Oocyte cryopreservation as a fertility preservation measure for cancer patients

Reproductive BioMedicine Online (2011) 23, 323– 333

www.sciencedirect.com www.rbmonline.com

SYMPOSIUM: OOCYTE CRYOPRESERVATION REVIEW

Oocyte cryopreservation as a fertility preservation measure for cancer patients Nicole Noyes a,*, Jaime M Knopman a, Katherine Melzer a, M Elizabeth Fino a, Brooke Friedman b, Lynn M Westphal b a

NYU Fertility Center, NYU School of Medicine, New York, NY 10016, USA; University School of Medicine, Stanford, CA 94305, USA

b

Department of OB/GYN, Stanford

* Corresponding author. E-mail address: [email protected] (N Noyes). Dr Noyes has worked full-time in infertility since 1990. She received her medical degree from the University of Vermont, then completed residency in obstetrics/gynaecology and fellowship in reproductive endocrinology at the New York Hospital-Cornell Medical Center. She is board-certified in both obstetrics/gynaecology and reproductive endocrinology. Dr Noyes has been involved in the treatment of over 17,000 infertility patients using assisted reproductive technologies. In addition, since 2004, she and Dr Westphal have been actively involved in fertility preservation, including oocyte freezing. Their continued academic collaboration has culminated in this important and informative clinical review.

Abstract Advances in cancer treatment have allowed women to live longer, fuller lives. However, gonadotoxic therapies used to

effect cancer ‘cures’ often significantly impair a woman’s reproductive potential. Thus, in accordance with improved survival rates, there is an increase in demand for fertility preservation. Initially, fertility preservation was limited to embryo cryopreservation; therefore, the number of patients enrolling was relatively low. Recently, substantial improvements have increased available options, specifically oocyte cryopreservation, thereby expanding and altering the make-up of the patient population undergoing treatment for fertility preservation. Patient diversity requires the treating physician(s) to be cognizant of issues specific to cancer type and stage. Furthermore, patients often have comorbidities which must be attended to and addressed. Although not all patients will be candidates for, or will elect to pursue, fertility preservation, all should receive counselling regarding their options. This practice will ensure that the reproductive rights of those patients facing impending sterility are maintained. Here, fertility preservation protocols, practices and special considerations, categorized by most frequently encountered cancer types, are reviewed to guide reproductive endocrinologists in the management of fertility preservation in such patients. The formation of a multidisciplinary patient-structured team will ensure a successful, yet safe, fertility-preservation outcome. RBMOnline ª 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: cancer, fertility preservation, oocyte cryopreservation, quality of life, survivorship

Introduction Dramatic improvements in cancer treatment have had a significant impact on long-term survival. Therefore, qual-

ity-of-life issues such as fertility preservation have become paramount in the lives of reproductive-age women battling malignancy and an integral component in cancer management. Historically, embryo cryopreservation was

1472-6483/$ - see front matter ª 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.rbmo.2010.11.011

324 the only option offered to female patients and, while successful, was underutilized and has disadvantages. First, a sperm source is required; male gametes are often not available to young single women except through an anonymous donor. Second, a myriad of ethical, religious and social issues are associated with the creation and storage of embryos, especially in the face of a malignancy. The introduction of a newer technique, oocyte cryopreservation, satisfied several of the above concerns and offered women an ideal modality to not only preserve their fertility but also their reproductive autonomy. Despite this, initial outcome data were unsatisfactory and gamete survival and fertilization were poor; the gamete’s high water content and temperature-sensitive internal structures compromised its ability to survive the cryopreservation process. However, continued research allowed for procedural modifications, such as dehydration protocols obviating osmotic stress and cryo-tools to store the oocytes, that significantly improved and fostered the growth of this technique. In addition, the use of intracytoplasmic sperm injection resulted in more consistent fertilization (Gook et al., 1995). There are now over 1000 reported live births as a result of oocyte cryopreservation (Noyes et al., 2009a; Rudick et al., 2010) with some centres reporting pregnancy rates similar to those of standard fresh IVF treatments (Cobo et al., 2010; Nagy et al., 2009; Noyes et al., 2010a). Although still considered experimental by the American Society for Reproductive Medicine (Practice Committee Bulletin, 2008), a recently published survey showed that more than 50% of US infertility clinics currently offer oocyte cryopreservation for cancer patients (Rudick et al., 2010), indicating that this technology is becoming a mainstream technique. In addition, ovarian stimulation parameters and oocyte yield (both the total number and the percentage mature) in cancer patients have been shown to be comparable to those of healthy women undergoing fertility treatment (Noyes et al., 2010b). Other fertility preservation methods that have earned attention in recent years include ovarian tissue cryopreservation with orthotopic transplantation and in-vitro maturation (IVM). The rationale for orthotopic transplantation is that primordial follicles within excised ovarian tissue may be more resistant to the cryopreservation process and that it can be performed without a delay in cancer treatment. However, this method is surgically invasive and requires two procedures (one for harvesting and one for transplantation). There is also the possibility of reintroducing malignant cells (Meirow et al., 2008) and the concern for short-term viability of the transplant. When considering this technique, practitioners should ensure that there is no evidence of preoperative ovarian metastases using imaging (e.g. positron emission tomography/computed tomography) as well as post-operative histological evaluation to rule out micrometastases (Azem et al., 2010; Meirow et al., 2008). To date, there have only been seven reported live births in cancer patients undergoing such procedures and all but one used ovarian tissue preserved before age 28 (Andersen et al., 2008; Demeestere et al., 2007, 2010; Donnez et al., 2004; Meirow et al., 2004; Sanchez-Serrano et al., 2010). In addition, none of the pregnancies have occurred in the absence of remaining in-vivo (albeit non-functioning) ovarian tissue. IVM involves the retrieval of immature oocytes after minimal or no gonadotrophin stimulation, followed by in-vitro

N Noyes et al. maturation and subsequent cryopreservation of matured oocytes (or embryos, if a male partner is involved). Advantages of this approach are that it is minimally invasive and can be accomplished rapidly in the absence of gonadotrophin stimulation, even in the luteal phase, in order to start cancer treatment without delay (Demirtas et al., 2008). The outcomes of two oocyte IVM vitrification trials involving 58 patients without cancer have recently been reported, with a total of 19 live births and 26 healthy newborns resulting (Chian et al., 2008). This group has also demonstrated the feasibility of IVM followed by oocyte and embryo vitrification in a group of breast cancer patients (Huang et al., 2010). The technology of IVM holds promise but further studies are necessary to assess whether it will have widespread utility as a fertility preservation measure in patients newly diagnosed with malignancy. Cancer patients represent a diverse patient population, even within certain cancer types. Thus, providers must be cognizant of all procedures and options available for such patients. This review presents statistics treatment options and stimulation protocols suitable for the most commonly encountered cancers, as well as special considerations necessary for providing fertility preservation to female cancer patients in a safe and efficient manner.

Cancer treatments that result in fertility compromise Chemo- and radiotherapy often cause varying degrees of compromise on reproductive function; in general, the impact is proportionate to treatment dose, patient age and chemotherapeutic regimen. In particular, alkylating agents (e.g. cyclophosphamide), abdominal/pelvic and/or total body irradiation, bone marrow transplantation and/or removal of critical reproductive organs can leave a ‘cured’ cancer patient unable to naturally conceive after treatment. The gonadal effects of varying cancer regimens have been previously presented in detail in Knopman et al. (2010) and Noyes et al. (2010c), the controversial use of a longacting gonadotrophin-releasing hormone (GnRH) agonist as a potential means to protect the ovaries during chemotherapeutic treatment is also addressed.

Candidates for fertility preservation In selecting candidates for fertility preservation, several factors must be considered prior to the initiation of treatment. The most important is age (optimal <40 years), as it not only determines the woman’s ability to achieve a pregnancy using autologous oocytes but also the desire to preserve fertility. Next, tumour type, disease stage and overall health status dictate the timing and appropriateness of fertility preservation treatment. Oocyte cryopreservation requires ovarian stimulation and retrieval, which together take an average of 12 days in cancer patients (Noyes et al., 2010b) and may conflict with schedules for cancer treatments. In addition, oocyte cryopreservation has risks such as ovarian hyperstimulation syndrome and intra-abdominal bleeding, which are low (5%) but can strain an already medically-stressed patient. Lastly, cost can hinder a patient’s ability to pursue fertility preservation

Egg freezing as a fertility preservation measure for cancer

325

treatment. In general, cancer patients in the USA are not afforded coverage for oocyte cryopreservation at this time and therefore are not always able to bear the added financial burden. Despite such considerations, all reproductive-age women undergoing cancer treatment who desire fertility preservation should be informed of their options and referred promptly for fertility preservation counselling by an experienced provider. This affords an interested patient the greatest opportunity for successful fertility preservation treatment.

tion, although oocyte and embryo cryopreservation are more appropriate if a 2-week cancer treatment delay is feasible. Table 1 lists methods to initiate ovarian stimulation as quickly as possible. Young patients are often already on oral contraceptive pills (OCP), allowing fertility providers to initiate cryopreservation treatment right away. In fact, ovarian stimulation can be started 1–2 days after discontinuation of OCP, significantly abbreviating cancer treatment delay as compared with waiting for the next natural menses. In addition, a GnRH antagonist (ganirelix, Merck; cetrorelix, EMD Serono Pharmaceuticals), with or without OCP, can be administered at any point in the menstrual cycle, initiating ovarian stimulation soon after. Finally, given the young age of these patients, the ovarian stimulation protocol should include a modest, although relatively aggressive (300–375 IU), daily dosage of gonadotrophins. Special consideration should be made for patients with a low body mass index or low baseline gonadotrophin assessment in that some form of LH supplementation should be utilized. Because patients with haematological malignancies pursuing oocyte/embryo cryopreservation often proceed directly from ovarian stimulation to cancer therapy (sometimes within 1–3 days of oocyte harvest), an alternative to the human chorionic gonadotrophin ovulation trigger may be considered (Table 1); in a treatment cycle where a GnRH-antagonist has been used for LH suppression, leuprolide acetate (TAP Pharmaceuticals) can be substituted as a single 0.4 ml (2 mg) subcutaneous dose, which causes final maturation of the oocytes followed by rapid and profound luteolysis, decreasing the interval from oocyte harvest to next menses by approximately 1 week (Engmann et al., 2008). This generally allows patients to safely transition to oncological treatments without commensurate ovarian stimulation sequelae.

Fertility preservation by common tumour types Haematological malignancies Over the past 30 years, advances in treatment for haematological malignancies have led to marked improvement in survival (Figure 1; Altekruse et al., 2010) affording young survivors the opportunity to pursue parenthood post treatment. However, many such treatments, particularly chemotherapy and total body irradiation in preparation for bone marrow transplantation, are associated with significant gonadal toxicity (Grigg et al., 2000; Meirow, 1999; Socie et al., 2003; Teinturier et al., 1998; Thibaud et al., 1998). In fact, with the exception of good-prognosis Hodgkin’s patients who can often be treated with a combination of less gonadotoxic drugs, such as doxorubicin, bleomycin, vinblastine and dacarbazine, lymphoma patients require treatment with highly gonadotoxic agents. Although treatment regimens for leukaemia patients (antimetabolites and anthracyclines) pose only a moderate risk for gonadal failure (Maltaris et al., 2006; Waring and Wallace, 2000), oocyte/embryo cryopreservation should be offered. Time is of the essence when formulating a treatment plan for patients with haematological malignancies. In general, the tumour burden is high at the outset of diagnosis, requiring that cancer therapy begins almost immediately. If no window of opportunity exists, ovarian tissue or oocyte harvest with IVM can be considered in this patient popula-

Breast cancer Breast cancer is the most frequently diagnosed malignancy among women, with 25% of cases occurring prior to menopause and 7% diagnosed in women younger than age

Figure 1 Improved 5-year survival rates from 1975 to 2006 for female lymphoma and leukaemia patients. The survival differences between 1975–1977 and 1999–2006 were statistically significant (P < 0.05). (Based on Surveillance, Epidemiology and End Results data; Altekruse et al., 2010.)

326 Table 1

N Noyes et al. Methods to initiate ovarian stimulation for fertility preservation treatment in cancer patients.

Situation

Method

To determine a starting point for treatment in patients without a uterus or with irregular menses

Measure serial serum progesterone/oestradiol concentrations, or, alternatively, urinary or serum LH concentrations Once ovulation is detected, a daily subcutaneous GnRH agonist can be initiated one week later Alternatively, oral medroxyprogesterone acetate (10 mg for 10 days) can be administered at any point in the menstrual cycle concurrently with GnRH agonist injections (beginning agonist treatment on day 6 of progesterone administration) Administer a single 3mg dose or 2–3 consecutive daily 250lg doses of GnRH antagonist; begin ovarian stimulation 5–7 days after the single/first dose. If serum estradiol is high at that time, add a daily subcutaneous dose of GnRH antagonist to the first 2 days of gonadotropin stimulation or Give OCP for 4–6 days, initiating a daily 250lg dose of GnRH antagonist on the last 2–3 days of OCP treatment; begin ovarian stimulation 2 days later or In the luteal phase, initiate daily 250lg doses of GnRH antagonist at the same time as daily subcutaneous gonadotrophin administration Administer 1–6 daily 250lg doses or a single 3mg dose every 4 days of GnRH antagonist or Give OCP for 4–14 days; initiating daily 250lg dose of GnRH antagonist on the last 2–3 days of OCP treatment Letrozole (oral aromatase inhibitor 5 mg per day) can be initiated concurrently with gonadotrophin stimulation and continued 7 days post-oocyte retrieval to mitigate the oestradiol rise of stimulation Leuprolide acetate (single 0.4 ml (2 mg) injection) can be administered in lieu of the traditional HCG ovulation trigger. Employing a GnRH agonist to achieve final oocyte maturation results in profound luteolysis and heralds rapid onset of the next menses (approximately 5–7 days post retrieval)

To initiate treatment immediately to avoid a delay in cancer treatment, irrespective of menstrual cycle

To hold off treatment while completing a cancer evaluation

Special stimulation considerations for hormone-sensitive tumours

To limit the incidence of ovarian hyperstimulation syndrome in patients with a high response to gonadotrophins or those undergoing cancer treatment in close proximity to oocyte retrieval

GnRH = gonadotrophin-releasing hormone; HCG = human chorionic gonadotrophin; OCP = oral contraceptive pill.

40 (Bines et al., 1996; Hankey et al., 1996; Parkin et al., 2005). Fortunately, there has been a decline in mortality in young breast-cancer patients and an increase in disease-free survival, resulting in part from improved treatments with adjuvant cytotoxic chemo- and hormonal therapy (Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2005) and earlier detection. Now, over 90% of all breast cancers are diagnosed at local/regional stages, with a 98% 5-year survival rate for those with local disease and 84% with regional disease (Altekruse et al., 2010). As cure rates for breast cancer improve, there has been a growing awareness of the long-term impact of cytotoxic treatment on cancer survivors. Particularly, as women more frequently delay childbearing, breast-cancer patients of reproductive age often face infertility as a result of their treatment. Loss of reproductive potential is a major concern for young women faced with a breast-cancer diagnosis, with nearly a third of patients reporting that infertility concerns influenced their treatment decisions (Avis et al.,

2004; Partridge et al., 2004). Oocyte and embryo cryopreservation are often reasonable options in this patient population. Regarding fertility preservation treatment, breast tumours are known to be hormone-sensitive in approximately 60% of patients, with oestrogen and its metabolites implicated in disease progression. Moreover, animal models suggest that oestrogen may also play a role in stimulating the growth of oestrogen receptor-negative breast cancers (Gupta et al., 2007). Therefore, conventional stimulation protocols with gonadotrophins prior to oocyte retrieval are often modified to include administration of the aromatase inhibitor letrozole (Oktay et al., 2006) or the selective oestrogen modulator tamoxifen (Oktay et al., 2003; Table 1). Although tamoxifen causes an increase in oestradiol concentrations, its action as a competitive antagonist of oestrogen at the receptor site has been shown to inhibit breast tumour development. Alternatively, concurrent use of letrozole with gonadotrophins can reduce the likelihood of a marked

Egg freezing as a fertility preservation measure for cancer

327

increase in oestradiol concentrations, as seen with conventional gonadotrophin-stimulated IVF treatment (Oktay et al., 2006). These protocols have been used with success in mitigating the oestradiol excesses that are normally seen with conventional protocols. Short-term follow up on the use of these modified regimens in a small cohort of patients (including both oestrogen-receptor positive and negative tumours) found comparable disease-free and survival rates as compared with those not undergoing fertility preservation procedures (Azim et al., 2008). Long-term data, however, showing any benefit relative to cancer prognosis is not yet available and thus, the treatment modification is probably not necessary in light of the fact that the oestradiol rise in ovulation induction lasts only about 10 days. Nonetheless, it is reasonable to employ these newer regimens to decrease oestrogen exposure. A means of further reducing oestradiol concentrations quickly is using a GnRH-agonist rather than human chorionic gonadotrophin to trigger ovulation (Table 1). Timing of fertility preservation treatment in such patients is important. Therefore, patients should receive a prompt referral to a fertility preservation specialist while their cancer evaluation is still underway. If possible and when surgery is the first step in tumour management, proceeding with the surgical portion of treatment is recommended and thereafter returning immediately for initiation of a fertility preservation treatment cycle. The latter can usually be accomplished in 2–3 weeks and patients can then proceed with additional cancer treatment (i.e. chemo, radiation and/or hormonal therapy). Standard ovarian stimulation starts early in the menstrual cycle and therefore, if the patient is seen and is about to start or has just started her menstrual cycle, she can be given a GnRH antagonist to ‘hold’ her cycle to finish her cancer evaluation (Table 1). She will then be ready to start stimulation as soon as her cancer treatment has been determined. If the patient needs to start stimulation quickly and is mid-cycle, a GnRH antagonist can be used to induce menses within 5–7 days (Table 1). Retrospective reviews have revealed that stimulation and oocyte retrieval do not significantly delay breast-cancer treatment, with no significant differences seen in median time from diagnosis to chemotherapy or from definitive operation to chemotherapy between patients who chose to undergo stimulation and oocyte harvest and those who did not (Baynosa et al., 2009; Madrigrano et al., 2007). IVM without gonadotrophin stimulation can also be considered in the setting of breast cancer when there is no time available to pursue other fertility preservation measures.

or unilateral salpingo-oophorectomy (both performed with appropriate staging procedures to ensure limited disease) as well as uterine preservation. Ovarian preservation not only allows for fertility preservation using either oocyte or embryo cryopreservation, but also avoids the consequences of early surgical menopause and oestrogen deprivation. Although ovarian cancer is the global term applied to tumours that arise in the ovary, there are several distinct subtypes which differ in patient characteristics, prognoses and thus potential for fertility preservation that warrant individual attention. Epithelial ovarian cancer (EOC), the most common subtype, is primarily a disease of older women; however 3–17% of EOC are diagnosed in women younger than age 40 (Schilder et al., 2002). Furthermore, of stage-I tumours, 7–8% are in patients younger than age 35 (DiSaia, 1990; Scully, 1970). Fertility preservation surgery has been evaluated for early-stage disease in these women and a recent review of Surveillance, Epidemiology and End Results (SEER) data that compared patients who had fertility-sparing procedures with those that did not found no difference in 5-year survival between the groups (Wright et al., 2009). Of note, lymphadenectomy is recommended in such patients, as occult lymph node disease will be identified in 10–25% of patients with clinically apparent stage-I disease (Burghardt et al., 1991; Cass et al., 2001) and upstaging would have consequences with regards to fertility preservation candidacy. In patients with early-stage EOC, fertility-sparing procedures do not appear to compromise survival and thus can be offered in appropriate situations. Tumours of low malignant potential are considered a subset of EOC, accounting for 10–15% of this tumour category (Park et al., 2009). Their less aggressive nature and lower rate of metastases often result in diagnosis at an earlier age and stage. Multiple investigators have advocated conservative surgery for these patients and it is generally accepted as an appropriate therapeutic option for patients with early-stage disease who desire fertility preservation. Furthermore, recurrences in these patients tend to be local and can be treated with additional fertility-sparing surgery when appropriate. Germ cell tumours are most often diagnosed in young women and adolescent girls. They are frequently unilateral and are curable if detected and treated early. Patients can be treated with unilateral salpingo-oophorectomy or total abdominal hysterectomy and bilateral salpingooophorectomy, depending on their wishes for future fertility. However, all patients, except those with stage-I, grade-I immature teratomas and stage-IA dysgerminomas require post-operative chemotherapy, which is often platinum-based. With a moderate risk for gonadotoxicity, fertility preservation should be considered accordingly. Both oocyte cryopreservation and embryo cryopreservation are reasonable options in reproductive-age patients diagnosed with ovarian tumours. Ovarian stimulation in this patient population can present a challenge for several reasons. In those who have undergone a unilateral salpingo-oophorectomy, oocyte count is decreased due to reduced ovarian volume. Furthermore, for patients that have already undergone adjuvant chemotherapy, higher doses of gonadotrophins (i.e. 450 IU daily) may be necessary to induce an adequate ovarian response. Additionally, there

Gynecological cancers Ovarian cancer Fertility preservation for patients diagnosed with ovarian cancer has earned considerable attention in the past decade with several paradigm shifts in management options. Historically, the standard-of-care for ovarian-cancer treatment was total abdominal hysterectomy, bilateral salpingooophorectomy and concomitant staging procedures. However, in recent years, for appropriately selected patients, a shift towards less radical surgery is now considered. In certain cases, patients may be candidates for a simple ovarian cystectomy (low malignant potential cancer)

328 are patients who have previously undergone treatment for early-stage ovarian cancer with a unilateral salpingooophorectomy and return with a localized recurrence to the other ovary. Fertility preservation requires stimulation of the remaining affected ovary prior to its planned removal. Although stimulation/retrieval of the affected ovary does not appear to have an impact on staging or disease progression, this practice warrants close monitoring and patients should be counselled of such. This review recommends attempting to avoid penetrating the tumour, even if this results in leaving follicles/oocytes. In addition, the role of completion surgery following ovarian stimulation or childbearing remains unclear. Longer follow-up and increased patient numbers will likely clarify these complex situations and guide clinicians in management in the future. Regardless, fertility preservation should be entertained in patients with treatable ovarian malignancies. Endometrial cancer/hyperplasia Endometrial carcinoma, the most common malignant tumour occurring in the female genital tract, is largely a disease of post-menopausal women. Premenopausal women, however, are not spared and account for approximately 2–14% of all endometrial cancer diagnoses (Crissman et al., 1981; Gitsch et al., 1995; Kempson and Pokorny, 1968). In young patients, this tumour tends to be associated with prolonged unopposed oestrogen exposure, often seen in clinical states such as obesity, anovulation, infertility and polycystic ovarian syndrome. Atypical endometrial hyperplasia (AEH) is considered to be the precursor lesion to endometrial cancer and is frequently found in association with endometrial cancer in young women. Conventional management of endometrial carcinoma and AEH includes total hysterectomy and bilateral salpingo-oophorectomy. For many premenopausal women diagnosed with either disease, this treatment option is unacceptable because of the desire for future parenthood and therefore oocyte and/or embryo cryopreservation should be considered in such patients. Interestingly, an estimated 15% of younger patients are actually diagnosed with endometrial cancer and/or AEH in the course of an infertility work up and the majority of young endometrial cancer patients experience infertility (Kempson and Pokorny, 1968). Conservative management, as opposed to standard treatment, may be considered in motivated young women diagnosed with either a low-grade endometrial carcinoma or AEH. This would include the administration of hormonal therapy (oral progestational agents, such as medroxyprogesterone acetate or megestrol, or a levonorgestrel-containing intrauterine device) in an effort to convert the endometrium back to normal. Importantly, this option allows for preservation of the uterus for future childbearing. Promising results have been reported in multiple retrospective, albeit small, series (Farhi et al., 1986; Gotlieb et al., 2003; Kim et al., 1997; Lai et al., 1994; Lee and Scully, 1989; Niwa et al., 2005; Ota et al., 2005; Paulson et al., 1990; Ramirez et al., 2004; Randall and Kurman, 1997; Thornton et al., 1985; Yang et al., 2005). Evidence from these data suggests that hormonal treatment can be effective with a 57–77% initial response rate. However, there are considerable risks associated with this treatment approach, including a 50%

N Noyes et al. incidence of disease recurrence and/or progression and 5–29% chance for developing synchronous or metachronous ovarian malignancies (Crissman et al., 1981; Duska et al., 2001; Evans-Metcalf et al., 1998; Gitsch et al., 1995; Lee et al., 2007; Walsh et al., 2005). Thus, the management of these young women can be challenging and must involve careful oncological, genetic and reproductive counselling prior to any deviation from the standard of care, as well as close surveillance once treatment is initiated. Patients should also be encouraged to actively pursue pregnancy as soon as a response to hormonal therapy is achieved, this being accomplished most expeditiously through assisted reproductive technologies. Given the risks associated with conservative management, patients may consider an intermediate treatment plan including ovarian stimulation with either oocyte or embryo cryopreservation, followed by definitive surgical tumour removal. The patient must be aware that this option requires the use of a gestational carrier in the future. Another treatment option would be to conserve the ovaries at the time of hysterectomy, affording the patient the potential for subsequent ovarian stimulation and oocyte harvest but allowing for primary treatment of disease and the option of future biological offspring through assisted reproduction treatment (again through the use of a gestational carrier). If considering a carrier, in the USA patients need to be aware that the Food and Drug Administration mandates special screening and testing to be done within 30 days of the oocyte retrieval for the female (and if creating embryos, within 7 days for the male). Additional regulations vary by state and treatment should be performed as recommended according to geographical location. The study centres’ typical screening recommendations are listed in Table 2. Serum progesterone concentrations, particularly in patients with irregular cycles or without a uterus, are helpful in assessing hormonal/menstrual status. Over-the-counter ovulation kits that test for the presence of urinary LH can also be useful but are sometimes misleading in patients with chronically elevated LH concentrations (e.g. polycystic Table 2 Routine screening for females considering a gestational carrier after oocyte cryopreservation. Investigation Oocyte donor application/medical history form History and physical Medical history interview form Human immunodeficiency virus types 1 and 2 Human immunodeficiency virus-1 NAT Hepatitis B surface antigen Hepatitis B core antibody Hepatitis C virus and NAT Syphilis (RPR or STS screening test) Neisseria gonorrhoeae NAT Chlamydia trachomatis NAT Human T-lymphotropic virus types I and II West Nile virus (if recent outbreak) NAT = nucleic acid testing; RPR = rapid plasma regain; STS = serological tests for syphilis.

Egg freezing as a fertility preservation measure for cancer

329

ovarian syndrome). A GnRH agonist can be administered once ovulation is documented; alternatively, regardless of ovulation status, a progestational agent overlapped with a GnRH agonist can be utilized (Table 1). If time is of the essence, the ‘quick start’ method (OCP plus GnRH-antagonist overlap or GnRH antagonist alone) may be used (Table 1). The potential risk of endocrine stimulation on any residual tumour foci exists. Therefore, alternatives to standard ovarian stimulation protocols, such as those incorporating letrozole (Azim and Oktay, 2007), may be considered (Table 1) but are not felt necessary. In summary, careful selection of candidates, thorough informed consent and close surveillance are imperative. Importantly, patients are encouraged to proceed with standard surgical treatment once childbearing is completed.

factor infertility. In addition, cervical stenosis can make embryo transfer challenging, if not impossible (Noyes et al., 2009b). In the more difficult situations, a transmyometrial embryo transfer may be necessary; thus, uterine sounding prior to oocyte or embryo thaw is recommended so that proper steps are taken to assure successful intrauterine embryo placement. In addition, due to the high risk of premature delivery following trachelectomy, all such patients should undergo preconception counselling with a perinatologist prior to attempting pregnancy. For example, of reported successful pregnancies after trachelectomy, 29% were noted to deliver prematurely, with one-third lost in the second trimester (Plante et al., 2005). Therefore, when this patient population pursues IVF, a single-embryo transfer is advocated.

Cervical cancer Cervical cancer, unlike other gynaecological malignancies, is most commonly diagnosed during the childbearing ages with 40% of cases occurring in reproductive-age women (Altekruse et al., 2010). Traditionally, treatment has included radical hysterectomy with or without ovarian transposition, post-operative adjuvant pelvic radiation and chemotherapy, depending on disease stage and type. However, because many of these women have not yet satisfied their reproductive desires at time of diagnosis, surgical treatment of early-stage (1A2 and 1B1) disease has been modified. For such patients, radical hysterectomy has often been replaced by radical trachelectomy. In fact, it is estimated that up to half the patients diagnosed in the childbearing years are eligible for this fertility-preserving procedure (Sonoda et al., 2004). In addition, accumulating data suggest that in carefully selected patients, survival is similar to that of radical hysterectomy (Diaz et al., 2008; Plante et al., 2004). Such data demonstrate that quality-of-life measures can be implemented without compromising survival. Despite the ability of select pathology departments to offer an immediate diagnosis from a frozen specimen, the extent of surgical resection, the potential need for ovarian transposition and other post-operative treatments often require a global pathological assessment. Fertility preservation through oocyte/embryo cryopreservation can be performed either pre- or post-surgical staging, but there are a few additional challenges when fertility preservation is initiated post-operatively. First, if ovarian transposition is performed at the time of the staging surgery, the abdominal position of the ovaries requires that ovarian monitoring and oocyte retrieval be performed transabdominally rather than transvaginally. This modification has been associated with a lower yield in the number of oocytes retrieved. Second, initiating ovarian stimulation after hysterectomy requires determining the starting point of treatment serologically (no menses occurs) or alternatively artificially creating a starting point as previously described for endometrial patients (Table 1). In those patients who elect to maintain their uterus and undergo a radical trachelectomy, it is imperative to discuss the high incidence (up to 40%) of cervical stenosis following such a procedure (Carter et al., 2008). Thus, in the event that fertility is maintained with regard to ovarian function, often such patients require assisted reproduction treatment to overcome cervical-

Other special considerations Cancer patients desiring fertility preservation require a careful assessment of their global health and medical status prior to initiating treatment. Often, conventional fertility protocols must be tailored to ensure that all the patient’s needs are appropriately met (Table 1). Therefore, in addition to selecting a stimulation protocol, the reproductive endocrinologist should consider the need for adjuvant medications and diagnostic studies. In many instances, there are significant underlying medical conditions associated with a particular malignancy that warrant pre-operative medical evaluation and clearance from the treating oncologist or internist. For example, the study centres require all patients with a pulmonary process (e.g. mediastinal mass, pulmonary fibrosis, pulmonary hypertension) to obtain a chest X-ray, and, in some instances, pulmonary function tests and even a chest computed tomography to assess pulmonary status. This strategy has been found to be extremely helpful in planning for the upcoming stimulation and oocyte harvest. Furthermore, patients with haematological malignancies occasionally present with pancytopenia. Therefore, a complete blood count, as well as coagulation studies, is required both at the outset and the completion of the ovarian stimulation cycle. Nadiring patients can only begin fertility preservation treatment when their counts are clearly on the rise. Those with significant thrombocytopenia or coagulopathy are advised to cease treatment if, in the treating team’s opinion, the risk of the procedure outweighs the potential benefits. In some thrombocytopenic patients, platelet transfusions have been given just prior to oocyte retrieval with no complications. In addition, for leukopenic patients, antibiotic prophylaxis is recommended both at the time of the oocyte retrieval and often post retrieval to decrease the risk of a postoperative infection. In addition, an awareness of primary tumour site (and significant areas of metastasis) is essential prior to performing the oocyte harvest procedure. Specifically, tumours arising from the genital-urinary tract can alter blood flow to the vaginal wall thereby making the patient’s risk for intra-operative and/or post-operative bleeding higher. Thus, the operating surgeon should take great care to avoid puncturing the tumour or areas with increased vascularity in an effort to diminish the incidence of intra- and post-operative bleeding. Lastly, it is the centres’ practice to have all cancer patients undergoing

330 oocyte/embryo cryopreservation evaluated by the treating anaesthesiologist approximately 7 days before the oocyte harvest procedure. This ensures that any outstanding studies can be performed in a timely manner so as not to delay the stimulation cycle or the patient’s upcoming cancer treatment. An open dialogue exists between members of the treating team – reproductive endocrinologist, oncologist(s), internist, anaesthesiologist, nurse(s) – to ensure patient safety. In order to perform a successful oocyte/embryo cryopreservation cycle, the treating reproductive endocrinologist must not only address the concurrent medical processes that can afflict cancer patients, but also remain cognizant of time constraints surrounding the patient’s cancer treatment. Although breast- and gynaecological-cancer patients often have a 4–6 week window before or between surgery and chemo/radiotherapy, those with other malignancies frequently require emergent treatment. The expediency for treatment requires that the stimulation cycle be completed quickly. This can be somewhat difficult depending on where the patient is in her menstrual cycle as well as the number of days she requires to achieve adequate ovarian stimulation. Ideally, the patient presents on OCP or in the late luteal or early follicular phase of her menstrual cycle and can initiate treatment relatively quickly. Importantly, patients taking OCP can be started without delay; of note, in general, oncologists are advised to continue patients on OCP at the time of diagnosis to facilitate oocyte cryopreservation. Although it can be somewhat more complicated when patients present in the late follicular or early luteal phase of their cycle, stimulation can be successfully initiated at this time utilizing the ‘quick start’ method which initiates OCP for 4–6 days (at any point in the menstrual cycle), overlapped with a daily 250 lg dose of GnRH antagonist for the latter 2–3 days, then beginning ovarian stimulation 1–2 days later. Alternatively, a single 3 mg dose of GnRH antagonist can be administered alone, followed by initiation of ovarian stimulation at or before the onset of the next menses which will occur 5–7 days later (Table 1). These treatments result in rapid follicular degeneration or luteolysis depending on menstrual cycle stage at administration. When initially evaluating patients for oocyte/embryo cryopreservation, the study centres routinely perform a transvaginal (transabdominal if virginal) pelvic ultrasound (to assess ovarian volume and antral follicle count) and, if time permits, serum hormone concentrations (oestradiol, progesterone, LH, FSH, anti-Mu ¨llerian hormone) to gauge the patient’s hormonal status. This information, coupled with the patient’s menstrual history, guides management and allows for an immediate appraisal of the patient’s medication requirements. Although Noyes et al. (2010b) reported a statistically significant difference in the number of days needed to achieve stimulation in cancer patients undergoing oocyte cryopreservation compared with patients without cancer undergoing the same procedure (10 ± 0.3 days versus 9 ± 0.2 days, respectively), the clinical significance is minimal. The slight delay noted in response to injectable gonadotrophins could be the result of stress and/or medication-induced hypothalamic dysfunction and suppression. It is also important to consider this information when selecting gonadotrophin dosing; the study centres tend to give an additional 75 IU of medication than is ordinarily prescribed in the respective age group so as to achieve max-

N Noyes et al. imum ovarian stimulation even in a medically stressed patient. The reproductive endocrinologist must be cognizant of all such factors when formulating a treatment protocol. In addition to timing issues associated with the patient’s upcoming cancer treatment and menstrual cycle, there are occasionally time constraints related to the embryology laboratory’s schedule. In general, laboratories close two to three times a year for equipment servicing and cleaning purposes. Offering fertility preservation for cancer patients mandates that at least minimal laboratory staff and one incubator and hood remain in operation at all times so as not to jeopardize a patient’s cancer treatment schedule. In addition, particularly in those patients pursuing a gestational carrier, if oocytes or embryos are to be transported, it is important that the new facility has expertise in thawing the transferred material. Patients with cancer are in a hypercoagulable state and thus are at a considerably higher risk of developing a venous thromboembolism (VTE). In fact, a large population-based case–control study reported that patients with cancer were 6.7 times more likely to develop a VTE than the general population (Blom et al., 2005). Therefore, the combination of malignancy and ovarian stimulation could further potentiate one’s risk of developing a VTE. In light of this, at times, in concurrence with a haematologist, the study centres initiate VTE prophylaxis (low-molecular-weight heparin, 40 mg per day) at the initiation of ovarian stimulation or, most often, beginning 24 h post retrieval for a period of 2 weeks. Although the benefit of such treatment in fertility preservation for cancer patients has not been documented, VTE prophylaxis should be considered when treating patients at increased risk. If elected, this must be discussed with the treating oncologist to assure there is no conflict with upcoming cancer treatment. In addition to identifying comorbid medical conditions and tailoring an optimal treatment protocol, the reproductive endocrinologist must consider the patient’s social status. Those presenting for fertility preservation are often young and sexually active and should be counselled regarding the need for contraception or sexual abstinence during ovarian stimulation. In the event that the patient does engage in unprotected intercourse in close proximity to the oocyte retrieval and emergency contraception is required, immediate insertion of the copper intrauterine device is a possibility (which has been successfully performed mid-stimulation).

Conclusions The demand for fertility preservation services is increasing as advances in cancer diagnosis and treatment allow women to live longer, fuller lives. Fertility preservation, particularly oocyte and embryo cryopreservation, should be considered an integral and essential component of the patient’s treatment plan. Although not all women will elect to pursue these measures, all women should be cognizant of the available options and have the opportunity to exercise their reproductive choice. Fertility preservation in the setting of cancer can positively influence a patient’s overall feeling of wellbeing by reducing the added stress of potential fertility loss. A multidisciplinary approach, where constant communication between the treating oncologist(s), reproductive

Egg freezing as a fertility preservation measure for cancer endocrinologist and additional support professional(s) exists and allows for prompt referrals and treatment, is imperative. Formulating an effective team ensures that fertility preservation is accomplished efficiently and safely while optimizing the patient’s global needs.

References Altekruse, S.F., Kosary, C.L., Krapcho, M., Neyman, N., Aminou, R., Waldron, W., Ruhl, J., Howlader, N., Tatalovich, Z., Cho, H., Mariotto, A., Eisner, M.P., Lewis, D.R., Cronin, K., Chen, H.S., Feuer, E.J., Stinchcomb, D.G., Edwards, B.K. (Eds.). SEER Cancer Statistics Review, 1975–2007. National Cancer Institute, Bethesda, MD; 2010. Available from: , based on November 2009 SEER data submission, posted to the SEER web site, 2010 (accessed 13.11.10). Andersen, C.Y., Rosendahl, M., Byskov, A.G., Loft, A., Ottosen, C., Dueholm, M., Schmidt, K.L., Andersen, A.N., Ernst, E., 2008. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Hum. Reprod. 23, 2266– 2272. Avis, N.E., Crawford, S., Manuel, J., 2004. Psychosocial problems among younger women with breast cancer. Psychooncology 13, 295–308. Azem, F., Hasson, J., Ben-Yosef, D., Kossoy, N., Cohen, T., Almog, B., Amit, A., Lessing, J.B., Lifschitz-Mercer, B., 2010. Histologic evaluation of fresh human ovarian tissue before cryopreservation. Int. J. Gynecol. Pathol. 29, 19–23. Azim, A., Oktay, K., 2007. Letrozole for ovulation induction and fertility preservation by embryo cryopreservation in young women with endometrial carcinoma. Fertil. Steril. 88, 657–664. Azim, A., Costantini-Ferrando, M., Oktay, K., 2008. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J. Clin. Oncol. 26, 2630–2635. Baynosa, J., Westphal, L.M., Madrigrano, A., Wapnir, I., 2009. Timing of breast cancer treatments with oocyte retrieval and embryo cryopreservation. J. Am. Coll. Surg. 209, 603–607. Bines, J., Oleske, D.M., Cobleigh, M., 1996. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J. Clin. Oncol. 14, 1718–1729. Blom, J., Doggen, C., Osanto, S., Rosendaal, F., 2005. Malignancies, prothrombotic mutations and the risk of venous thrombosis. JAMA 293, 715–722. Burghardt, E., Girardi, F., Lahousen, M., Tamussino, K., Stettner, H., 1991. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol. Oncol. 40, 103–106. Carter, J., Sonoda, Y., Chi, D., Raviv, L., Abu-Rustum, N., 2008. Radical trachelectomy for cervical cancer: postoperative physical and emotional adjustment concerns. Gynecol. Oncol. 111, 151–157. Cass, I., Li, A.J., Runowicz, C., FieLds, A.L., Goldberg, G.L., Leuchter, R.S., Lagasse, L.D., Karlan, B.Y., 2001. Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas. Gynecol. Oncol. 80, 56–61. Chian, R.C., Huang, J.Y., Gilbert, L., Son, W.-Y., Holzer, H., Cui, S.J., Buckett, W.M., Tulandi, T., Tan, S.L., 2008. Obstetric outcomes following vitrification of in vitro and in vivo matured oocytes. Fertil. Steril. 91, 2391–2398. Cobo, A., Meseguer, M., Remohi, J., Pellicer, A., 2010. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Hum. Reprod. 25, 2239–2246. Crissman, J.D., Azoury, R.S., Barnes, A.E., Schellhas, H.F., 1981. Endometrial carcinoma in women 40 years of age or younger. Obstet. Gynecol. 57, 699–704.

331 Demeestere, I., Simon, P., Emiliani, S., Delbaere, A., Englert, Y., 2007. Fertility preservation: successful transplantation of cryopreserved ovarian tissue in a young patient previously treated for Hodgkin’s disease. Oncologist 12, 1437–1442. Demeestere, I., Simon, P., Moffa, F., Delbaere, A., Englert, Y., 2010. Birth of a second healthy girl more than 3 years after cryopreserved ovarian graft. Hum. Reprod. 25, 1590–1591. Demirtas, E., Elizur, S.E., Holzer, H., Gidoni, Y., Son, W.-Y., Chian, R.-C., Tan, S.L., 2008. Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients. Reprod. Biomed. Online 17, 520–523. Diaz, J.P., Sonoda, Y., Leitao, M.M., Zivanovic, O., Brown, C.L., Chi, D.S., Barakat, R.R., Abu-Rustum, N.R., 2008. Oncologic outcome of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma. Gynecol. Oncol. 111, 255–260. DiSaia, P.J., 1990. Fertility-sparing treatment of patients with ovarian cancer. Compr. Ther. 16, 35–42. Donnez, J., Dolmans, M.M., Demylle, D., Jadoul, P., Pirard, C., Squifflet, J., Martinez-Madrid, B., Van Langendonckt, A., 2004. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 364, 1405–1410. Duska, L., Garrett, A., Rueda, B., Haas, J., Chang, Y., Fuller, A., 2001. Endometrial cancer in women 40 years old or younger. Gynecol. Oncol. 83, 388–393. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2005. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 365, 1687–1717. Engmann, L., DiLuigi, A., Schmidt, D., Nulsen, J., Maier, D., Benadiva, C., 2008. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil. Steril. 89, 84–91. Evans-Metcalf, E., Brooks, S., Reale, F., Baker, S., 1998. Profile of women 45 years and younger with endometrial cancer. Obstet. Gynecol. 91, 349–354. Farhi, D.C., Nosanchuk, J., Silverberg, S., 1986. Endometrial adenocarcinoma in women under 25 years of age. Obstet. Gynecol. 68, 741–745. Gitsch, G., Hanzal, E., Jensen, D., Hacker, N., 1995. Endometrial cancer in premenopausal women 45 years and younger. Obstet. Gynecol. 85, 504–508. Gook, D., Schiewe, M., Osborn, S., Asch, R., Jansen, R., Johnston, W., 1995. Intracytoplasmic sperm injection and embryo development of human oocytes cryopreserved using 1,2-propanediol. Hum. Reprod. 10, 2637–2641. Gotlieb, W.H., Beiner, M.E., Shalmon, B., 2003. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet. Gynecol. 102, 718–725. Grigg, A.P., McLachlan, R., Zaja, J., Szer, J., 2000. Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplant. 26, 1089–1095. Gupta, P.B., Proia, D., Cingoz, O., Weremowicz, J., Naber, S.P., Weinberg, R.A., Kuperwasser, C., 2007. Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers. Cancer Res. 67, 2062–2071. Hankey, B.F., Miller, B., Curtis, R., Kosary, C., 1996. Trends in breast cancer in younger women in contrast to older women. J. Natl. Cancer Inst. Monogr. 16, 7–14. Huang, J.Y., Chian, R.C., Gilbert, L., Fleiszer, D., Holzer, H., Dermitas, E., Elizur, S.E., Gidoni, Y., Levin, D., Son, W.Y., Tan, S.L., 2010. Retrieval of immature oocytes from unstimulated ovaries followed by in vitro maturation and vitrification: a novel

332 strategy of fertility preservation for breast cancer patients. Am. J. Surg. 200, 177–183. Kempson, R., Pokorny, G., 1968. Adenocarcinoma of the endometrium in women aged forty and younger. Cancer 21, 650–662. Kim, Y.B., Holschneider, C., Ghosh, K., Nieberg, R., Montz, F., 1997. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer 79, 320–327. Knopman, J.M., Papadopoulos, E., Grifo, J., Fino, M.E., Noyes, N., 2010. Surviving childhood and reproductive age malignancy: effects of treatment on fertility, gametes and future parenthood. Lancet Oncol. 11, 490–498. Lai, C.H., Hsueh, S., Chao, A.S., Soong, Y.K., 1994. Successful pregnancy after tamoxifen and megestrol acetate therapy for endometrial carcinoma. Br. J. Obstet. Gynaecol. 101, 547–549. Lee, K.R., Scully, R., 1989. Complex endometrial hyperplasia and carcinoma in adolescents and young women 15 to 20 years of age. A report of 10 cases. Int. J. Gynecol. Pathol. 8, 201–213. Lee, T.S., Jung, J.Y., Kim, J.W., Park, N.H., Song, Y.S., Kang, S.B., Lee, H.P., 2007. Feasibility of ovarian preservation in patients with early stage endometrial carcinoma. Gynecol. Oncol. 104, 52–57. Madrigrano, A., Westphal, L., Wapnir, I., 2007. Egg retrieval with cryopreservation does not delay breast cancer treatment. Am. J. Surg. 194, 477–481. Maltaris, T., Koelbl, H., Seufert, R., Kiesewetter, F., Beckmann, W.M., Mueller, A., Dittrich, R., 2006. Gonadal damage and options for fertility preservation in female and male cancer survivors. Asian J. Androl. 8, 515–533. Meirow, D., 1999. Ovarian injury and modern options to preserve fertility in female cancer patients treated with high dose radio-chemotherapy for hemato-oncological neoplasias and other cancers. Leuk. Lymphoma 33, 65–76. Meirow, D., Levron, J., Eldar-Geva, T., Hardan, I., Fridman, E., Zalel, Y., Schiff, E., Dor, J., 2004. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N. Engl. J. Med. 353, 318–321. Meirow, D., Hardan, I., Dor, J., Fridman, E., Elizur, S., Ra’anani, H., Slyusarevsky, E., Amariglio, N., Schiff, E., Rechavi, G., Nagler, A., Ben Yehuda, D., 2008. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum. Reprod. 23, 1007–1013. Nagy, Z.P., Chang, C., Shapiro, D., Elsner, C., Mitchell-Leef, D., Kort, H., 2009. Clinical evaluation of the efficiency of an oocyte donation program using egg cryo-banking. Fertil. Steril. 92, 520–526. Niwa, K., Tagami, K., Lian, Z., Onogi, K., Mori, H., Tamaya, T., 2005. Outcome of fertility-preserving treatment in young women with endometrial carcinomas. Br. J. Obstet. Gynaecol. 112, 317–320. Noyes, N., Porcu, E., Borini, A., 2009a. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod. Biomed. Online 18, 769–776. Noyes, N., Abu-Rustum, N., Ramirez, P., Plante, M., 2009b. Options in the management of fertility-related issues after radical trachelectomy in patients with early cervical cancer. Gynecol. Oncol. 114, 117–120. Noyes, N., Knopman, J., Labella, P., McCaffrey, C., Clark-Williams, M., Grifo, J., 2010a. Oocyte cryopreservation outcomes including pre-cryo and post-thaw meiotic spindle evaluation following slow cooling and vitrification of human oocytes. Fertil. Steril. 94, 2078–2082. Noyes, N., Labella, P., Grifo, J., Knopman, J.M., 2010b. Oocyte cryopreservation: a feasible fertility preservation option for reproductive age cancer survivors. J. Assist. Reprod. Genet. 27, 495–499.

N Noyes et al. Noyes, N., Knopman, J., Long, K., Coletta, J., Abu-Rustum, N., 2010c. Fertility considerations in the management of gynecologic malignancies. Gynecol. Oncol. 2010. doi:10.1016/j.ygyno. 2010.09.012 (Epub ahead of print). Oktay, K., Buyuk, E., Davis, O., Yermakova, I., Veeck, L., Rosenwaks, Z., 2003. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum. Reprod. 18, 90–95. Oktay, K., Hourvitz, A., Sahin, G., Oktem, O., Safro, B., Cil, A., Bang, H., 2006. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J. Clin. Endocrinol. Metab. 91, 3885–3890. Ota, T., Yoshida, M., Kimura, M., Kinoshita, K., 2005. Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger. Int. J. Gynecol. Cancer 15, 657–662. Park, J.Y., Kim, D.Y., Kim, J.H., Kim, Y.M., Kim, Y.T., Nam, J.H., 2009. Surgical management of borderline ovarian tumors: the role of fertility-sparing surgery. Gynecol. Oncol. 113, 75–82. Parkin, D.M., Bray, F., Ferlay, J., Pisani, P., 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108. Partridge, A.H., Gelber, S., Peppercorn, J., Sampson, E., Knudsen, K., Laufer, M., Rosenberg, R., Przypyszny, M., Rein, A., Winer, E.P., 2004. Web-based survey of fertility issues in young women with breast cancer. J. Clin. Oncol. 22, 4174–4183. Paulson, R.J., Sauer, M.V., Lobo, R.A., 1990. Pregnancy after in vitro fertilization in a patient with stage I endometrial carcinoma treated with progestins. Fertil. Steril. 54, 735–736. Plante, M., Renaud, M.C., Fran1ois, H., Roy, M., 2004. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol. Oncol. 94, 614–623. Plante, M., Renaud, M.C., Hoskins, I.A., Roy, M., 2005. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol. Oncol. 98, 3–10. Practice Committee bulletin of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology, 2008. Ovarian tissue and oocyte cryopreservation. Fertil. Steril. 90, S241–S246. Ramirez, P.T., Frumovitz, M., Bodurka, D.C., Sun, C.C., Levenback, C., 2004. Hormonal therapy for the management of grade 1 endometrial adenoacarcinoma: a literature review. Gynecol. Oncol. 95, 133–138. Randall, T.C., Kurman, R.J., 1997. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet. Gynecol. 90, 434–440. Rudick, B., Opper, N., Paulson, R., Bendikson, K., Chung, K., 2010. The state of oocyte cryopreservation in the United States. Fertil. Steril.. doi:10.1016/j.fertnstert.2010.04.079 (Epub ahead of print). Sanchez-Serrano, M., Crespo, J., Mirabet, V., Cobo, A.C., Escriba ´, M.J., Simo ´n, C., Pellicer, A., 2010. Twins born after transplantation of ovarian cortical tissue and oocyte vitrification. Fertil. Steril. 93, 268.e11–268.e13. Schilder, J.M., Thompson, A.M., DePriest, P.D., Ueland, F.R., Cibull, M.L., Kryscio, R.J., Modesitt, S.C., Geisler, J.P., Higgins, R.V., Magtibay, P.M., Cohn, D.E., Powell, M.A., Chu, C., Stehman, F.B., van Nagell, J., 2002. Outcome of reproductive age women with stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing therapy. Gynecol. Oncol. 87, 1–7. Scully, R.E., 1970. Recent progress in ovarian cancer. Hum. Pathol. 1, 73–98. Socie, G., Salooja, N., Cohen, A., Rovelli, A., Carreras, E., Locasciulli, A., Korthof, E., Weis, J., Levy, V., Tichelli, A., 2003. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101, 3373–3385.

Egg freezing as a fertility preservation measure for cancer Sonoda, Y., Abu-Rustum, N., Gemignani, M., Chi, D.S., Brown, C.L., Poynor, E.A., Barakat, R.R., 2004. A fertility sparing alternative to radical hysterectomy: how many patients may be eligible? Gynecol. Oncol. 95, 534–538. Teinturier, C., Hartmann, O., Valteau-Couanet, D., Benhamou, E., Bougneres, P.F., 1998. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant. 22, 989–994. Thibaud, E., Rodriguez-Macias, K., Trivin, C., Espe ´rou, H., Michon, J., Brauner, R., 1998. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant. 21, 287–290. Thornton, J.G., Brown, L.A., Wells, M., Scott, J.S., 1985. Primary treatment of endometrial cancer with progestagen alone. Lancet 2, 207–208. Walsh, C., Holschneider, C., Hoang, Y., Tieu, K., Karlan, B., Cass, I., 2005. Coexisting malignancy in young women with endometrial cancer. Obstet. Gynecol. 106, 693–699.

333 Waring, A., Wallace, W., 2000. Subfertility following treatment for childhood cancer. Hosp. Med. 61, 550–557. Wright, J.D., Shah, M., Mathew, L., Burke, W.M., Culhane, J., Goldman, N., Schiff, P.B., Herzog, T.J., 2009. Fertility preservation in young women with epithelial ovarian cancer. Cancer 115, 4118–4126. Yang, Y.C., Wu, C.C., Chen, C.P., Chang, C.L., Wang, K.L., 2005. Reevaluating the safety of fertility-sparing hormonal therapy for early endometrial cancer. Gynecol. Oncol. 99, 287–293. Declaration: NN and LMW are current investigators on a contracted Merck clinical trial and LMW is on the advisory board for EMD Serono. The other authors report no financial or commercial conflicts of interest. Received 25 August 2010; refereed 14 November 2010; accepted 17 November 2010.