OncoFertility
Fertility Preserving Options & Outcomes in Gynecologic Cancers
CAROLINE BILLINGSLEY, MD
Thegos Annual Meeting
June 1, 2014
Objectives
 Background

Prevalence of US population affected
 Options for fertility preservation


 Etiology of cancer treatment-related

fertility failure



Chemotherapy
Radiotherapy
Surgery



Embryo cryopreservation
Oocyte cryopreservation
Ovarian tissue cryopreservation
Oophoropexy
GnRH analogue co-treatment
Candidates for fertility preservation




Breast cancer
Cervical cancer
Endometrial cancer
Ovarian cancer
Gynecologic cancer incidence in reproductive age women
Bleyer A et al. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000.
National Cancer Institute, NIH Pub. No. 06-5767. 2006
Gynecologic cancer incidence in reproductive age women
 Diagnosis and treatment of cancer often poses a threat to fertility
Cancer Site
Diagnosis
Death
Percentage
under age 44
(2007-2011)
Projection of
women to be
diagnosed under
age of 44
2014 Estimates
New cases
Endometrial
52,630
8,590
7.2%
3,789
Cervical
12,360
4,020
38.7%
4,783
Ovarian
21,980
14,270
12.1%
2,659
Vulvar
4,850
1,030
8.7%
421
SEER database, 5/2014 (http://seer.cancer.gov)
Etiology of cancer treatment-related fertility failure
Chemotherapy
High Risk
(>80%)
Intermediate Risk
Low/no risk (<20%)
Unknown
(examples)
Cyclophosphamide Cisplatin/
Ifosphamide
Carboplatin
Methotrexate
Taxanes
Cholarambucil
Adriamycin
5-Fluorouracil
Oxaliplatin
Melphalan
Imatinib (TKI)
Vincristine
Busulfan
Bevacizumab
Bleomycin
Nitrogen mustard
Actinomycin D
Procarbazine
Mitomycin
Etiology of cancer treatment-related fertility failure
Radiation
 Ovarian damage

Radiation toxicity varies with the
cell cycle




Lethal Dose



Highest in G and M cycles
Oocytes are particularly affected
Dose related reduction in the
primordial follicle pool
Dose >6 Gy usually causes
irreversible gonadal failure1
LDL50 <2
Gy2
Dependent on age, extent,
type/location and fractionation
schedule
Age
Dose of Radiotherapy
Birth
20.3 Gy
10 years
18.4 Gy
20 years
16.5 Gy
30 years
14.3 Gy
Cancer
Radiation Dosage
Cervical
Adjuvant
Definitive
45-50 Gy
45 Gy, boost to 54-60 Gy
Endometrial
WPRT
VcBT
45-50 Gy
21 Gy
Vulvar
Adjuvant
Definitive
45-50 Gy
54-60 Gy
1Howell
et al, 1998. 2Wallace et al, 1989, 2003.
Etiology of cancer treatment-related fertility failure
Radiation
 Uterine damage

 Childhood Cancer Survivor Study1

Obstetrical





Increased risk of SAB
Second trimester pregnancy
loss
Preterm birth
Low birth weight
Placenta accreta
 Risks dependent on dose,
site, age
• Prepubertal uterus is
particularly vulnerable
1Signorello
et al, J Natl Cancer Inst 2006;26:98:1453
Large, multicenter cohort

Birth outcomes of childhood radiation survivors
compared to sibling (no radiation exposure) controls

1264 cancer survivors

2201 singleton children
601 sibling controls (no radiation)
 1175 singleton children

Cancer
survivors
Sibling
controls
Odds
ratio
95% CI
P value
Preterm
birth
50.0%
19.6%
3.5
1.5-8.0
.003
Low birth
weight
36.2%
7.6%
6.8
2.1-22.2
.001
Small for
gestational
age
18.2%
7.8%
4.0
1.6-9.8
.003
High dose
(>500cGy)
Fertility Preserving Options
 Options for fertility preservation
 Embryo cryopreservation (via ovulation induction)

Oocyte cryopreservation

Ovarian tissue cryopreservation

Oophoropexy

GnRH analogue co-treatment
Fertility Preserving Options:
Embryo cryopreservation
 Definition

 Medications
Harvesting eggs, in vitro fertilization, and
freezing of embryos for later implantation


 Comment


Most established technique for fertility
preservation in women
 Considerations

Requires 10-14 days of ovarian stimulation
from the beginning* of menstrual cycle




* Random start ovarian stimulation
Outpatient surgical procedure (egg retrieval)
Requires partner or donor sperm
Cost (range $4000-8000 per cycle, $350 for
yearly storage fees)
1Rodriguez-Wallberg
Follicle stimulating hormone analogs
Aromatase inhibitors

Similar number of eggs and embryos and similar
pregnancy outcomes 1
Selective estrogen receptor inhibitors
 Rates

Success:



Intact embryos after thawing have similar
implantation rates as fresh embryos
59% pregnancy rate1
26% live birth rate1
et al, Cancer Treatment Reviews. 2012;38:354-361.
Fertility Preserving Options:
Oocyte cryopreservation
 Definition

Retrieving and freezing unfertilized eggs
through a vitrification process
 Comment

Now considered a standard practice per ASCO
2013 guidelines
 Considerations
Requires 10-14 days of ovarian stimulation
from the beginning* of menstrual cycle



1Loren


* Random start ovarian stimulation
Outpatient surgical procedure (egg retrieval)
Cost (range $4000-8000 per cycle, $350 for
yearly storage fees)
Follicle stimulating hormone analogs
(FolliStim)
Aromatase inhibitors

Previously considered experimental


 Medications

Similar number of eggs and embryos and similar
pregnancy outcomes 1
Selective estrogen receptor inhibitors
 Rates

Antinori et al:


The fertilization, pregnancy, and implantation rates
were 92.9%, 32.5%, and 13.2%, respectively2
Three hundred thirty-seven live births resulting
from 857 thawed cycles (39.3% pregnancy rate)
were reported across all centers3
et al, J Clin Oncol. 2013;31. 2Antinori et al, RBM Online. 2007;14:72–79. 3Rudick et al, Fertil Steril. 2010 Dec;94(7):2642-6.
Fertility Preserving Options:
Ovarian tissue cryopreservation
 Definition


Freezing of ovarian tissue and reimplantation
after cancer treatment
Reimplant:


Orthotopic: reimplant to the medullary portion of
the remaining ovary, or to the peritoneum of the
ovarian fossa
Heterotopic: to forearm, abdominal wall, chest wall
 *No live births reported for heterotopic
 Comment


Poor survival of ovarian stroma is a limiting
factor
Same day outpatient surgical procedure
 Rates

In women who have survived cancer, at least
24 live births have been reported using
cryopreserved ovarian tissue1,2,3
Preparing the
tissue for freezing
Transplantation of
ovarian tissue
 Considerations


Considered experimental
Not appropriate if the risk of ovarian
involvement is high


Leukemia
Risk of reintroduction of malignant cells

1Loren
No reports of cancer recurrence in humans1
Reimplantation
et al, J Clin Oncol. 2013;31. 2Donnez et al. Fertil Steril. 2013;99:1503-15. 3Fertil Steril 2014 May;101(5):1237-43.
Fertility Preserving Options:
Ovarian tissue cryopreservation
 American Society of Reproductive Medicine: 2014 Committee Opinion1

1Fertil
“an option in patients who must urgently undergo aggressive chemotherapy and/or
radiation, or who have medical conditions requiring treatment that may threaten ovarian
function and subsequent fertility. Ovarian tissue cryopreservation may be the only option
for prepubertal girls undergoing such treatments. However, these techniques are still
considered to be experimental and should be offered to carefully selected patients as an
experimental protocol”.
Steril. 2014 May;101(5):1237-43.
Fertility Preserving Options:
Ovarian transposition (Oophoropexy)
 Definition

Surgical repositioning of ovaries away from a
planned radiation field
 Comment



Same day surgical procedure
Must occur just prior to radiation therapy to
prevent migration of ovaries to original
position
May need repositioning or IVF to conceive
 Risks




Ovarian torsion
Chronic ovarian pain
Infarction of fallopian tube
Need for re-operation
 Efficacy

Menstruation






Pregnancy


1Loren
50% success rate1
altered blood flow to the ovary
scattered radiation (panumbra)
Age of the patient
Dose and extent of radiation
Variable
Morice et al2
 37 patients
 Ovarian transposition
 Uterine conservation
 Overall pregnancy rate: 12/37 (32%)
 18 pregnancies in 12 patients
et al, J Clin Oncol. 2013;31. 2Morice et al,Hum Reprod. 1998 Mar;13(3):660-3.
Fertility Preserving Options:
GnRH analogue co-treatment
 Definition

Use of hormonal therapies to protect ovarian
tissue during chemotherapy and radiation
therapy
 Efficacy



 Comment

Meta-analysis, 20111

Injections prior to and during gonadotoxic
treatments
 Risks

Side effects

6 RCTs
Conclusion: May be beneficial
Menstruation:
 Increased incidence spontaneous
menstruation (OR 3.46, CI 1.13-10.57)
 Increased incidence spontaneous ovulation
(OR 5.70, 95% CI 2.29-14.20)
 NO difference in spontaneous pregnancy rate
OPTION2

Menstruation:
 No difference between ovarian suppression
and no treatment with GnRH analogue
 ASCO 2013


1Bedaiwyi
.
GnRH is not an effective method of
fertility preservation
Should not solely be relied upon for fertility
preservation
et al, Fertil Steril. 2011;95(3):906. 2Leonard et al, J Clin Oncol. 2010;28:
Candidates for fertility preservation
 Candidates
 Breast cancer
 Cervical cancer
 Endometrial cancer
 Ovarian cancer
Candidates for fertility preservation
Breast Cancer
 Breast Cancer

232,340 women will be diagnosed in 20141

30% prior to age 44
 Treatment

Multi-agent, mainly cyclophosphamide
based, cytotoxic chemotherapy regimens
 Timing

6 week interval from surgery to
chemotherapy
 Concerns

Hormone responsive (ER, PR)
 Options

Ovulation induction



Tissue cryopreservation

1
Aromatase inhibitors
SERMs- Tamoxifen
Rare metastasis to ovaries
http://seer.cancer.gov/csr/ 1975_2011/results_single/ sect_01_table.01.pdf
Candidates for fertility preservation
Breast Cancer
 Azim, et al 20081



Risk of letrozole and FSH on recurrence
215 breast cancer patients
Prospective, non-randomized trial, 2002-2007




Recurrence


79 patients : letrozole + FSH
136 patients: controls, no fertility treatments
Mean follow up after chemotherapy: 23.4 months
vs 33 months (control)
PFS: No difference (HR 0.56, CI 95% .17-1.9)
Conclusion


Use of letrozole + FSH for ovarian stimulation does
not appear to increase the risk of recurrence in the
short term
Longer follow up is needed
Relapse-free survival in women with breast cancer stimulated with
letrozole versus control group. Kaplan-Meier plot (hazard ratio
0.56, 95% CI 0.17–1.9).
1 Azim AA et
al., J Clin Oncol 2008;26:2630–5
Candidates for fertility preservation
Cervical Cancer
 Cervical Cancer

12,360 women will be diagnosed in 20141
 Treatment

Early Stage:
 Radical surgery, lymphadenectomy
 Possible adjuvant chemoradiation
 Concerns

Ovarian involvement2,3


SCC: 0.5-0.79%
Adenocarcinoma: 1.7%-5.31%
1http://seer.cancer.gov/csr/
1975_2010/results_single/ sect_01_table.01.pdf, 2Sutton et al, Am. J. Obstet. Gynecol. 1992;166:50–53,
3Shimada et al, Gynecol Oncol. 2006;101(2):234-7. 4Lu et al, Gynecol Oncol. 2013;04:470.
Candidates for fertility preservation
Cervical Cancer
 Options

Surgical

Radical trachelectomy,
lymphadenectomy
 Vaginal
 Laparoscopic or robotic
The intent of the radical abdominal
trachelectomy was to resect the cervix,
upper 1–2 cm of the vagina,
parametrium, and paracolpos in a
similar manner to a type III radical
abdominal hysterectomy but sparing the
uterine corpus
Reconstruction of the uterine corpus to
upper vagina after the cerclage is placed
1http://seer.cancer.gov/csr/
1975_2010/results_single/ sect_01_table.01.pdf, 2Sutton et al, Am. J. Obstet. Gynecol. 1992;166:50–53,
3Shimada et al, Gynecol Oncol. 2006;101(2):234-7. 4Lu et al, Gynecol Oncol. 2013;04:470.
Candidates for fertility preservation
Cervical Cancer
Radical abdominal trachelectomy—
the cervical tissue and parametria are separated from the fundus
Candidates for fertility preservation
Cervical Cancer
The uterus is reattached to the vaginal apex
Candidates for fertility preservation
Cervical Cancer
The reconstructed fundus with remaining blood supply from the intact utero-ovarian ligaments—
uterine serosa without evidence of fundal ischemia
Candidates for fertility preservation
Cervical Cancer
 Survival outcomes
 Obstetric outcomes

>250 live births have been reported1


Recurrence
Mortality
 Plante et al, 20082, 20113
1Lu
Plante 2008
N=256 pregnancies
Plante 2011
N=106 pregnancies
1st trimester loss
18%
20%
2nd trimester loss
8.6%
3%
3rd trimester delivery
62%
73%
Preterm delivery
<37 weeks
<32 weeks
28%
12%
18%
4%
Term delivery
40%
55%
et al, Gynecol Oncol. 2013;04:470. 2Plante et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.
Candidates for fertility preservation
Cervical Cancer
 Oncologic outcomes


Plante et al, 20081, 20112
Recurrence risk factors:
 2008
• Lesions larger than 2 cms (29 vs 1%)
• Presence of LVSI (12 vs 2%)

2011
• Lesions larger than 2 cms
Plante 2008
N=603 patients (%)
Plante 2011
N=125 patients (%)
Recurrence rate
27 (4.5%)
6 (4.8%)
Death from disease
(%)
15 (2.5%)
2 (1.6%)
Abandoned VRT
10-12%
4 (11%)
5 year PFS
1Plante
et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.
96%
Candidates for fertility preservation
Endometrial Cancer
 Endometrial Cancer

It is estimated that 52,630 women will
be diagnosed in 20141
 Meta-analysis2



 Candidates



Early stage uterine cancer, FIGO Ia
Low grade histology (endometrioid)
No myometrial involvement (MRI)
Regression rate
Live birth rate:


Resolution of 76% of 408 patients
28% live birth rate
Recurrence rate:

41% of 267 of evaluable patients had
recurred
 Treatment

Progestin



1
Medroxyprogestone
Megestrol acetate
Levonorgestrel IUD
http://seer.cancer.gov/csr/ 1975_2010/results_single/ sect_01_table.01.pdf. 2Gallos et al, Am J Obstet Gynecol. 2012;207:(266):e1-2.
Candidates for fertility preservation
Endometrial Cancer
 Gunderson et al, 20121


Medical management (progestins)
45 studies, 391 patients


31.7 years old (median age)
Treatment:
 Medroxyprogesterone (49%), Megace (25%), IUD (19%)
Initial
Response
Complete
Response
CR with
recurrence
Persistence/
progressive
disease
Proportion
achieving
pregnancy
Number of live
birth
CAH
85.6%
65.8%
23.2%
14.4%
28/111
(41%)
28
EC
74.6%
48.2%
35.4%
25.4%
89/240
(34.8%)
89
0.03
0.002
0.03
0.02
0.39
n/a
P-value
1Gunderson
et al, Gynecol Oncol. 2012;125;477-482.
Candidates for fertility preservation
Ovarian Cancer
 Ovarian cancer

 Park, et al 20092
>22,000 women will be diagnosed in 20141

15% will be younger than 40
 Candidates


Borderline tumors
Early stage ovarian cancers



Germ cell
Sex cord stromal
Epithelial?



Borderline ovarian tumors
Recurrence Rate: 4.9% (SOC) vs 5.1% (fert
sparing)
Disease free survival


Overall survival


10 yr DFS: 92% (SOC) vs 95% (fert sparing)
10 yr OS: 97% (SOC) vs 98% (fert sparing)
Pregnancy

34 term pregnancies
 Treatment

Surgical


1
USO, omentectomy, washings,
peritoneal biopsies, pelvic and aortic
lymphadenectomy
Preservation of one ovary, uterus
http://seer.cancer.gov/csr/ 1975_2010/results_single/ sect_01_table.01.pdf
2 Park
et al, Gynecol Oncol. 2009;113:75-82.
Candidates for fertility preservation
Ovarian Cancer
 Epithelial Ovarian cancer?

Candidates
 Stage IA
 Stage IC, grade 1-2, favorable
histologic type


1Nam
Serous, mucinous,
endometrioid
Ineligible
 Stage >IC
 Grade III
 Unfavorable histologic type
 Clear cell
• Poorer survival
et al, Gynecol Obstet Invest. 2013;76(1):14-24.
 Nam, et al 20131




918 patients
Recurrence: 109 (11.9%)
Death: 48 (5.2%)
Obstetrical:





177 patients242 pregnancies
214 term births (88%), 1 preterm
(0.4%)
SAB rate: 25/242 (10%)
Ectopic rate: 2/42 (0.8%)
No congenital anomalies
American Society of Clinical Oncology (ASCO)
Clinical Oncology Clinical Practice Guidelines
 2006 ASCO1

Key Recommendations:







 2006 ASCO1

Discussion of fertility preservation
Refer patients who express interest to REI
specialists
Address fertility preservation early, before
treatment starts
Document fertility preservation discussions in
the medical record
Answer basic questions whether fertility
preservation may have an impact on successful
cancer treatment
Refer patients to psychosocial providers if they
experience distress about potential infertility
Encourage patient to participate in clinical
trials
Adult Female specific recommendations





Present embryo cryopreservation as an
established fertility preservation method
Discuss ovarian transposition (oophoropexy)
when pelvic radiation therapy is planned
Inform patients of conservative gynecologic
surgery and radiation therapy options
Inform patients that there is insufficient
evidence regarding the effectiveness of ovarian
suppression (GnRH analogs) as a fertility
preservation method, and cannot be relied
upon
Inform patients that other methods (ovarian
tissue preservation, oocyte cryopreservation)
are still experimental
 2013 ASCO2

Recommendation changes

1Lee
Oocyte cryopreservation is considered a
standard practice, and no longer
experimental
et al, J Clin Oncol. 2006;24:2917-2931. 2Loren et al, J Clin Oncol. 2013 Jul 1;31(19):2500-10.
 Fertility matters, even with a cancer diagnosis
Summary

Patients are concerned, and want to discuss options

Refer early. At the time of a cancer diagnosis, consider a
referral to REI, as time is often limited between diagnosis
and treatment

Physicians are not addressing the fertility concerns with
patients
 OncoFertility

Still in its infancy

Additional, long term studies are needed to know the
effects of these treatments on cancer recurrence and
survival
Thank You
Cuterus- the adorable uterus!