach.

− Gonadotoxicity derived from medical and/or radiation Tx did not represent the main cause of infertility.

• RTx− Abdomen pelvis RTx: high risk of POF, damage the uterus & uterine vessels affecting the

ability of a woman to carry a pregnancy to term. − Effective sterilising dose: the total dose at which premature ovarian failure occurs

immediately after RT in 97.5% of patients 20.3 Gy at birth to 14.3 Gy at 30 year. Radiation doses > 6 Gy in women older than 40 years of age -> the highest level of risk

for gonadal impact and immediate amenorrhoea. − Uterine dysfunction

De Felice F. et al., ecancer 2018

• CTx

De Felice F. et al., ecancer 2018

Women treated with high doses (≥5 g/m2 ) of

alkylating agents have a high risk (more than 70%) of developing permanent

amenorrhoea.

30- 70% of developing permanent amenorrhoea.

De Felice F. et al., ecancer 2018

G. Mangili et al. Cancer Treatment Reviews 2016

Borderline ovarian tumor

1. Ovarian cancer Survival is highest for women diagnosed aged under 40 years. Patients aged 15-39 years survive more than five years.

− Fertility preserving Surgery techniquesFertility sparing surgery: patients with low grade (grade 1-2) histology, high risk early-

stage epithelial ovarian cancer.

− Fertility preservation techniquesGnRH agonist: fewer relapses after GnRH agonist+CTx?Ovarian tissue cryopreservation: relapse risk after retransplantation.Oocyte/embryo cryopreservation: ovarian cancer does not affect the COH outcome

(number of oocytes retrieved, mature oocytes, fertilization rates) Borderline tumors: Letrozole can be used during COH to keep E2 low

2. Cervical cancer

− Fertility preserving surgical techniquesOnly be performed after careful evaluation and in early stages of cervical cancer.Trachelectomy, conization

− Fertility preservation techniquesOocyte/embryo cryopreservation: transvaginal oocyte retrieval may pose a challenge d/t

the cervical lesion.Ovarian tissue cryopreservation: can be harvested at the time of ovarian transposition.

3. Endometrial cancer 5% of uterine adenocarcinomas are diagnosed before <40 years. type I cancers, stage 1, low grade can be offered conservative treatment.

− Fertility preserving treatmentFIGO stage IA, grade 1 confined to EM on MRI.Progestational agents: high dose of megestrol or medroxyprogesterone acetate If spontaneous conception does not occur, ART is advised, as definitive surgery needs to

be planned as soon as child bearing is complete.

− Fertility preservation techniquesOocyte/embryo cryopreservation: Letrozole can be used during COH to keep E2 low.Ovarian tissue cryopreservation: high risk of concurrent ovarian malignancy, concern

remains.

Ending… • Fertility preservation (oncofertility) counseling should be individualized.

• Estimating the risk of infertility can be difficult.− Do not overestimate the risk of Tx related infertility in cancer patients. − Even with regimens associated with low risk of gonadotoxicity, ovarian reserve is reduced &

fertility may be impaired. − GYN cancer: A multidisciplinary team (gynaecologic oncologists, radiation oncologists, medical oncologists,

reproductive endocrinologist and perinatologist) evaluation should be the standard. Since the main cause of infertility consists of surgical removal of the reproductive organs, a

modulation of the surgical approach is the most desirable procedure.

Absolute benefits of the proposed anticancer Tx

Risk of infertility for each individual (Age, comorbidities,

ovarian reserve in women), sterilizing potential of the Tx

proposed

감사합니다!