Review Article

Infertility in Reproductive-Age Female Cancer Survivors Jennifer M. Levine, MD, MSW1; Joanne Frankel Kelvin, MSN, RN, AOCN2; Gwendolyn P. Quinn, PhD3; and Clarisa R. Gracia, MD, MSCE4

Improved survival rates among reproductive-age females diagnosed with cancer have increased the focus on long-term quality of life, including maintenance of the ability to conceive biological children. Cancer-directed therapies such as high-dose alkylating agents and radiation to the pelvis, which deplete ovarian reserve, radiation to the brain, which affects the hypothalamic-pituitarygonadal axis, and surgical resection of reproductive structures can decrease the likelihood of having biological children. Standard fertility preservation strategies such as embryo and oocyte cryopreservation before the onset of therapy offer the opportunity to conserve fertility, but they may not be feasible because of the urgency to start cancer therapy, financial limitations, and a lack of access to reproductive endocrinologists. Ovarian tissue freezing is considered experimental, with limited data related to pregnancies, but it minimizes treatment delay. Studies evaluating gonadotropin-releasing hormone analogues have had mixed results, although a recent randomized, prospective study in women with breast cancer demonstrated a protective effect. Fertility preservation programs are increasingly being developed within cancer programs. In this article, we describe risks to infertility and options for preservation, raise psychosocial and ethical issues, and propose elements for establishing an effective fertility preservation program. C 2015 American Cancer Society. Cancer 2015;000:000-000. V KEYWORDS: adolescent and young adult, cancer, fertility preservation, infertility.

INTRODUCTION More than 35,000 women between the ages of 15 and 39 years are diagnosed annually with cancer.1 Advances in multimodality treatments and supportive care mean that the majority will survive but risk long-term complications from their treatment, including infertility. Losing the ability to have biological children has been identified as a source of distress to cancer survivors affecting their quality of life.2 Several medical organizations, including the American Society of Clinical Oncologists, the American Society for Reproductive Medicine, and the National Comprehensive Cancer Network, have issued guidelines regarding fertility preservation in female cancer patients. Each guideline recommends discussing reproductive risks of cancer therapies as early as possible before the start of treatment, outlining available fertility preservation options, and making prompt referrals to reproductive endocrinologists for interested patients.1,3,4 Despite these guidelines, surveys of physicians suggest that discussions about fertility preservation are not routinely occurring.5,6 Educating individual physicians may improve the frequency of discussions and referrals because a lack of knowledge is often cited as a barrier to providing fertility preservation services.5,6 However, establishing institutional standards for fertility preservation, including the development of a fertility preservation program with dedicated staff, is more likely to improve the reliability with which females of reproductive age are made aware of their risks and options. OVARIAN RESERVE At birth, female ovaries contain approximately 1,000,000 nonrenewable primordial follicles that decline in number over time, primarily through apoptosis and atresia. Fertility is directly related to ovarian reserve, so as ovarian reserve tapers, so does fertility. A significant mechanism through which cancer-directed therapies reduce fertility is the accelerated depletion of ovarian reserve. The depletion may be sufficient to cause acute ovarian failure, that is, entry into menopause immediately or shortly after the completion of therapy. A more modest depletion may result in retention of fertility after therapy but premature menopause, that is, menopause before the age of 40 years7 (see Fig. 1).

Corresponding author: Jennifer M. Levine, MD, MSW, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, 161 Fort Washington Avenue, IP-7, New York, NY 10032; Fax: (212) 305-5848; [email protected] 1 Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, New York, New York; 2Cancer Survivorship Center, Memorial Sloan Kettering Cancer Center, New York, New York; 3Health Outcomes and Behavior Program, Moffitt Cancer Center, Morsani College of Medicine, University of South Florida, Tampa, Florida; 4Division of Reproductive Endocrinology, University of Pennsylvania, Philadelphia, Pennsylvania

DOI: 10.1002/cncr.29181, Received: July 28, 2014; Revised: October 2, 2014; Accepted: October 3, 2014, Published online Month 00, 2015 in Wiley Online Library (wileyonlinelibrary.com)

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Review Article

RISKS TO FERTILITY FROM CANCERDIRECTED THERAPY Broadly, female fertility is affected by systemic chemotherapy; radiation to the pelvis, abdomen, or brain; and surgeries that remove reproductive organs. Estimates of infertility risk for a given individual remain inexact because most treatments involve multi-agent regimens and because the long-term follow-up necessary to assess outcomes of interest (ie, live births and onset of menopause) is difficult to obtain. Consequently, surrogate measures of fertility, such as serum markers and resumption of menses, are often used to estimate infertility risk. Among chemotherapies, alkylating agents, including cyclophosphamide, procarbazine, and busulfan, have most consistently been linked to ovarian failure in a dosedependent fashion.8 Estimates of dosing thresholds vary among reports; the American Society of Clinical Oncologists identifies a cyclophosphamide dose  7.5 g/m2 in females younger than 20 years and a dose  5 g/m2 in females older than 40 years as a high risk for amenorrhea after therapy, with an intermediate risk from doses  5 g/ m2 in females who are 30 to 40 years old.3 The ovaries are also sensitive to radiation: doses of abdominal or pelvic radiation > 6 Gy in adults, > 10 Gy in postpubertal girls, and > 15 Gy in prepubertal girls carry a high risk of infertility.3 Radiation to the pelvis can damage the uterus and uterine vessels and affect the ability of a woman to carry a pregnancy to term.9 Radiation to the brain in doses > 35 Gy can impair the hypothalamic-pituitary-gonadal axis and lead to hypogonadism through gonadotropinreleasing hormone deficiency.10 Regimens that include total body irradiation and alkylating agents as conditioning for stem cell transplantation are highly gonadotoxic in all age groups. Surgeries that remove the reproductive organs have an obvious impact on fertility. It is likely, although less well studied, that host factors contribute to risk in a given individual. Data are beginning to emerge about the role that drug-metabolizing enzyme polymorphisms may have in an individual patient’s risk.11,12 FERTILITY PRESERVATION OPTIONS Embryo and Oocyte Preservation

Established fertility preservation methods include cryopreservation of oocytes (designated as standard by the American Society for Reproductive Medicine in 2013) or embryos. This technique involves stimulating the ovaries with subcutaneously injected gonadotropins for approximately 8 to 14 days. Frequent monitoring with transvaginal ultrasound and serum hormone testing during this time is required, and this is followed by transvaginal 2

oocyte retrieval under sedation. Oocytes are then examined for maturity and cryopreserved. Alternatively, oocytes may be fertilized with donor or partner sperm to cryopreserve embryos. Stimulation protocols have been developed to expedite the process of ovarian stimulation in cancer patients to complete the process in approximately 2 weeks.13,14 Patients undergoing an initial treatment with surgical excision often have an interval of time available to them for an oocyte retrieval before the initiation of adjuvant chemotherapy.15 When they are used to conceive, oocytes or embryos are thawed, oocytes are fertilized to create embryos, and embryos are transferred into a woman’s uterus. Patients who carry genetic mutations for familial cancers may also be candidates for pre-implantation genetic diagnosis to select unaffected embryos and thus avoid passing the mutation to offspring. There are scant data on pregnancy and live birth rates after embryo and oocyte cryopreservation in cancer patients; therefore, success rates must be extrapolated from other populations. According to 2012 national in vitro fertilization (IVF) data from the Society of Assisted Reproductive Technologies, the live birth rate per thawed embryo transfer was 42% in women < 35 years old, 40% in women who were 35 to 37 years old, and 34% in women who were 38 to 39 years old.16 Although oocyte cryopreservation success has improved, it is important to recognize that most studies assessing the success of oocyte cryopreservation have been conducted in highly selected populations with a good pregnancy prognosis. Randomized controlled trials of fresh oocytes versus vitrified/ warmed oocytes in these populations have demonstrated that implantation and clinical pregnancy rates are similar.17,18 The single most important predictor for success with artificial reproductive techniques using cryopreserved oocytes is a patient’s age, with pregnancy rates declining with advancing age.19 In addition to age, surrogate measures of ovarian reserve (including early follicular phase follicle-stimulating hormone, anti-Mullerian hormone, and antral follicle count) are predictive of the number of oocytes retrieved with ovarian stimulation and are associated with pregnancy rates.20 Therefore, the assessment of ovarian reserve can assist in counseling cancer patients about expected success with fertility preservation techniques. There is observational evidence suggesting that cancer patients may have diminished ovarian reserve at diagnosis and a lower response to stimulation in comparison with infertile patients in the general population.21,22 It is unclear whether these differences are related to the cancer diagnosis itself or to differences in stimulation protocols because randomized trials are not available. Cancer

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Ovarian Tissue Cryopreservation

Figure 1. Depletion of Ovarian Reserve.

Limited data exist addressing the risks of ovarian stimulation in cancer patients. Of paramount concern in females with estrogen-sensitive cancers is the potential for disease progression secondary to hyperestrogenism associated with ovarian stimulation. Although the effect of short-term hyperestrogenism in the setting of breast cancer is not known, stimulation protocols have been developed that maintain estrogen levels in the physiologic range.23,24 The most commonly used protocol involves letrozole administration in conjunction with follicle-stimulating hormone. A single observational study assessed relapsefree survival after ovarian stimulation with letrozole and gonadotropins in breast cancer patients versus breast cancer patients who did not undergo stimulation.25 No difference in relapse-free survival was detected over 23 months, and this suggests that ovarian stimulation does not pose a major risk in these patients. Other potential risks associated with ovarian stimulation include the risk of severe ovarian hyperstimulation syndrome, thromboembolic phenomena, ovarian torsion, and perioperative complications, which occur in less than 1% of patients.26 Immature Oocyte Cryopreservation

One of the major limitations of mature oocyte and embryo cryopreservation is the time and cost required to complete ovarian stimulation. Retrieving immature oocytes transvaginally with limited or no hormonal stimulation, maturing them in vitro, and then cryopreserving mature or fertilized oocytes overcome some of these obstacles. However, these techniques are not as successful as cryopreserving oocytes or embryos that have matured in vivo, and they are still considered experimental. Only 1 live birth has been reported in a cancer patient with this technology.27,28 Cancer

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Another experimental option gaining considerable attention is cryopreservation of surgically resected ovarian tissue. Typically, laparoscopic oophorectomy or ovarian tissue biopsy is performed; ovarian cortical tissue is dissected into small fragments and cryopreserved. Because no ovarian stimulation is required, there is minimal delay in treatment, and no partner is needed. This is the only available option for prepubertal children. Orthotopic autologous transplantation has resulted in more than 30 live human births to date among patients who were postpubertal at the time of cryopreservation.29 Although there have been no reported cases of recurrent cancer after transplantation in humans, there is concern that transplanted ovarian tissue could be contaminated with cancer cells.30 This is principally a concern for leukemias and tumors that involve the ovaries. Ideally, to avoid transplantation after ovarian tissue cryopreservation, immature oocytes would be matured in vitro from cryopreserved ovarian tissue for use in IVF. Although this strategy has been possible in animal models, no births have been reported in humans with this technique.31 Ovarian Transposition

In cases for which pelvic radiation is necessary, it may be possible to move one or both ovaries to reduce radiation exposure. Although there are limited data demonstrating the efficacy of this approach in preserving fertility, there is evidence that ovarian transposition is associated with preserved hormonal function.32 Communication and coordination of care between the radiation oncologist and the gynecologist or surgeon performing the transposition are critical for optimizing outcomes. Gonadotropin-Releasing Hormone Analogues

There is significant interest in developing strategies to protect the ovaries from damage during chemotherapy. The most widely studied approach uses gonadotropinreleasing hormone agonists to suppress ovarian function during chemotherapy. Studies are conflicting, with some demonstrating an increased likelihood of ovulation and menstruation after therapy and other studies showing no benefit.33-35 More recently, the Prevention of Early Menopause Study, which evaluated fertility in breast cancer patients randomized to receive standard therapy or standard therapy with goserelin, demonstrated lower rates of ovarian failure (measured by amenorrhea and elevated follicle-stimulating hormone) and a higher pregnancy rate in the goserelin arm.36 3

Review Article Fertility-Preserving Interventions for Gynecologic Malignancies

In gynecologic cancers with a good prognosis, more conservative resection of reproductive organs may preserve fertility. Radical trachelectomy in young women with early-stage cervical cancer limits resection to the cervix and pelvic lymph nodes and allows females to retain the capacity to carry a pregnancy, although relatively high rates of preterm labor have been reported.37 In ovarian tumors, laparoscopic cystectomy or the removal of only 1 ovary can be performed to retain ovarian tissue to preserve fertility. The risk of this procedure is the possibility of incompletely resecting malignant cells.38 The use of medical hormonal therapy in welldifferentiated endometrial cancer instead of surgical intervention allows preservation of the uterus, fallopian tubes, and ovaries and does not appear to compromise outcomes.39 SURROGATE MEASURES OF FERTILITY POTENTIAL Unfortunately, the reproductive effects of cancer therapies cannot be predicted with accuracy from age and treatment parameters alone. The severity of the reproductive effects may depend on the size of the follicular pool before treatment. There has been interest in identifying surrogate markers of oocyte quantity and quality to assist in counseling women about their remaining reproductive window. Current candidates for surrogate markers include early follicular phase measures of serum folliclestimulating hormone, anti-Mullerian hormone, and ultrasound measures of the antral follicle count. These measures are associated with ovarian aging and are routinely used to evaluate a woman’s fertility potential and response to fertility treatments in the infertility clinic setting.20 A prospective study of 42 breast cancer patients found that pretreatment serum anti-Mullerian hormone predicted amenorrhea after chemotherapy (odds ratio, 13.0; 95% confidence interval, 2.5-66.7).40 Furthermore, another prospective study demonstrated that lower ovarian reserve at the baseline (pretreatment anti-Mullerian hormone < 2 ng/mL) was associated with a slower recovery of ovarian reserve (2.6% vs 11.9% per month) after chemotherapy.41 Although these data are preliminary, they suggest that pretreatment anti-Mullerian hormone may be helpful in predicting reproductive function after treatment. Furthermore, there is evidence that surrogate measures of ovarian reserve are compromised after chemotherapy in reproductive-age women after cancer versus controls of similar ages.8,42 4

ESTABLISHED METHODS AFTER CANCER THERAPY After cancer therapy, females at risk for premature menopause can consider cryopreserving embryos or oocytes if they are not ready to start a family. Menstruating females with infertility may pursue a traditional fertility treatment such as superovulation, intrauterine insemination, or IVF. Patients who are unable to conceive with infertility treatments may be candidates for IVF with donor eggs. In addition, the use of donated embryos and adoption are options for having nonbiological children after cancer. Patients with uterine damage who are unable to carry a pregnancy may consider using a surrogate gestational carrier. PSYCHOSOCIAL AND ETHICAL CONSIDERATIONS For young women diagnosed with cancer, learning that their cancer treatment could render them infertile can be devastating. Before a woman pursues the fertility preservation options outlined previously, a cascade of assessments and decisions, including the level of risk that the proposed cancer treatment will bring to her reproductive capability and her own desire for a child or children, need to be made.3 If the cancer treatment is likely to impair fertility and if the patient thinks that she would like to have a biological child or more children in the future, the options for fertility preservation depend on her cancer treatment as well as her social and financial resources. Recent research suggests that few women make use of fertility preservation, but the majority of women appreciate receiving information about potential fertility loss and options for preservation.43 In fact, women who received this information reported better quality of life and less distress than women who did not discuss reproductive issues with a health care professional.44,45 Even among women for whom the timing of their treatment or other factors did not allow fertility preservation, the vast majority reported appreciation for the opportunity to grieve their fertility loss.46 For women who are interested in fertility preservation, embryo cryopreservation with partner or donor sperm or oocyte cryopreservation offers the best chance for future biological children. Some women opt to freeze both oocytes and embryos to increase their chances for a future child and to take into account that their relationship status may have changed when they are ready to start a family. Oocyte cryopreservation may be preferred by women who do not have a partner, do not wish to use donor sperm, or have ethical and/or religious objections to embryo cryopreservation.47 Embryo cryopreservation in particular raises ethical considerations that include but not are limited to the Cancer

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TABLE 1. Building a Model to Support a Cancer and Fertility Program Recommended Elements A policy, procedure, or guideline outlining organizational expectations regarding fertility discussions and referrals An individual or team designated to champion fertility discussions and referrals

Resources for educating patients about fertility

Resources to assist clinical staff in discussing fertility with patients

Relationships with reproductive specialists

Navigator designated to provide education, counseling, and referrals for individual patients

A defined process for informing patients of their fertility risks and options before the initiation of therapy

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Development, Implementation, and Evaluation Define expectations of clinicians clearly and explicitly. Ensure that staff are aware of and have access to documents. When holding clinicians accountable, maintain respect for the challenges faced in initiating these often difficult patient discussions. Establish a multidisciplinary group to: Assess the organization (eg, the number of patients of reproductive potential starting treatment annually, common diagnoses, and existing resources). Advise on program development. Obtain buy-in from stakeholders. Advocate for needed resources. Disseminate information to clinicians. Assist clinicians as they integrate this into practice. Ensure available written materials: Create your own. Have reproductive specialists create them. Use established materials. Examples include Cancer.Net (http://www.cancer.net/research-and-advocacy/asco-care-and-treatment-recommendations-patients/fertility-preservation). MyOncofertility.org (http://www.myoncofertility.org/). SaveMyFertility.org (http://www.savemyfertility.org/). American Cancer Society (http://www.cancer.org/treatment/treatmentsandsideeffects/ physicalsideeffects/sexualsideeffectsinwomen/fertilityandwomenwithcancer/index). Livestrong Fertility (http://assets.livestrong.org/we-can-help/LIVESTRONG-Fertility-Brochure.pdf?_ga51.213269459.673017106.1360183256). Fertile Action (http://www.fertileaction.org/). Create a library of references on treatment-related risks; fertility preservation options; talking points; and institutional policies, procedures, and processes. Ensure the availability of the information when it is needed in the clinical setting (eg, intranet site or paper toolkit). Develop electronic prompts or reminders. Examples include: Reports listing young patients scheduled for consultation. Patient intake forms with fields indicating interest or concerns. Clinician documentation forms with fields indicating the discussion of risks, options, and offers of referral. Chemotherapy orders with alerts to discuss fertility before treatment begins. Identify internal or local reproductive endocrinologists for referral: American Society for Reproductive Medicine (http://www.asrm.org). Society for Assisted Reproductive Technology (http://www.sart.org/). Select partners on the basis of their ability to provide desired services. Examples include: Timely appointments (24-48 h). Point person for scheduling and coordinating care. Willingness to offer previsit phone discussions. Comprehensive reproductive technologies. Multidisciplinary approach (eg, mental health services and genetic counselors). Knowledgeableness about relevant medical issues in patients with cancer. Sensitivity to the unique needs of patients with cancer (eg, emotional distress, complexity and urgency of decision making, lack of reproductive health knowledge, and financial barriers). Willingness to provide discounted rates (eg, an affiliation with programs such as Livestrong Fertility [http://www.livestrong.org/we-can-help/fertility-services/] and Heart Beat [https://www.ferringfertility.com/heartbeatprogram/heartbeatprogram.pdf]) Maintenance of data on services provided and outcomes. Identify a specific individual or individuals to provide these services with allocated time. Establish responsibilities on the basis of their roles (eg, medical doctor, registered nurse, social worker, or lay person): Assess cancer history (diagnosis and prior and planned treatment), reproductive history, and social history. Educate patients on relevant risks and options. Facilitate referrals. Coordinate care between oncology and reproductive endocrinology teams. Serve as an expert resource to clinicians. Clinicians should initiate discussion as early as possible in treatment planning. Clarify specific roles of various clinicians and/or navigators. Outline the process clearly with numbered steps or a work flow/algorithm. Ensure that the outlined process is accessible to clinicians.

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Review Article TABLE 1. Continued Recommended Elements A defined process for referring interested patients to appropriate reproductive specialists

Education of clinical staff

Metrics for program evaluation

Development, Implementation, and Evaluation The process will vary with the practices of the specific reproductive endocrinology group and according to whether or not it is within your organization. Clarify specific roles of various clinicians and/or navigators. Outline the process clearly with numbered steps or a work flow/algorithm. Ensure that the outlined process is accessible to clinicians. Provide information on cancer-related infertility and fertility preservation options with a variety of approaches: Didactic presentations (eg, grand rounds, disease-team presentations, and fellow and nursing orientations). Interactive presentations (eg, journal clubs and case presentations). Information accessible on a need-to-know basis (eg, videos and intranet site). Disseminate information about resources and processes when in place. Identify outcomes of value to patients and to the organization. Examples include: Number/percentage of patients informed and/or referred. Patient satisfaction with information received. Clinician knowledge, attitudes, and practices.

following: Will the woman be permitted to use the embryos if the current relationship ends? What happens to the embryos if either partner dies? Will the surviving partner consider posthumous reproduction? Would a future partner accept parenthood of an embryo created with a former partner or sperm donor? What happens if the embryos are not used? The American Society for Reproductive Medicine suggests that these issues should be discussed and documented in consent forms before the commencement of stimulation.48 These decisions can be particularly taxing because they occur in the context of managing a new cancer diagnosis. The American Society of Clinical Oncologists suggests that women be referred to psychosocial professionals for counseling and assistance with these decisions.3 With the uncertainty in determining the actual risk for infertility in a given individual, the increasing use of fertility preservation options, and improvements in reproductive technologies, the real possibility exists that cryopreserved embryos/oocytes will remain unused.49 There are several options for unused embryos/oocytes, including donation to another infertile couple or for research. The few studies examining couples’ thoughts on the disposition of unused embryos suggest that women have altruistic motivations about donation to other couples or research before they undergo IVF,50 but once a child has been born, they are less certain. Couples may opt to continue to pay for the storage of cryopreserved embryos/oocytes to delay decision making, may stop paying their bill to leave the decision up to the IVF clinic,51 or may opt for authorizing the discarding of unused embryos/oocytes.50,51 6

In addition to the psychological considerations, there are financial aspects. The cost of oocyte and embryo cryopreservation ranges from approximately $7000 to $15,000 in the United States, with annual storage fees ranging from $100 to $1500.52 Insurance coverage is highly variable for cryopreservation, and storage costs are not covered. Even states with mandated insurance coverage for artificial reproductive techniques may exclude cancer patients, who are generally not infertile when they are seeking services.53 Financial assistance programs exist to defray the cost of stimulation medications and, in some cases, the cryopreservation process and storage fees (see Table 1). However, even with these programs, fertility preservation options remain financially out of reach for many. This disparity in access raises the ethical issue of justice54: fertility preservation technologies with their high costs are used more frequently by women who are white,55 educated,56 and middle- to upper-class.57 Although health insurance policies are not required to cover these costs for the cancer patient, the landscape is changing. The argument has been put forward that coverage for fertility preservation should be considered in the context of coverage for other side effects of treatment.47 Several major insurers have made individual decisions to provide coverage, and the American Medical Association has issued a statement urging insurers to cover fertility preservation services in the setting of a cancer diagnosis.58 BUILDING A PROGRAM Providing clinicians with information about the fertility effects of cancer treatment and options for fertility preservation is not enough to ensure that they will discuss these Cancer

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issues with their patients. A small but growing body of literature has emerged that describes key elements needed to build a program to address fertility.59-68 Table 1 presents a detailed, practical outline to address the core elements, strategic considerations, and pragmatic factors involved in the development of a formal fertility program. No single strategy has been established to build a successful program; the idiosyncrasies of a given institution need to be considered as a program is being developed. Together with organizational commitment, skilled leadership, persistence, and patience, these components provide guidance in building a cancer and fertility program that ensures widespread improvement in clinical practice sustained over time. CONCLUSIONS Fertility preservation is important to reproductive-age females diagnosed with cancer, and conversely, facing the risk of or developing infertility can be a source of stress and grief. Although imperfect and often costly, fertility preservation interventions exist and may offer the opportunity to have biological children to females at risk. Areas of research needed to improve counseling about fertility preservation in a given individual include refinement of the ability to determine risk before the start of therapy, the degree to which fertility is altered during treatment, and the length of the remaining reproductive window after treatment. Improvements in reproductive technologies, including the development of the capacity to mature immature oocytes from cryopreserved ovarian tissue, will provide a more reliable option for females who cannot delay therapy. Importantly, the expansion of insurance coverage for these procedures will greatly expand the number of individuals who can avail themselves of fertility preservation techniques. FUNDING SUPPORT No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES The authors made no disclosure.

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