A call to action: unified clinical practice guidelines for oncofertility care

Abstract

By 2030, WHO estimates that 1.4 million reproductive-aged women will be diagnosed with cancer annually. Fortunately, cancer is no longer considered an incurable disease in many cases. From 2008–2014, 85% of women under the age of 45 years diagnosed with cancer survived. This increase in survival rate has shifted attention from focusing exclusively on preserving life to focusing on preserving quality of life after treatment. One aspect of this is preserving the ability to have a biological family. Oncofertility, the field that bridges oncology and reproductive endocrinology with the goal of preserving fertility, offers these patients hope. Though it is clear that ASCO and ASRM recognize the importance of fertility preservation as an aspect of comprehensive oncology care, there are not yet unified guidelines for oncologists and fertility specialists for treating oncofertility patients. First, we identify the need for reproductive counseling prior to cancer treatment, as many patients report that their fertility preservation concerns are not addressed adequately. We then delineate multi-modal fertility preservation options that are available and appropriate for different patients with corresponding outcomes using different treatments. We discuss the unique challenges and considerations, including ethical dilemmas, for delivering timely and comprehensive care specifically for oncofertility patients. Finally, we address the multidisciplinary team that includes oncologists, reproductive endocrinologists, surgeons as well as their staff, nurses, genetic counselors, mental health professionals, and more. Since oncofertility patient care requires the coordination of both physician teams, one set of unified guidelines will greatly improve quality of care.

Introduction

As of 2021, ten states have mandated fertility preservation coverage laws (California, Colorado, Connecticut, Delaware, Illinois, Maryland, New Hampshire, New Jersey, New York, and Rhode Island) that require insurance ART coverage for patients receiving gonadotoxic treatment. While this is a progressive and victorious mandate for both the state and patients alike, making fertility preservation (FP) more affordable and accessible, it is now the responsibility of the healthcare providers overseeing these patients to ensure they are utilizing these benefits to the best of their ability. Unfortunately, studies continue to demonstrate oncologists’ lack of knowledge as well as discomfort with discussing FP with patients, leading to half of patients without necessary information and/or referral to an REI [1]. The main barriers to initiating discussions about FP with patients include lack of time to have such discussions, lack of knowledge on treatment and success of FP, individual patient prognosis, and, to a lesser extent parity, marital status, and socioeconomics [2].

It is estimated that 878,980 women were newly diagnosed with cancer in 2018 [3]. By 2030, the World Health Organization estimates that 1.4 million reproductive-aged women will be diagnosed with cancer each year. Fortunately, cancer is no longer considered an incurable disease in many cases. Due to improved cancer detection and diagnosis, as well as improved treatment strategies, survival rates have improved over the last several decades with hopes that this trend will continue with further research and innovation. From 2008–2014, 85% of women under the age of 45 years diagnosed with cancer survived [4]. This increase in survival rate has shifted the attention of doctors from focusing exclusively on preserving life to focusing on preserving quality of life after treatment.

In 2018, the American Society of Clinical Oncology (ASCO) published updated recommendations on fertility preservation in patients with cancer [5]. In 2019, the American Society for Reproductive Medicine (ASRM) published clinical guidelines for patients seeking fertility preservation before undergoing gonadotoxic treatment [6]. Despite these recent guidelines, fertility preservation counseling remains underutilized. We believe developing unified clinical guidelines for fertility specialists and oncologists alike are needed to treat this unique patient population in order to improve quality of and access to oncofertility care. We suggest a taskforce combined with oncologists and fertility specialists to create comprehensive guidelines to streamline care and improve healthcare delivery.

The need for reproductive counseling

Although there are many ways to have a family, including adoption and the use of donor eggs, preserving the ability for patients to have biological children safeguards the quality of life of cancer survivors. Unfortunately, the most commonly used cancer treatments in females involve gonadotoxic treatment or surgical removal of the ovaries and/or uterus. The toxic effects of alkylating chemotherapy agents on the ovaries are well documented and include increased risk of infertility and early menopause [7]. Research suggests that even lower risk chemotherapy, such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimens, decreases the probability of producing a live birth 5 years after cancer diagnosis [8]. Total body and abdominal radiation therapy also have pronounced effects on the uterus and ovaries, causing decreased blood flow and tissue fibrosis, thus leaving women with reduced fertility potential [9]. In addition to the toxic effects of cancer treatment, another aspect to consider is the societal shift in which women are delaying initiation of childbearing. It is becoming more and more common for women to attempt to conceive later in life [10]. Because the risk of cancer increases with age, there is therefore a greater number of women diagnosed with cancer who have not yet begun to build their families. For these women, the diagnosis of cancer coincides with the potential loss of future children due to the added effect of diminished oocyte quality and quantity. Oncofertility, the field that bridges oncology and reproductive endocrinology with the goal of preserving fertility, offers these patients hope.

Research demonstrates that oncology patients are concerned about the possibility of becoming infertile secondary to cancer treatment. A survey by Partridge et al. revealed that 73% of breast cancer patient respondents were concerned about the possibility of becoming infertile due to treatment, and 29% of respondents indicated that fertility concerns impacted their cancer treatment decisions [11]. According to Anazodo et al., as few as 15% of oncologists regularly refer female patients to fertility specialists [1]. Even when patients are informed of fertility preservation options, only 51% report that their concerns were addressed adequately [11].

In 2018, the American Society of Clinical Oncology published recommendations on fertility preservation stating, “All oncologic health care providers should be prepared to discuss infertility as a potential risk of therapy. This discussion should take place as soon as possible once a cancer diagnosis is made and can occur simultaneously with staging and the formulation of a treatment plan.” [5]. The reason oncologists do not suggest fertility preservation options may be due to a variety of reasons including prognosis, treatment-related complications, the cost of fertility treatment, or lack of knowledge or emotional comfort discussing fertility preservation procedures [1]. Oncologists may also not know who they should be referring to fertility preservation services. Ideal candidates include the large majority of male and female patients planning to undergo gonadotoxic treatment, including adolescent patients and now prepubertal girls. Though the majority of patients undergoing gonadotoxic treatment are those with malignancies, that is not always the case. Patients with vasculitis [12], systemic lupus erythematosus [13], and other autoimmune disorders also could benefit from fertility preservation prior to initiation of treatment due to iatrogenic effects on the gonads.

In addition to patients with an existing cancer diagnosis and those suffering from autoimmune conditions, patients recently diagnosed with deleterious gene mutations (e.g., BRCA1 and BRCA2 mutations) that increase the risk for cancer may also be considered for fertility preservation. As genetic testing improves for identifying pathologic variants that place certain patients at risk of developing gynecological cancers, more patients will be seeking out options for fertility preservation prior to prophylactic surgical procedures. BRCA1 and BRCA2 mutation carriers have a cumulative ovarian cancer risk of 44% and 17%, respectively [14], making risk-reducing salpingo-oophorectomy (RRSO) and/or total abdominal hysterectomy necessary for many women. For these patients, embryo or oocyte preservation is an option prior to definitive surgery. While most expert guidelines recommend prophylactic surgery before the age of 40, some patients may elect to undergo surgery earlier in order to further reduce the risk of cancer diagnosis. Additionally, some patients may elect to pursue IVF regardless in order to perform preimplantation genetic testing for monogenic disorders (PGT-M) to avoid transmission of known BRCA mutations to their offspring. PGT-M for BRCA does remain controversial, however, given the pathologic variants are incompletely penetrant and their presence does not guarantee disease occurrence [15]. Research does suggest a link between BRCA1/2 mutations and reduced ovarian reserve [16–18]. Therefore, young healthy BRCA carriers should be advised to discuss fertility options with a specialist [15].

Fertility preservation options

For male patients, fertility preservation options are fairly straightforward. According to ASCO guidelines for fertility preservation, male patients should undergo sperm cryopreservation with sperm banking prior to receiving cancer treatment [5]. Collecting sperm prior to treatment ensures that the quality of the sperm sample is not negatively impacted by gonadotoxic therapy. Obtaining ejaculated sperm for cryopreservation is safe, non-invasive, and effective. Multiple vials of sperm can be obtained at once, making the process quick and easy for patients. Unlike their female counterparts, male patients do not have to provide samples at a particular time of the month and there is no hormonal cycle that would make timing difficult. Male cancer patients can also undergo sperm banking with an REI, providing a global approach to fertility preservation. Reproductive outcomes for male cancer patients using cryopreserved sperm are promising. Recent research has indicated fertilization rates of up to 71% using cryopreserved sperm for ART [19]. For patients with cancer-induced azoospermia due to testicular tumors, testicular sperm extraction (“onco-TESE”) may be a useful technique for preserving fertility [20, 21]. Other methods to preserve male fertility, such as testicular tissue cryopreservation and autotransplantation should only be performed as part of a clinical trial [5]. These experimental alternatives may provide an option for prepubertal male patients that cannot provide an ejaculated sperm sample.

There are several options for fertility preservation for female patients, depending on a variety of factors. For female adolescent patients, the options for fertility preservation depend on whether or not the patient has begun menstruating. For premenarchal patients, ovarian tissue cryopreservation (OTC) is an option as patients have not yet begun ovulating. In this procedure, ovarian cortex tissue is removed from the patient and frozen for subsequent autotransplantation after treatment. The greatest benefit to this being that it not only preserves the patient’s fertility but can also restore ovarian endocrine function [22]. Ovarian tissue cryopreservation may also be an option for patients starting cancer treatment who do not have enough time available to undergo ovarian stimulation and oocyte/embryo cryopreservation [23]. As of December 2019, ASRM removed the experimental label from OTC [6]. ASCO also recommends OTC for premenarchal patients, though more research is needed to confirm the safety of the procedure in patients with leukemias [5]. A recent meta-analysis reports live birth and ongoing pregnancy rates of 37.7% and endocrine restoration rate of 63.9% using OTC [24]. Autologous ovarian tissue transplantation has resulted in around 90 live births thus far, suggesting it may be a viable option for premenarchal patients who cannot be stimulated.

The main concern regarding autologous transplantation of cryopreserved ovarian tissue is the potential for transplanting malignant cells, resulting in cancer recurrence after reimplantation [25]. This risk is highest in leukemia patients. In leukemia, malignant cells may be present in the bloodstream, and therefore also in the ovaries, which may increase the risk of transferring diseased cells back into the treated patient. A retrospective analysis of autopsy findings of female patients found ovarian involvement in 8.4% of leukemia patients [26]. Ovarian tissue histology and PCR should therefore be utilized to detect malignant cells prior to transplantation. In 2008, Meirow et al. were the first to demonstrate the presence of malignant cells in cryopreserved ovarian tissue for two patients with chronic myeloid leukemia (CML) using PCR, which excluded the tissue from transplantation [27]. In addition to tissue histology and PCR, harvesting tissue for OTC for patients in complete remission (after one or two chemotherapy courses) decreases the risk of contamination. Thus, it is safer to harvest tissue for OTC after remission has been achieved.

In 2018, a case study of a 19-year-old acute myeloid leukemia patient who underwent OTC during complete remission was published [28]. Histology, immunohistochemistry, FISH, next-generation sequencing, and xenotransplantation were performed to evaluate thawed ovarian tissue samples for the presence of malignant cells. All tests were negative for signs of leukemia and transplantation with subsequent ovarian stimulation and IVF were performed, resulting in the delivery of a healthy newborn. This case demonstrates the essential aspects of achieving success with OTC in leukemia patients: harvesting during complete remission and intense tissue evaluation prior to autotransplantation. While OTC in leukemia patients presents a unique dilemma, it is clear that success is possible. Oocyte in vitro maturation (IVM), an experimental strategy that consists of retrieving immature oocytes from unstimulated ovaries, may be an option in the future to avoid the reintroduction of malignant cells [29].

The preferred method of fertility preservation for adult female patients is controlled ovarian stimulation (COS) for embryo cryopreservation (in vitro fertilization or IVF) or mature oocyte cryopreservation. Similar to other areas of medical practice (especially oncology), COS is evolving from a “one size fits all” approach to patient-tailored treatment to maximize both safety and success [30]. Prior to COS, a baseline assessment of fertility status is performed. First, a thorough history is taken from the patient, including any prior fertility treatments and attempts at pregnancy. A baseline ultrasound is performed during the patient’s follicular phase (cycle day 2 or 3), while she is still on her period, to evaluate pelvic structures. Uterine cavity assessments, including hysterosalpingogram and/or saline infusion sonohysterography, can be omitted since the patient will not be undergoing an embryo transfer until cancer treatment is complete. An additional ultrasound at mid-cycle will provide more information regarding the patient’s developing follicles and predict ovulation. Endocrine markers are measured in conjunction with imaging. Anti-Müllerian hormone (AMH) and inhibin B are used as markers for follicular quantity, while day 3 follicle-stimulating hormone (FSH) and estradiol are used as indirect markers that reflect hormonal status as a response to oocyte quantity. Physicians determine individual patient protocols using age, AMH, FSH, and estradiol levels, in conjunction with their antral follicle count (AFC) [31].

For patients with gynecological cancers, carrying may no longer be an option after treatment. Depending on the patient’s cancer diagnosis, proper FDA testing should be performed if a gestational carrier may be used in the future. Nearly half of patients returning for cryopreserved embryo utilization following cancer treatment use a gestational carrier [32, 33]. Several cases of successful pregnancy using a gestational carrier following cancer treatment have been described [34–36]. These patients should therefore be counseled on the future use of a gestational carrier and proper infectious disease testing should be performed [32].

Patients undergoing COS typically begin stimulation in the follicular phase of the menstrual cycle, following the start of their period or cycle day 1. Patients begin stimulation using exogenous gonadotropins, including FSH and luteinizing hormone (LH), to induce follicular, or oocyte, growth, in addition to GnRH agonists/antagonists. A typical stimulation time frame is approximately 8-15 days. During this time, the patient is monitored closely as the follicles grow and reach maturity. Once the follicles are of appropriate size, ovulation is induced most often via an exogenous HCG trigger that acts similarly to an LH surge. Thirty-six hours later, oocytes are retrieved in a short outpatient procedure. It is at this point that a patient can opt to either cryopreserve her oocytes or have the oocytes inseminated by sperm to create embryos.

The decision to undergo IVF versus oocyte cryopreservation is dependent on a number of factors, such as age, religious/ethical objections, and relationship status. Younger patients or those without a partner may opt to undergo oocyte cryopreservation if they do not want to use donor sperm. Regardless of the patient’s choice, either form of fertility preservation does not appear to affect the ability to achieve pregnancy later on. Cobo et al. investigated embryo development after inseminating previously vitrified oocytes and found that while there was a delay from time of cleavage to blastulation, the embryo quality was not impaired, and these embryos led to similar rates of implantation [37]. The increase in efficacy using frozen oocytes is likely due to a transition from slow-freezing techniques to vitrification—a cryopreservation method that allows solidification of the cell into a glass-like state, without the formation of ice, using a cryoprotectant [38]. In a recommendation published by the London National Institute for Health and Clinical Excellence guidelines, vitrification is now the recommended technique for oocyte cryopreservation for this reason [39]. However, the efficacy of using vitrified oocytes versus fresh oocytes remains controversial, as literature also suggests use of vitrified oocytes is correlated to lower live birth rates. Although contradictory evidence exists between use of vitrified versus fresh oocytes, the American Society for Reproductive Medicine (ASRM) concluded in 2012 that sufficient evidence warranted oocyte cryopreservation for fertility preservation as a viable option [40].

Data is limited regarding fertility preservation efficacy during chemotherapy treatment. Given the gonadotoxic effects of chemotherapy, COS during chemotherapy treatment is not recommended. Research demonstrates a lower embryo yield in patients who have begun chemotherapy [41]. Though data regarding embryo cryopreservation during chemotherapy are limited, it is generally not recommended to perform COS once chemotherapy has damaged gonadal structures. Therefore, oocyte/embryo cryopreservation should be offered prior to starting gonadotoxic treatment.

Among the available strategies for fertility preservation, embryo and oocyte cryopreservation are considered standard procedures. However, temporary ovarian suppression is the only technique that can protect the ovaries from gonadotoxic treatment. Though controversial, ovarian suppression using gonadotropin-releasing hormone agonists (GnRHa), such as leuprolide, may be used to prevent chemotherapy-induced premature ovarian failure (POF) in premenopausal breast cancer patients. Potential advantages are its suitability for premenopausal women of all ages, non-invasive nature, and low health risk [42]. It is important to note that after two decades of clinical trials and research, GnRHa have not been shown to interfere with effectiveness of chemotherapy agents [42]. The role of GnRHa in fertility preservation for cancer patients has remained controversial. In 2013, the ASCO and the European Society for Medical Oncology (ESMO) guidelines considered the use of temporary ovarian suppression with GnRHa during chemotherapy an experimental strategy [43, 44]. Two years later, a large meta-analysis of randomized, controlled trials demonstrated a significant reduced risk of POF with the use of GnRHa for breast cancer patients [45]. Moreover, as compared with chemotherapy alone, the use of GnRHa during chemotherapy was associated with a significant higher number of patients who achieved pregnancy. In 2018, ASCO updated their guidelines to include a recommendation for ovarian suppression using GnRHa, specifically in young women with breast cancer, when other strategies (such as oocyte and embryo cryopreservation) are not feasible [5]. In 2020, ESMO also published guidelines recommending that temporary ovarian suppression with chemotherapy be considered a standard option for premenopausal breast cancer patients wishing to preserve fertility [23]. Options for fertility preservation will continue to evolve with increasing clinical trials and as more long-term data is obtained regarding subsequent pregnancies.

Outcomes for controlled ovarian stimulation in fertility preservation patients

Although COS protocols were initially developed for patients with diagnosed infertility, oncofertility patients have shown similar success utilizing these protocols. In one study of female cancer patients, ovarian reserve, response to gonadotropins, oocytes retrieved, and oocyte maturity remained unchanged when compared to controls [46]. Another study comparing response to ovarian stimulation in women with cancer (both local and systemic) and without, demonstrated similar oocyte and embryo yields among the groups [47]. Age and AMH still appear to be the most important determinants of stimulation response. Based on these results, oncofertility patients should be treated similarly to infertility patients, though they do not have an infertility diagnosis. However, it is important to consider utilizing FSH with selective estrogen receptor modulators (SERMs) or aromatase inhibitors in oncology patients whose cancer may be responsive to the supraphysiological estrogen levels [48] Furthermore, random start protocols are necessary for oncofertility patients unlike those being treated for infertility. Further research is needed on blastocyst formation rates, embryo viability, and birth rates in order to optimize care for oncofertility patients.

Pregnancy success rates vary by fertility preservation option chosen by the patient. One study found that following oocyte thaw and insemination, pregnancy rates using vitrified oocytes from non-oncologic patients resulted in fertilization and pregnancy rates of 93% and 32.5%, respectively [49]. Data on pregnancy rates and live birth rates for oncology patients are limited [1]. In one study of nine patients who returned for embryo thaw and transfer following embryo cryopreservation for gonadotoxic treatment, 6 pregnancies occurred [24]. In the largest study of oncofertility outcomes to date, a study of 6,362 patients undergoing fertility preservation (5289 women for age-related elective reasons and 1073 patients for cancer treatment), overall oocyte survival was comparable [50]. However, the implantation rate, ongoing pregnancy rate, and live birth rates were lower among patients undergoing FP prior to cancer treatment. There is a need for data in all aspects of oocyte/embryo cryopreservation for oncofertility patients. Further studies are needed to assess particular stimulation protocols, oocyte quality, pregnancy rates, and cumulative live birth rates [23]. Additionally, long-term follow-up is needed with a large number of oncofertility patients in order to evaluate the efficacy and safety of fertility preservation treatment and subsequent embryo transfer in these patients.

Fertility preservation challenges and considerations

Though fertility preservation procedures have had success, there are special considerations and challenges to keep in mind when performing COS on oncofertility patients. One of the most common challenges involves timing. Often oncofertility patients seek out fertility preservation with limited time before starting chemotherapy or radiation treatment. Because of this, expediting care is essential and waiting for patients to begin their menstrual cycle is not always an option. Fortunately, random start protocols, which begin stimulation at any time in the menstrual cycle, have been introduced to allow fertility specialists to expedite care. Some studies demonstrate that random start protocols are just as effective as more conventional follicular phase protocols, however additional clinical studies are needed [51]. Additionally, it is important to recognize that, though oncologists may be concerned that fertility treatment will delay cancer treatment, this is often not the case. In one study of 523 breast cancer patients, the median number of days for chemotherapy initiation following definitive surgery was 34 days [52]. In another study of 24,843 patients using data from the California Cancer Registry, median time to chemotherapy initiation was 46 days [53]. As previously noted, the timeframe for COS is typically 2 weeks at most. Given the aforementioned studies, for many patients, the length of ovarian stimulation would coincide with the waiting period prior to chemotherapy initiation.

Another major concern of many oncologists is whether or not to refer hormone-receptor-positive cancer patients for fertility preservation. Some studies suggest that exogenous gonadotropins, such as those required during ovarian hyperstimulation, result in supraphysiological levels of estradiol, stimulating estrogen-receptor-positive (ER+) breast and endometrial cancers [54]. Fortunately, aromatase inhibitors, such as letrozole, suppress serum estrogen levels and therefore can be used in fertility preservation protocols to avoid the possibility of stimulating tumor cells while undergoing COS [23, 51]. A prospective study demonstrated that patients using letrozole protocols do not appear to have a significantly raised risk of breast cancer recurrence in the short-term [55]. Tamoxifen, a selective estrogen receptor modulator, is another hormonal intervention option for patients with ER+ cancers [56, 57]. Similar to letrozole, it has antiestrogenic effects, specifically on mammary epithelium; however, it also has estrogenic actions depending on the target tissue. It is important to note that research demonstrates that COS with letrozole may be more effective than COS with tamoxifen [58, 59]. In a study of women with infertility due to anovulation, protocols with letrozole resulted in higher pregnancy rates and less side effects when compared with protocols with tamoxifen [58]. Protocols with letrozole result in greater retrieved and fertilized oocytes [60] and do not appear to increase the short-term risk of breast cancer recurrence [54].

The risk of ovarian hyperstimulation syndrome (OHSS) presents another concern for patients undergoing fertility treatment, especially those with malignancy. OHSS is a clinical diagnosis that describes patients presenting with hyperstimulation symptoms, ranging from mild (abdominal discomfort, nausea, vomiting) to more severe (ascites, pulmonary edema, electrolyte imbalance) [61]. Severe cases result in hospitalization, which could delay cancer treatment. Many oncology patients may only have one opportunity to undergo an egg retrieval procedure so aggressive stimulation is tempting, but this must be balanced with the risk of OHSS. Fortunately, slight adjustments to IVF protocols can allow for balance between the benefit of optimal hyperstimulation and the risk of OHSS. Using a GnRH agonist trigger, such as leuprolide acetate, rather than an hCG trigger is one way to prevent OHSS [62]. While it was previously thought that the use of an agonist trigger reduces the number of mature oocytes retrieved, recent studies have suggested that using GnRHa triggers, rather than hCG triggers, actually increases the yield of mature oocytes and embryos available for cryopreservation, even after accounting for age, BMI, and cancer type. A recent study by Thorne et al. demonstrated that GnRHa triggers resulted in comparable euploid rates compared to hCG triggers [63]. OHSS risk can be further reduced by managing post-retrieval care proactively and improving patient education on how to prevent OHSS. For instance, lifestyle modifications can be implemented to decrease risk, such as a high sodium/protein diet, electrolyte-rich fluids, and hydration; however, no data has yet been published to support this.

Blood clots represent another risk for cancer patients. Patients with neoplasms, especially those with hematological malignancies, inherently have a hypercoagulable state and are thus at risk for thromboembolism. Supraphysiological levels of estradiol due to COS further increase this risk. Thromboprophylactic treatment, such as the addition of blood thinners to the stimulation protocol, can help to reduce risk of blood clots in these patients [61]. Fortunately, given the minimally invasive nature of transvaginal oocyte aspiration, it is of minimal risk to patients with bleeding abnormalities secondary to cancer. Egg retrieval procedures are ultrasound-guided and require no incision. Typical blood loss in healthy patients is about 230 mL [64]. Minimally invasive procedures, such as superficial aspiration and biopsies, are generally considered to have a low risk of bleeding and bleeding that is easily detected and controllable [65]. Venous thromboembolism among cancer patients following minimally invasive surgery is rare, in contrast to patients undergoing laparotomy [66].

Role of healthcare providers

It is of utmost importance to improve the process for oncofertility patients and this can be best accomplished by well-defined roles for healthcare providers. Given that oncologists are the first physicians that oncofertility patients will interact with, it is important for them to be involved in fertility preservation care. One of the largest barriers in accessing fertility preservation services is that oncologists do not feel that they are knowledgeable enough to discuss fertility options with their cancer patients [1]. Almost half of oncologists in one study reported not being aware of fertility preservation options for female patients [67]. Moreover, the study proposed that many of the barriers that exist among oncologists in discussing fertility preservation were not just limited to lack of knowledge about fertility itself, but lack of knowledge about referrals and a perception that patients are not interested in discussing fertility simply because they never mentioned it. Research does suggest that clinicians who attend educational sessions on fertility preservation are more likely to discuss these services with their patients [68]. Education sessions led by fertility specialists for oncologists and other health care providers therefore offer a solution to this knowledge gap.

Recently released guidelines by the Oncofertility Consortium, an international, interdisciplinary initiative designed to explore the unmet fertility preservation needs of cancer patients, lay the groundwork for educating patients and providers on fertility preservation [69]. Educating providers consists of oncofertility training to ensure proper technology usage, online patient/provider resources that are easily updated, and educational training videos. A free online course offered by ASRM provides an evidence-based review of established and experimental therapies for fertility preservation and recommendations for providers seeking additional training in this area. Additionally, formal interdisciplinary mentor-mentee programs will drive expansion in this emerging field.

One strategic goal of the Oncofertility Consortium is to continue collaboration and connection among members of the field [69]. Connecting oncologists with fertility specialists in the area will create relationships that facilitate quick and easy referrals. A “hub and spoke” model should be implemented, with several oncology/hematology units efficiently referring patients interested in fertility preservation to fewer, more experienced fertility centers [23]. Streamlined referral pathways will make it easier for oncofertility patients to access the services they need in a timely manner, providing effective multidisciplinary care. Nurses, social workers, and patient navigators can aid in this referral process. Utilizing these individuals will help to ensure that patients feel informed and empowered throughout their treatment. Additionally, annual conferences including all members of the field (including REIs, oncologists, OBGYNs, urologists, and allied health professionals) will help to facilitate communication and collaboration [69].

Cultivating a collaborative environment with a multidisciplinary team is essential to the success of this process. Unfortunately, there remain concerns about the effectiveness of communication among REIs and oncologists, which is evidenced by the absence of programs that offer both approaches in clinics and hospitals [69]. Fertility specialists should work in conjunction with the patient’s oncology team to ensure consensus regarding the treatment plan. Including a liaison on the fertility team can help to ensure clear communication between the REI and Oncology teams. Oncologists have the responsibility to discuss the reproductive risks of cancer treatment with their patients and offer them choices to mitigate those risks [9]. The reproductive endocrinologist, on the other hand, should discuss fertility preservation options in detail, including risks, future utilization of their preserved fertility, and the various options for genetic testing. Genetic counselors should thus be included in cases of heritable cancers to further disclose with the patient the risk of passing on such cancers, as well as technology available to possibly reduce these risks or prevent them [9]. Studies have shown that the psychological stress experienced by those diagnosed with infertility is similar to the stress experienced by patients diagnosed with cancer [70]. For oncofertility patients, the psychosocial impact of receiving both can be overwhelming. One survey study demonstrated that women who have lost their ability to conceive due to treatment for gynecological cancers experience feelings of depression, grief, stress, and sexual dysfunction [71]. Therefore, including a psychologist or psychiatrist may also help to provide the patient with psychosocial support given the overwhelming nature of a cancer diagnosis and fertility treatment [1].

Ethical considerations

While fertility preservation provides hope and reassurance for the future, there are numerous ethical considerations that need to be taken into account prior to beginning the ovarian stimulation process. When choosing a treatment plan for patients, there are many things for the oncologist to consider, including the risk of fertility damage/failure, the overall prognosis of the patient, the risk of delaying treatment, the impact of hormonal therapy on the cancer, and the impact of future pregnancy on the risk of cancer recurrence in the future. It is then the role of the REI to be open and honest about the patient’s fertility options, given their age, relationship status, prognosis, and success rates of various forms of fertility preservation. Fertility potential should be a core component of oncofertility treatment, and it is up to the oncologist and consulting REI to properly inform patients of these risks before treatment so that future reproductive options are not lost.

One of the largest concerns for patients and their families, as well as REIs, is the disposition of frozen gametes and/or embryos following fertility preservation. It is essential that prior to gamete/embryo cryopreservation, a decision is made by the patient/legal guardians regarding direction of the stored tissue in the future should the patient die or otherwise be unavailable (e.g., does not pay storage fees or abandons tissue). There are a variety of options for the patient and/or legal guardians, including designating legal ownership to spouse/partner; donating for use by another person or couple, directed or anonymous; donating for research purposes; or destroying all frozen tissue. In cases where there may be posthumous use of the cryopreserved tissue, ASRM recommends that the patient clearly states in writing her desires for such use by her spouse, life partner, or designee [72].

Finally, there has been discussion regarding the quality of life for the resulting child following oncofertility treatment, including concern for their welfare and a potential increased risk of cancer in the child. The ASRM Ethics Committee reports, however, that this should be of little concern when deciding whether or not a patient should have the option to receive fertility preservation [73]. Additionally, in cases of hereditary cancers, patients may opt for preimplantation genetic testing of embryos to avoid transmission of genetic mutations. Overall, there are many factors to consider when counseling cancer patients on fertility preservation. Each case is unique and guidance and counseling should be tailored to individual patients.

A call to action

Ten states now mandate fertility preservation coverage for patients undergoing gonadotoxic treatment. Through this mandate, oncofertility services are becoming more affordable and accessible, allowing for comprehensive care for cancer patients. As more and more states begin to mandate fertility preservation coverage for gonadotoxic treatments, there will be an increase in oncofertility patients seeking fertility preservation services. With this comes the need for healthcare providers to step up and ensure that these services are being provided to their full potential.

It is clear that both oncologists and fertility specialists recognize the importance of oncofertility care. Unfortunately, there are currently no unified protocol and clinical care guidelines for fertility preservation for these patients. Since oncofertility patient care requires the coordination of both physician teams, one set of guidelines will greatly improve the care and referral process. As lawmakers recognize that fertility preservation is not elective, but oftentimes a medical necessity to improve quality of life for patients, it is imperative that clinicians continue to improve the patient experience by meeting oncofertility patients at their particular point of need.

Declarations

Conflict of interest

All authors declare no competing interests.