1. CAROLINE BILLINGSLEY, MD Thegos Annual Meeting June 1, 2014
OncoFertility Fertility Preserving Options & Outcomes in Gynecologic Cancers
CAROLINE BILLINGSLEY, MD
Thegos Annual Meeting
June 1, 2014

2. Objectives Background Options for fertility preservation
Prevalence of US population affected
Etiology of cancer treatment-related fertility failure
Chemotherapy
Radiotherapy
Surgery
Options for fertility preservation
Embryo cryopreservation
Oocyte cryopreservation
Ovarian tissue cryopreservation
Oophoropexy
GnRH analogue co-treatment
Candidates for fertility preservation
Breast cancer
Cervical cancer
Endometrial cancer
Ovarian cancer
In this talk, I hope to cover several objectives, including:
Identify the population at risk for infertility due to cancer treatments
The more common causes of cancer treatment-related fertility failure, including chemo, radiation and surgery.
The different options for fertility preservation,
and finally will talk about who is an appropriate candidate for fertility preservation.

3. Gynecologic cancer incidence in reproductive age women
The graph illustrates SEER data, again from 1975 to 2000, and shows the the increasing proportion of invasive gyn cancers as age increases.
Among 15- to 19- year-old females, the proportion of all invasive cancers that were genital tract tumors was 11.9%.
This increases to 15% among the years old, and further increased to 21% in the year olds.
Studies have indicated that women are delaying child bearing for various reasons (including gyn onc fellowship), and the number of women who wish to have a first child at age is increasing.
Therefore an increasing proportion of women are being diagnosed with gyn cancers who may desire future fertility.
Bleyer A et al. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: National Cancer Institute, NIH Pub. No

4. Gynecologic cancer incidence in reproductive age women
Diagnosis and treatment of cancer often poses a threat to fertility
Cancer Site
2014 Estimates
Diagnosis
New cases
Death
Percentage under age 44 ( )
Projection of women to be diagnosed under age of 44
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
More than 91,000 new gynecologic malignancies are projected to be diagnosed in 2014.
Approximately 13% of those cancer cases will occur in women under the age of 44.
This translates to approximately 12,000 women under the age of 44 who will be diagnosed with a gynecological malignancy in 2014.
Overall in cancer in general, there have been improvements in the survival rates in the past 30 years, due to progress in cancer treatment.
But, these treatments, including radical surgery, multi-agent chemotherapy regimens and radiotherapy are associated with long term complications, including reproductive failure.
SEER database, 5/2014 (

5. Etiology of cancer treatment-related fertility failure Chemotherapy
High Risk (>80%)
Intermediate Risk
Low/no risk (<20%)
Unknown
(examples)
Cyclophosphamide
Ifosphamide
Cisplatin/
Carboplatin
Methotrexate
Taxanes
Cholarambucil
Adriamycin
5-Fluorouracil
Oxaliplatin
Melphalan
Imatinib (TKI)
Vincristine
Busulfan
Bevacizumab
Bleomycin
Nitrogen mustard
Actinomycin D
Procarbazine
Mitomycin
Most chemotherapy drugs act on rapidly dividing cells, and therefore often affect the granulosa and theca cells of the ovary more than the non-dividing oocytes.
But, the effect of these drugs on ovarian function varies widely, from no effect to others causing permanent hypogonadism.
The risk of infertility with the chemotherapy drugs are categorized into high, intermediate, low/none, and unknown.
The data for associated risk of infertility with the individual drugs is actually poor and heterogenous, and most often these reports are using amenorrhea rates as a surrogate for infertility.
In women, the greatest risk includes regimens that involve the alkylating agents (particularly cyclophosphamide, ifosphamide,).
Alkylators alter base pairs, leading to DNA cross linking and lead to single strand breaks. As a result, they can theoretically affect both resting cells, such as oocytes, and dividing cells.
The effects are age-, dose- and drug-dependent.
Several agents are associated with low or no risk of infertility, including MTX, 5-FU, vincristine, bleomycin, dactinomycin.
There is actually very little human data on the risk of taxanes.
More recent data has emerged regarding bevacizumab, and was discussed in the 2013 ASCO update on recommendations of fertility preservation.
In October 2011 the FDA issued a warning for bev, reporting that ovarian failure occurred in 34% of women receiving a bev containing regimen for CRC compared to 2% of women receiving the same regimen without bev.
Only 1/5 of these women regained ovarian function.
The FDA issued a statement that recommends that oncologists inform women of this risk prior to the start of treatment.

6. Etiology of cancer treatment-related fertility failure Radiation
Ovarian damage
Radiation toxicity varies with the cell cycle
Highest in G and M cycles
Oocytes are particularly affected
Dose related reduction in the primordial follicle pool
Lethal Dose
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 Gy
Endometrial
WPRT
VcBT
21 Gy
Vulvar
54-60 Gy
Radiation is actually more damaging to ovarian tissue than is chemotherapy.
It is a well known cause of ovarian damage and permanent infertility.
The effects are also dose and age dependent, but radiation is particularly more damaging to oocytes.
The damage occurs not only by direct exposure with pelvic or low abdominal radiation, but also by scatter radiation that may cause damage, even if the ovaries are out of the radiation field.
Radiation toxicity varies with the cell cycle, being greatest during mitosis prenatally, the early stages to the first meiosis, and preovulatrory maturation, so small primordial oocytes are more sensitive to radiation than are oocytes in larger follicles.
It causes a dose-related reduction in the primordial follicle pool.
Irradiation dosage and patient age also largely determine the degree of follicular loss and the likelihood of developing premature menopause. Approximately, half of the total number of nongrowing follicles are lost at doses of 2 Gy (LDL 50)
Based on this estimate, estimates of radiation dose are calculated that would result in immediate and permanent ovarian failure in 97.5% patients.
Below is a table with very rough estimates of the radiation doses commonly used in the treatment of gyn cancers, highlighting the fact that the doses used for both definitive and adjuvant therapy are more than double to amount needed to cause permanent ovarian failure.
Older patients are more susceptible to radiation-induced damage. Lower doses of radiation cause ovarian failure in older patients whereas young patients are more resilient, and succumb to ovarian failure at higher doses
1Howell et al, Wallace et al, 1989, 2003.

7. Etiology of cancer treatment-related fertility failure Radiation
Uterine damage
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
Childhood Cancer Survivor Study1
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
High dose
(>500cGy)
Cancer survivors
Sibling controls
Odds ratio
95% CI
P value
Preterm birth
50.0%
19.6%
3.5
.003
Low birth weight
36.2%
7.6%
6.8
.001
Small for gestational age
18.2%
7.8%
4.0
Not only is there damage to the gonadal function due to radiation, but there are also effects on uterus.
Radiation can lead to restricted growth of the uterus, as well as alterations to uterine blood flow.
This can become a major issue during pregnancy. There is data to suggest that there are increased risk of SAB, 2nd trimester pregnancy loss, preterm birth, low birth weight and problems with placentation.
These risks are dose, site and age dependent, with the prepubertal uterus being to most susceptible to damage
Once such study with the Childhood Cancer Survivor Study, published in This was large, multicenter cohort of childhood cancer survivors, including obstetrical outcomes on their 2201 children versus 1175 children of a comparison group of 601 female siblings.
Compared with the children of survivors who did not receive any radiation, the children of survivors who were treated with high dose radiation to the uterus (>500 cGy) were at statistically significant increased risk of preterm birth, low birth weight and SGA. This held true and SS at lower doses of XRT.
1Signorello et al, J Natl Cancer Inst 2006;26:98:1453

8. Fertility Preserving Options
Options for fertility preservation
Embryo cryopreservation (via ovulation induction)
Oocyte cryopreservation
Ovarian tissue cryopreservation
Oophoropexy
GnRH analogue co-treatment
We will move on now to different options of fertility preservation.
This is not an exhaustive list, but represents what we as providers should be familiar with as options for future fertility in a cancer patient.

9. Fertility Preserving Options: Embryo cryopreservation
Definition
Harvesting eggs, in vitro fertilization, and freezing of embryos for later implantation
Comment
Most established technique for fertility preservation in women
Considerations
Requires 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 $ per cycle, $350 for yearly storage fees)
Medications
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
Embryo cryopreservation is considered an established fertility preservation method as it has routinely been used for storing surplus embryos after in vitro fertilization after IVF cycles.
Historically, it has required about 2 weeks of ovarian stimulation with daily injections of Follistim (FSH) from the onset of menses.
New data has now indicated that although it is ideal to start within 3 days of the menstrual cycle, random stimulation can be successful as well.
Therefore, patients with limited time can complete a stim cycle within 2 weeks.
This has been an important advance in the field.
Also there has been the addition of newer hormonal stimulation regimens, to include aromatase inhibitors such as letrozole and SERMs such as tamoxifen, which is preferred in women with hormone sensitive cancers.
AIs are used to treat hormone receptor positive breast cancer, and act as ovarian stimulants yet suppress estrogen levels.
When combined with standard fertility meds, letrozole enhances ovarian stimulation while keeping E2 levels near physiologic levels.
Studies have suggested that this approach results in similar number of eggs and embryos and similar pregnancy outcomes .
Short term follow up has shown no impact on cancer-free survival.
1Rodriguez-Wallberg et al, Cancer Treatment Reviews. 2012;38:

10. Fertility Preserving Options: Oocyte cryopreservation
Definition
Retrieving and freezing unfertilized eggs through a vitrification process
Comment
Previously considered experimental
Now considered a standard practice per ASCO 2013 guidelines
Considerations
Requires days of ovarian stimulation from the beginning* of menstrual cycle
* Random start ovarian stimulation
Outpatient surgical procedure (egg retrieval)
Cost (range $ per cycle, $350 for yearly storage fees)
Medications
Follicle stimulating hormone analogs (FolliStim)
Aromatase inhibitors
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
Oocyte cyropreservation is a similar process, but in this case, the oocyte is retrieved and then flash frozen via vitrification, and then stored without ever being fertilized.
Oocyte cryopreservation success rates have improved significantly over the past several years, and is no longer considered experimental per the American Society of Reproductive Medicine, andis offered in more than 50% of ART clinics in the United States.
As the methods for cryopreservation of oocytes have developed in the recent years with the development of vitrification, improving success in oocyte survival and fertilization rates has been achieved, approaching that of fresh oocytes.
1Loren et al, J Clin Oncol. 2013;31. 2Antinori et al, RBM Online. 2007;14:72–79. 3Rudick et al, Fertil Steril Dec;94(7):

11. 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
Considerations
Considered experimental
Not appropriate if the risk of ovarian involvement is high
Leukemia
Risk of reintroduction of malignant cells
No reports of cancer recurrence in humans1
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
Ovarian tissue cyropreservation is an investigational method of fertility preservation, but has the advantage of requiring neither a sperm donor or ovarian stimulation.
The ovarian tissue is often removal laparoscopically and frozen.
The tissue is then thawed and reimplanted at a later date, after cancer treatment.
Primordial follicles can be cryopreserved with great efficacy, but due to internal ischemia encountered after transplantation, a quarter of these follicles may be lost based on xenografting studies.
To offset this loss, typically the entire cortex from an ovary is cryopreserved in adults.
Women older than 40 have limited benefit from this procedure due to the lower number of primordial follicles at that age.
This type of procedure has been performed in humans for less than 15 years, with the first ovarian transplant procedure described in 2000.
The tissue may be transplanted orthotopically to the pelvis, or heterotopically to the forearm or lower abdomen.
Initial studies reported restoration of ovarian endocrine function after both types of transplantation.
There is a theoretical concern that the thawed tissue might harbour malignant cells, and the cancer could be reseeded by ovarian transplantation.
Ovarian tissue autotransplantation may pose a risk of cancer recurrence in patients with colorectal, gastric and endometrial cancer.[6]
However, no metastases have been detected in ovarian tissue from lymphoma and breast cancer patients who have been undergoing ovarian tissue cryopreseration to date.[6]
In women who have survived cancer, at least 24 live births have been reported using cryopreserved ovarian tissue.
Reimplantation
1Loren et al, J Clin Oncol. 2013;31. 2Donnez et al. Fertil Steril. 2013;99: Fertil Steril May;101(5):

12. Fertility Preserving Options: Ovarian tissue cryopreservation
American Society of Reproductive Medicine: 2014 Committee Opinion1
“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”.
Ovarian tissue cyropreservation is an investigational method of fertility preservation, but has the advantage of requiring neither a sperm donor or ovarian stimulation.
The ovarian tissue is often removal laparoscopically and frozen.
The tissue is then thawed and reimplanted at a later date, after cancer treatment.
Primordial follicles can be cryopreserved with great efficacy, but due to internal ischemia encountered after transplantation, a quarter of these follicles may be lost based on xenografting studies.
To offset this loss, typically the entire cortex from an ovary is cryopreserved in adults.
Women older than 40 have limited benefit from this procedure due to the lower number of primordial follicles at that age.
This type of procedure has been performed in humans for less than 15 years, with the first ovarian transplant procedure described in 2000.
The tissue may be transplanted orthotopically to the pelvis, or heterotopically to the forearm or lower abdomen.
Initial studies reported restoration of ovarian endocrine function after both types of transplantation.
There is a theoretical concern that the thawed tissue might harbour malignant cells, and the cancer could be reseeded by ovarian transplantation.
Ovarian tissue autotransplantation may pose a risk of cancer recurrence in patients with colorectal, gastric and endometrial cancer.[6]
However, no metastases have been detected in ovarian tissue from lymphoma and breast cancer patients who have been undergoing ovarian tissue cryopreseration to date.[6]
In women who have survived cancer, at least 24 live births have been reported using cryopreserved ovarian tissue.
1Fertil Steril May;101(5):

13. 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
50% success rate1
altered blood flow to the ovary
scattered radiation (panumbra)
Age of the patient
Dose and extent of radiation
Pregnancy
Variable
Morice et al2
37 patients
Ovarian transposition
Uterine conservation
Overall pregnancy rate: 12/37 (32%)
18 pregnancies in 12 patients
Ovarian transposition is surgically moving the ovaries as far out of the planned radiation field.
The vascular pedicle remains intact in ovarian transposition, which distinguishes this procedure from ovarian transplantation.
This is often used when pelvic radiation is anticipated.
This can be done laparoscopically or at the time of laparotomy.
Contemporary procedures transpose the ovaries above the pelvic brim and as lateral as possible, which minimizes the ovarian dose of radiation and improves efficacy compared with medial approaches.
Various lateral locations have been used, including the base of the round ligament,the level of lower kidney pole, and the paracolic gutters
Due to the high risk of ovarian migration, this needs to be done as close the planned radiation as possible.
Complications of ovarian transposition are rare and include reports of injury and torsion of the ovarian blood vessels resulting in vascular ovarian injury, chronic ovarian pain, and infarction of the fallopian tube.
Ovarian cyst formation is described more commonly (incidence 0 to 23 percent), but may be unrelated to the procedure
The overall success rate as judged by preservation of the short term menstrual function is 50%.
Scatter radiation (panumbra) and alteration of ovarian blood supply are likely the main reasons for failure.
Ovarian re-positioning after surgery is not always needed, as spontaneous pregnancies have been reported.
But if infertility occurs, IVF and oocyte retrieval become more complicated due to the new location of the ovaries.
Pregnancy — Pregnancy rates depend on many factors, including age, type of cancer treatment, and underlying infertility factors.
In a study by Morice et al, published in 1998:
A series of 37 consecutive patients who underwent ovarian transposition with uterine conservation and pelvic irradiation therapy for pelvic cancer, the overall pregnancy rate was 12/37 (32 percent);
A total of 18 pregnancies were achieved among the 12 patients.
In women who undergo hysterectomy, surrogate pregnancy is possible using oocytes retrieved from the transposed ovaries; several successful cases have been reported.
1Loren et al, J Clin Oncol. 2013;31. 2Morice et al,Hum Reprod Mar;13(3):660-3.

14. Fertility Preserving Options: GnRH analogue co-treatment
Definition
Use of hormonal therapies to protect ovarian tissue during chemotherapy and radiation therapy
Comment
Injections prior to and during gonadotoxic treatments
Risks
Side effects
Efficacy
Meta-analysis, 20111
6 RCTs
Conclusion: May be beneficial
Menstruation:
Increased incidence spontaneous menstruation (OR 3.46, CI )
Increased incidence spontaneous ovulation (OR 5.70, 95% CI )
NO difference in spontaneous pregnancy rate
OPTION2
No difference between ovarian suppression and no treatment with GnRH analogue
ASCO 2013
GnRH is not an effective method of fertility preservation
Should not solely be relied upon for fertility preservation
In women undergoing chemotherapy, both the efficacy and safety of GnRH agonists for prevention of ovarian toxicity are controversial and active areas of investigation.
If used, the GnRH agonist is begun one week to six months before beginning chemotherapy and continued until the end of chemotherapeutic treatment.
Side effects include hot flushes and vaginal dryness.
The biologic plausibility of ovarian suppression for prevention of premature menopause following chemotherapy has been questioned and randomized trials have reported discordant findings of its efficacy.
A 2011 meta-analysis including six randomized trials that evaluated ovarian function after co-treatment with a GnRH agonist and chemotherapy concluded that co-treatment may be beneficial for protection of menstrual function .
GnRH agonist co-treatment increased the incidence of women with spontaneous menstruation and spontaneous ovulation after chemotherapy compared to controls who did not receive a GnRH agonist.
However, GnRH agonist co-treatment was not associated with a statistically significant difference in the rate of spontaneous pregnancy after chemotherapy.
There were limitations and weaknesses of this study though.
The Ovarian Protection Trial in Estrogen Negative (OPTION) published in 2010 early breast cancer, preliminary data did not demonstrate a clear benefit of treatment with goserelin throughout adjuvant chemotherapy; the rate of resumption of menses was similar for women who did and did not receive ovarian suppression
When these and other data published since the 2011 meta-analysis are considered, GnRH agonist use does not have a significant beneficial effect on either maintenance of menstruation or fertility
ASCO 2013 states that there is no definitive data that shows GnRH analogues preserve fertility, and remains a subject of ongoing research
The safety of the use of GnRH agonists in cancer patients has also not been established.
Since GnRH receptors are expressed by a variety of cancers and mediate several effects, it is possible that GnRH agonist therapy concomitant with chemotherapy might reduce the efficacy of the implemented chemotherapy .
GnRH agonist suppression may be safer in women with hormone-receptor negative
More data establishing the safety of ovarian suppression in cancer patients and its long-term efficacy in preserving fertility (not just resumption of menses) are needed.
Given the lack of strong evidence of safety and efficacy, it is not recommended for fertility preservation during chemotherapy.
1Bedaiwyi et al, Fertil Steril. 2011;95(3):906. 2Leonard et al, J Clin Oncol. 2010;28: .

15. Candidates for fertility preservation
Breast cancer
Cervical cancer
Endometrial cancer
Ovarian cancer
So who is a candidate for fertility preservation.
Clearly not all gynecologic cancers are amenable to fertility preservation.
But, in the appropriately selected patient, it may be considered and discussed.
Because each cancer patient’s clinical situation is unique, not one technique alone would be appropriate.
Therefore each cancer patient must be considered, and patient age, presence or absence of ovarian involvement, available time to cancer treatment, and the indication for fertility preservation must be considered.
Therefore we will discuss some of the gyn cancer patients that may have the option for fertility conserving therapies.

16. Candidates for fertility preservation 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
Aromatase inhibitors
SERMs- Tamoxifen
Tissue cryopreservation
Rare metastasis to ovaries
Breast cancer is the most common malignant disease in reproductive age women, and as ob/gynecologists, we may be the ones faced with telling our young patients of their diagnoses, and we need to know what the impact of breast cancer treatment can have on their reproductive potentials.
Based on SEER data projections, there will be over 230K women diagnosed with breast cancer in 2014, and 30% of those will be diagnosed before the age of 44.
This represents a large number of women whose fertility will be potentially at risk.
Many of these women will undergo surgery, followed by cytotoxic chemotherapy, often with cyclophosphamide containing regimens.
Often there is a 6 week interval in between surgery and chemotherapy, in which there is a window for a fertility sparing plan.
Ovulation induction can take place during this time, allowing for oocyte or embryo cryopreservation.
The concern of stimulation of estrogen receptor positive tumors with conventional ovulation induction regimens using follistim which leads to markedly elevated levels of estrogen is recognized.
But newer techniques for ovulation induction with aromatase inhibitors and SERMs such as tamoxifen, a well known anti-estrogen breast cancer treatment, are currently being used for ovulation induction as safe and effective alternatives.
The short-term use of AIs, and subsequent reduction in circulating estrogen, should release the hypothalamic-pituitary axis from the central effects of estrogen-mediated negative feedback.
As a result, FSH is increased, which is ultimately responsible for folliculogensis.
Given the growing body of evidence linking prolonged estrogen exposure and breast cancer, most oncologists and breast cancer patients are nervous to pursue assisted reproductive technologies (ART), fearing that the high estrogenic state can promote cancer growth or recurrence.
As a result, breast cancer patients are usually offered natural-cycle IVF, which has been found to result in a single embryo in ∼60% of the preservation cycles.
Furthermore, breast cancer survivors may even question the safety of future pregnancy.
Several population-based studies have failed to identify a detrimental association between pregnancy and risk of recurrence or mortality from breast cancer.
A recent meta-analysis of 14 studies, which included more than 18,000 control and 1,200 case subjects, reported similar relapse-free survival rates between women who conceived and women who chose not to conceive.
This further highlights the importance of providing breast cancer survivors with accurate information to make informed decisions regarding future fertility.
_2011/results_single/ sect_01_table.01.pdf

17. 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,
79 patients : letrozole + FSH
136 patients: controls, no fertility treatments
Mean follow up after chemotherapy: 23.4 months vs 33 months (control)
Recurrence
PFS: No difference (HR 0.56, CI 95% )
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
To further characterize the risk of ovarian stimulation using letrozole and FSH on the risk of breast cancer recurrence, Azim et al enrolled 215 breast cancer patients into a prospective nonrandomized controlled study from January 2002 to April 2007.
Seventy-nine women elected to undergo COH with letrozole and FSH, and the remaining 136 women declined fertility preservation and served as control subjects.
The mean follow-up after chemotherapy was 23.4 months (range 7.5–63.3 months) in the letrozole plus FSH group and months (range 4.5–63.3 months) in the control group.
There was no difference in relapse-free survival between the two groups (hazard ratio 0.56, 95% CI 0.17–1.9; Fig. 1).
Based on these findings we concluded that the use of letrozole plus FSH for COH for fertility preservation in breast cancer doesn’t appear to significantly raise the risk of breast cancer recurrence in the short term.
Longer follow-up was needed before definitive judgment can be rendered on the risk of breast cancer recurrence attributed to COH with the use of AIs and gonadatropins
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

18. Candidates for fertility preservation Cervical Cancer
12,360 women will be diagnosed in 20141
Treatment
Early Stage:
Radical surgery, lymphadenectomy
Possible adjuvant chemoradiation
Concerns
Ovarian involvement2,3
SCC: %
Adenocarcinoma: 1.7%-5.31%
Cervical cancer is a serious health problems, affecting over 500,000 women each year, world wide.
It is estimated that 12,340 women will be diagnosed with and 4,030 women will die of cancer of the cervix uteri in 20131
We know that roughly half of these women will be under the age of 35 at diagnosis.
This is the patient that you will or already have encountered at some point in your career.
Options for treatment are based on stage and histology.
Early stage disease (IA1, IA2, IB1) is traditionally treated with radical hysterectomy, with or without chemotherapy and radiation depending on pathologic risk factors.
Given the high number of child bearing aged women diagnosed with cervical cancer, surgical options that offer fertility preservation without effecting survival should be considered.
The first fertility issue is the decision regarding ovarian conservation.
One concern is that of the risk of ovarian metastases and the safety of leaving the ovaries behind.
The rough estimate for ovarian involvement is less than one percent for SCC, and between 1.5-5% for adenocarcinoma.
(GOG 49 SCC 0.5%, AC 1.7%)
Given the that the overall risk of ovarian metastases is low, a properly counseled patient can consider ovarian conservation.
Cut:
The GOG performed a study to evaluate the risk of ovarian metastasis of cervical cancer.
Sutton et al published data in 2006.
In their study, 990 patients with stage Ib were examined, and ovarian metastasis was identified in 4 of 770 (0.5%) patients with squamous cell carcinoma and 2 of 121 (1.7%) patients with adenocarcinoma.
Although the frequency of metastases was greater among patients with adenocarcinoma, this was not statistically significant.
A larger study was performed by Shimada et al and published in 2006.
The study population consisted of 3471 patients with stage Ib to IIb cervical cancer who underwent radical hysterectomy, including pelvic lymphadenectomy and bilateral salpingo-oophorectomy, at six institutions between 1981 and Ovarian metastasis occurred more frequently among patients with adenocarcinoma than among those with squamous cell carcinoma (5.31% vs. 0.79% P < 0.01).
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): Lu et al, Gynecol Oncol. 2013;04:470.

19. 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
If the ovaries can stay, what about the uterus?
Radical trachelectomy was first described via the vaginal approach with l/s pelvic LND by Dragent in 1987 and first performed in 1994.
This method describes division of the uterus beneath the isthmus, and at completion of the surgery, the uterus is sutured to vagina.
Options for radical conservative surgery include the originally described vaginal technique, as well as more recent techniques utilizing minimally invasive techniques, including l/s and robotic.
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): Lu et al, Gynecol Oncol. 2013;04:470.

20. Candidates for fertility preservation Cervical Cancer
In these photos, you can see:
The radical abdom trachelectomy, in which the cervix and parametria are seperated from the fundus.
And the uterine fundus is then reattached to the vaginal apex, following the placement of a cerclage.
Finally, the reattached uterus can be seen here, with blood supply from the intact utero-ovarian ligaments.
Radical abdominal trachelectomy—
the cervical tissue and parametria are separated from the fundus

21. Candidates for fertility preservation Cervical Cancer
In these photos, you can see:
The radical abdom trachelectomy, in which the cervix and parametria are seperated from the fundus.
And the uterine fundus is then reattached to the vaginal apex, following the placement of a cerclage.
Finally, the reattached uterus can be seen here, with blood supply from the intact utero-ovarian ligaments.
The uterus is reattached to the vaginal apex

22. Candidates for fertility preservation Cervical Cancer
In these photos, you can see:
The radical abdom trachelectomy, in which the cervix and parametria are seperated from the fundus.
And the uterine fundus is then reattached to the vaginal apex, following the placement of a cerclage.
Finally, the reattached uterus can be seen here, with blood supply from the intact utero-ovarian ligaments.
The reconstructed fundus with remaining blood supply from the intact utero-ovarian ligaments—uterine serosa without evidence of fundal ischemia

23. Candidates for fertility preservation Cervical Cancer
Survival outcomes
Recurrence
Mortality
Obstetric outcomes
>250 live births have been reported1
Plante et al, 20082, 20113
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% 4%
Term delivery
40%
55%
Since the advent of the VRT, more than 1000 cases of vaginal trachelectomy have been reported, with over 250 live births.
Plante et al (2008) tabulated obstetrical outcomes for 603 patients who underwent VRT, combining data from several publications, with 256 pregnancies documented.
Approx: 62% of pregnancies delivered in the third trimester, of which 65% will reach term.
The PTD rate was 28%, of which only 12% ended with significant prematurity (<32 weeks).
Overall, 40% of the pregnancies resulted in a healthy newborn at term.
An update in 2011 on prospective data collected from 1991 to 2010 in 125 VRTs.
In terms of obstetrical outcome, 58 women conceived a total of 106 pregnancies.
The first and second trimester miscarriage rates were 20% and 3% respectively, and 77 (73%) of the pregnancies reached the third trimester, of which 58 (75%) delivered at term. Overall, 15 (13.5%) patients experienced fertility problems, 40% of which were due to cervical factor.
Twelve (80%) were able to conceive, the majority with assisted reproductive technologies.
1Lu et al, Gynecol Oncol. 2013;04:470. 2Plante et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.

24. Candidates for fertility preservation Cervical Cancer
Recurrence risk factors:
2008
Lesions larger than 2 cms (29 vs 1%)
Presence of LVSI (12 vs 2%)
2011
Lesions larger than 2 cms
Oncologic outcomes
Plante et al, 20081, 20112
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
96%
Oncologic outcomes are critical to evaluate as well.
Cervical cancer recurrence rate is between 4.2 – 5.3%, with mortality rate 2.5 – 3.2%.
In the 2008 study, 603 patients were reviewed, and recurrence rate and death from disease was evaluated.
The outcomes have been satisfactory, with an overall recurrence rate of 4.5%, and death from disease of 2.5%.
Risk factors for recurrence included lesions larger than 2 cms (29 vs 1%), and presence of LVSI (12 vs 2%).
The update in 2011 was prospective data on 125 patients who underwent VRT.
The mean follow-up time is 95 months.
Overall, 6/125 patients (4.8%) have developed a recurrence and 2 have died of their disease (1.6%) for a 5-year recurrence free survival of 96%. Interestingly, all recurrences were in node negative patients.
The only statistically significant risk factor for recurrence was lesion size greater than 2 cm.
Abdominal approaches have been developed, including laparoscopic and robotic techniques.
Retrospective analyses have been reported on these techniques that support the safety and efficacy, but long term follow ups are needed for details on obstetrical outcomes and survival analyses.
1Plante et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.

25. Candidates for fertility preservation Endometrial Cancer
Meta-analysis2
Regression rate
Resolution of 76% of 408 patients
Live birth rate:
28% live birth rate
Recurrence rate:
41% of 267 of evaluable patients had recurred
Endometrial Cancer
It is estimated that 52,630 women will be diagnosed in 20141
Candidates
Early stage uterine cancer, FIGO Ia
Low grade histology (endometrioid)
No myometrial involvement (MRI)
Treatment
Progestin
Medroxyprogestone
Megestrol acetate
Levonorgestrel IUD
It is estimated that over 50K women will be diagnosed with cancer of the uterus in 2014
Endometrial cancer is the most frequently occurring gyn malignancy in the United States, and while it is predominantly a disease of postmenopausal women, greater than 25% of cases occur in premenopausal women.
The SOC would be hysterectomy, bso, and staging with PPALND.
However, despite the oncologic risk, the treatment may be undesirable to some women who wish to maintain fertility.
Studies have described the feasibility and safety of treating women with early stage, low grade carcinoma of the uterus with high dose progestins.
The hypothesis is that through activation of the progesterone receptors, resulting in stromal descidualization and subsequent thinning of the endometrial lining.
Who are candidates?
Early stage uterine cancer, without myometrial invasion, and favorable, low grade histology (endometriod).
Clear cell and serous histologies are associated with more aggressive tumors, and are not recommended as candidates for hormonal therapy.
Options for progrestin therapy include medroxyprogesterone, megace, and the Mirena IUD, among others.
Although the first publication describing fertility preservation in uterine cancer using progestins was published in 1961, the number of publications describing outcomes are still limited, around 40 manuscripts and 620 patients.
Many questions still remain unanswered.
Based on data up to 2012, conservative treatment resulted in the resolution of 76% of 408 patients, with less than 1% reporting a poor outcome.
However, only 22% of 325 patients achieved live births, and 41% of 267 of evaluable patients had recurred.
_2010/results_single/ sect_01_table.01.pdf. 2Gallos et al, Am J Obstet Gynecol. 2012;207:(266):e1-2.

26. 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
P-value
0.03
0.002
0.02
0.39
n/a
Gunderson et al performed a systematic review of all oncologic and pregnancy outcomes in women with CAH or cancer who underwent medical management with progestins from 2004 to 2011, which was published in 2012.
45 studies were included with 391 patients evaluable.
The median age was 31.7 years old.
The majority of these women were treated with medroxyprogesterone (49%), megace (25%), IUD (19%) among others.
Not unexpectedly, those with a cancer diagnosis did worse compared to those with hyperplasia.
Overall, over 75% demonstrated a response to hormonal therapy.
The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%).
**CLICK***
The median time to complete response was 6 months.
Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p = .03).
***CLICK***
Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p = .02).
During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p = .39), with 117 live births reported.
Conclusion
Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.
Unfortunately, there is no definitive consensus regarding the optimal progestin regimen and duration. (megace 160 mg BID)
Progestin therapy has an effect as early as 10 weeks after initiation of treatment, but most wait 3 months before assessing effect of treatment.
9 months has previously been reported as the median time required for regression.
Obesity and anovulatory women have been shown to require longer periods of progestin therapy for a complete response.
Therefore the type and duration of therapy must be tailored to the patient.
With appropriate surveillance for disease status, hormonal therapy can be a safe and moderately effective treatment.
But these patients must be counseled regarding soc therapy, and the risk of lack of response and even progression of disease while on hormonal therapy.
1Gunderson et al, Gynecol Oncol. 2012;125;

27. Candidates for fertility preservation Ovarian Cancer
Park, et al 20092
Borderline ovarian tumors
Recurrence Rate: 4.9% (SOC) vs 5.1% (fert sparing)
Disease free survival
10 yr DFS: 92% (SOC) vs 95% (fert sparing)
Overall survival
10 yr OS: 97% (SOC) vs 98% (fert sparing)
Pregnancy
34 term pregnancies
Ovarian cancer
>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?
Treatment
Surgical
USO, omentectomy, washings, peritoneal biopsies, pelvic and aortic lymphadenectomy
Preservation of one ovary, uterus
It is estimated that 22K women will be diagnosed w ovarian cancer in 20141
But as up to 15% of women diagnosed with ovarian cancer are less than 40, fertility preservation warrants consideration.
The mainstay of treatment is full staging, to include TAH BSO.
Removal of the contralateral ovary and uterus is recommended due to risk of metastasis in most cases.
Fertility preservation is widely accepted in early-stage borderline, germ cell and sex cord-stromal tumors.
Park et al published a retrospective study in 2008 looking at 360 women who had been diagnosed with a BOT, with 344 of those early stage.
176 underwent full staging, while 184 underwent fertility preserving surgery.
After a median follow up was 70 months, 18 patients has recurred, and 5 died of disease.
The rate of recurrence was similar between the two groups, about 5% for each.
The 10 year DFS was also similar, 92% vs 95%.
The 10 OS was also similar 97 vs 98%, and seen here on this Kaplan Meyer.
The pregnancy outcomes was collected on 71% of those who underwent fert preserving surgery. Of those, 31 women had attempted to conceive, and 27 patients had succeeded (32 singletons and 1 set of twins). At the time of the publications, 34 term babies had been born, and to date, none of those patients has undergone radical surgery after completion of childbearing.
_2010/results_single/ sect_01_table.01.pdf 2 Park et al, Gynecol Oncol. 2009;113:75-82.

28. Candidates for fertility preservation Ovarian Cancer
Epithelial Ovarian cancer?
Candidates
Stage IA
Stage IC, grade 1-2, favorable histologic type
Serous, mucinous, endometrioid
Ineligible
Stage >IC
Grade III
Unfavorable histologic type
Clear cell
Poorer survival
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
In younger patients with invasive EOC, the role of fertility sparing surgery has not been well defined.
Based on data from retrospective studies, fertility-sparing surgery in epithelial ovarian cancer can be recommended in stage IA, stage IC grade 1–2 and favorable histologic type ovarian cancer.
Above stage IA, or in grade 3, or in clear-cell tumors decision making process about fertility-sparing surgery should be individual.
The most recent data published is a retrospective meta-analysis published by Nam at al, in 5/2013.
All articles dealing with fertility-sparing surgery for EOC published between 1969 and 2012 were collected.
To date, 918 patients with EOC underwent fertility-sparing surgery; 109 (11.9%) had disease recurrence and 48 (5.2%) died of disease.
To date, 177 patients have succeeded in achieving 242 pregnancies, resulting in 214 term (88%) and 1 preterm (0.4%) births.
Miscarriage rate was about 10% (25/242) and ectopic pregnancy rate was 0.8% (2/242) after fertility-sparing surgery.
No congenital anomaly has been reported.
Conclusions: Although randomized controlled trials have yet to be performed, many studies have suggested that fertility-sparing surgery is safe, with promising reproductive outcomes.
Cautious selection of patients is important because of 5.2% mortality and 11% recurrence after this surgery.
1Nam et al, Gynecol Obstet Invest. 2013;76(1):14-24.

29. American Society of Clinical Oncology (ASCO) Clinical Oncology Clinical Practice Guidelines
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
Oocyte cryopreservation is considered a standard practice, and no longer experimental
2006 ASCO1
Key Recommendations:
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
In 2006, ASCO published clinical guidelines on fertility preservation for adults and children with cancer.
A systematic review of the literature was performed from 1987 to 2005.
This was updated in 5/2013.
A review of the latest literature and publications determined the same recommendations held true, except for adding oocyte preservation as a standard practice, and no longer experimental. ***CLICK***
1Lee et al, J Clin Oncol. 2006;24: Loren et al, J Clin Oncol Jul 1;31(19):

30. Summary Fertility matters, even with a cancer diagnosis OncoFertility
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
Summary
In Summary- the main drive behind this talk was to stress the importance of considering fertility preservation when it is appropriate.
Studies have shown that it is of importance to our patients to address this, and it is important to refer these patients promptly when appropriate to REI prior to the start of treatment.
Studies also show that we as physicians are not good addressing these topics with our patients.
Oncofertility is still in it’s infancy.
Though we have made strides to improve the options for fertility preservation, more studies are needed in order to know the effects of these treatments on cancer recurrence and survival.

31. Thank You
Cuterus- the adorable uterus!