Fertility preservation ‘central’ to health, wellness of AYA patients

Oncology providers administer treatment to approximately 70,000 adolescent and young adult patients each year in the United States.

Fertility preservation is central to the health and wellness of this population, defined as those aged 15 to 39 years.

As such, it is of great importance to distinguish which patients are at risk for infertility, understand what options — both established and experimental — are available to preserve fertility, and know how to advocate for and educate our patients about those options.

The focus of this article is on AYA patients with cancer, as this population is the most likely to be fertile. However, we understand and appreciate that women and men aged 40 years or older may desire to have a family following their cancer diagnosis and, if this is the case, the same options discussed below may be applicable to these patients.

The desire to have a family is prevalent in young cancer survivors. However, many patients may not raise the topic of fertility preservation at the time of diagnosis for a variety of reasons. They may be overwhelmed by and focused exclusively on the cancer diagnosis. They could be unaware that potential fertility loss may occur, or they might be concerned that pursuing fertility preservation will delay treatment.

Therefore, it is incumbent on the oncology team to properly educate patients whose fertility may be affected by their treatment.

Established guidelines

ASCO has long recognized that fertility preservation is an important survivorship issue. The society released its initial recommendations for providers in 2006, then updated the recommendations in 2013. ASCO emphasizes that risks to fertility — as well as fertility preservation options — should be considered as part of informed decision-making before the start of cancer therapy, and all approaches should be discussed as early as possible.

Further, National Comprehensive Cancer Network guidelines emphasize that fertility preservation is an essential part of adolescent and young adult (AYA) patient management, with appropriate referrals made within 24 hours for any patient who chooses to pursue fertility preservation.

Conversations about the effects of treatment on fertility and ways to preserve fertility can reduce stress and improve quality of life among cancer survivors. Although a patient may choose one of many alternate ways to achieve a family — including use of donor eggs or sperm, or adoption — it is our obligation to maintain their available options. It is also a way for us to let patients know that we anticipate a future, past cancer, that includes a family if they desire.

Patients at risk

A comprehensive discussion about fertility must take into account the patient’s medical history, proposed treatment, biological sex and age, as well as the patient’s pre-treatment fertility status. Risks to fertility include surgery, chemotherapy, radiation therapy and stem cell transplant.

For female patients, fertility may be compromised by any treatment that potentially decreases the number of follicles, affects hormonal balance, or interferes with the function of the ovaries, fallopian tubes, uterus or cervix.

For example, radiation — either directly to the pelvis or through scatter — can affect resting eggs. A mathematical model created by Wallace and colleagues suggested that the dose required to destroy half of the immature oocytes is less than 2 Gy. Anatomic or vascular changes that occur from radiation or surgery to the uterus, cervix or vagina can prevent a pregnancy, requiring in vitro fertilization or use of a gestational donor. Depending on treatment given, female survivors are at risk for pregnancy complications, such as increased risk for miscarriage or premature birth, and development of cardiomyopathy.

Further, it is important to remember that fertility may be compromised despite resumption of regular menses. Patients may have low ovulatory reserves, which will decrease the chance of conception and increase the risk of early menopause. Even if a woman is fertile initially after cancer treatment, the duration of her fertility may be shorter.

Among male patients, the testis is one of the most sensitive organs in the body to radiation due to rapidly dividing germinal epithelium. Immature sperm are most sensitive to radiation injury, whereas Leydig cells are more resilient. Small doses as low as 0.1 Gy can affect the shape and number of sperm, exposure to 2 Gy to 3 Gy leads to a significantly altered number of sperm, and doses greater than 2 Gy could lead to irreversible azoospermia.

Risk estimation

Of greatest concern, aside from radiation, is the use of alkylating agents. A dose of cyclophosphamide at 7.5 g/m² is considered high risk for infertility, though the risk for infertility increases with cumulative doses of alkylating agents or combinations of agents.

As providers, we can estimate the risk for gonadotoxicity based on proposed treatments utilizing well-known gonadotoxic modalities. Providers may reference the ASCO guidelines or the Oncofertility Consortium for more information about treatment regimens that place patients at low, moderate or high risk for infertility.

Regardless of risk, each patient should be aware of the potential hazard their treatment will have on their ability to have a child following cancer treatment. If the risk profile warrants, the patient is desirous and time permits, referral should be made to reproductive specialists so patients are given the option to preserve their fertility prior to the start of gonadotoxic treatment.

Wallace and colleagues reported efficacy of the Edinburgh selection criteria after conducting a retrospective evaluation of patients who were either offered or not offered cryopreservation of ovarian tissue during a 15-year period at the Edinburgh Children’s Cancer Centre. The selection criteria (Table 1) accurately predicted which girls and young women developed premature ovarian insufficiency and who, appropriately, were referred for ovarian cryopreservation.

Though there are guidelines for estimating risk, there are no absolutes. Each patient’s risk for fertility damage should be assessed on a case-by-case basis and referred to appropriate fertility specialists as needed.

Though numerous patients have benefited from the introduction and use of targeted agents — such as bevacizumab (Avastin, Genentech), dasatinib (Sprycel, Bristol-Myers Squibb), vorinostat (Zolinza, Merck), ipilimumab (Yervoy, Bristol-Myers Squibb) and pazopanib (Votrient, GlaxoSmithKline) — we have limited data about how these agents affect long-term fertility.

Recent data show that ipilimumab may cause hypophysitis, interfering with the conducting system and resulting in damage to fertility. Ovarian failure is a known risk in women who receive bevacizumab-containing regimens, and only 20% are reported to regain ovarian function after receiving this type of treatment.

Due to the paucity of data pertaining to long-term reproductive risks, if the risk is unknown, fertility preservation should be offered.

Fertility preservation options

There are many established fertility preservation options for post-pubertal females, including cryopreservation of eggs, embryos or ovarian tissue. If pelvic radiation is to be administered, an oophoropexy may be performed.

The best option for a female who does not need to start therapy immediately — particularly if the patient does not have a partner with whom to fertilize eggs, or objects to the freezing and storage of embryos — is collection of eggs for cryopreservation.

Egg banking is a viable option and is no longer considered an experimental procedure, according to ASCO and the American Society for Reproductive Medicine. A procedure that has become increasingly popular in the field of fertility preservation is “random start” ovarian stimulation. This allows patients to begin fertility treatments at any time in their menstrual cycle, with egg collection performed within 2 weeks.

If a patient needs to start their therapy urgently or is a prepubertal female, they may be referred for ovarian cryopreservation. During this process, an entire ovary is removed laparoscopically and frozen for future use. This approach is only available as a research option through the Oncofertility Consortium at Northwestern University (oncofertility.northwestern.edu).

Lastly, in vitro maturation of human oocytes is in development. This approach requires very little or no stimulation to complete immature egg retrieval and may be used in prepubertal or postpubertal females. As the immature eggs are matured in an in vitro system, there is less time associated with this approach compared with mature ova collection. There are ongoing current studies in nonhuman primates, but the methodology is expected to soon be translated for human use.

Of note, though much work has been done on the use of gonadotropin-releasing hormone agonists to minimize chemotherapy-induced gonadotoxicity and premature ovarian failure, this approach remains controversial and under study.

In postpubertal males, the mainstay of fertility preservation is sperm banking. If a patient’s initial collection is suboptimal, they can attempt a second collection 48 to 72 hours after the first. After the second attempt, if still unsuccessful, patients may be referred to urology specialists for testicular sperm extraction.

Testicular tissue harvesting — an emerging technology intended for prepubertal boys and young men who cannot produce a viable sperm sample — is only available as a research option through the University of Pittsburgh (www.mwrif.org/476). Following consent to study, a wedge biopsy of the testis is obtained, frozen, and portioned for research use and future use by the patient. Research efforts from this team include attempts to grow harvested tissue in an in vitro system and establishment of spermatogenesis in a xenograft model.

Insurance coverage, post-treatment follow-up

Unfortunately, insurance coverage for these modalities is highly variable.

The Affordable Care Act does not require insurers to cover the costs of infertility; it is only mandated when infertility is included in a state’s “benchmark plan” as an “essential health benefit.”

Clinical trials should be considered and sought out as options to defray costs associated with fertility preservation for AYA patients with cancer. Regardless of potential financial constraints, decisions about oncofertility must be included for all patients who are in a position to have their future fertility compromised by their cancer care.

Though fertility preservation efforts have advanced considerably in the past several years, fertility in both men and women can be unpredictable. Even if fertility preservation efforts are successful upfront, a successful pregnancy cannot be guaranteed. Comprehensive conversations about fertility preservation must address the fact that there are no assurances.

For example, data from the Oncofertility Program at Colorado University Cancer Center indicates that — in a routine cryopreservation setting — 50% of sperm lose their viability simply from the process of freezing and thawing. However, survivability is much lower — about 10% to 20% — in patients with cancer.

Finally, as mentioned above, infertility resulting from cancer treatment may be temporary. As such, re-evaluation of a patient’s fertility should be performed beginning at 18 months post-therapy.

Evaluations for females should include follicle-stimulating hormone, estradiol and anti-Müllerian hormone levels. Male patients can be evaluated with a complete semen analysis. If a patient continues to demonstrate decreased function, testing can be repeated to definitively document reproductive capabilities.

Integration of oncofertility into clinical practice

Balancing efforts to extend fertility preservation to all patients can be a challenge. There are definitely times when patients will be too sick or critical, or families will be too overwhelmed to pursue preservation efforts. In these cases, patients and families still should be adequately informed in the event that the proposed treatment has the risk of causing temporary or permanent infertility.

Fertility preservation may be reconsidered once patients have stabilized or when involved parties have had an opportunity to come to terms with the cancer diagnosis. However, in light of new modalities — such as “random start” ovarian stimulation — it is more common that there is time to pursue fertility preservation, particularly if it is initiated once cancer is suspected rather than waiting for final pathological diagnosis.

We recognize that patients at the younger end of the AYA spectrum may not have considered their futures, including having children. For a pediatric oncology practitioner, it may be uncomfortable to broach the topic of fertility.

Though ASCO and the NCCN emphasize the importance of fertility preservation, they do not dictate that it must be the sole function of the physician. We encourage programs to identify a fertility “champion” who may facilitate discussions about fertility and fertility preservation efforts. This individual may be an advanced practitioner, a nurse or a social worker.

Further, the topic likely will not be perceived as being “out of bounds” if it is included as part of the routine discussion about the expected side effects of cancer treatment. In our experience, the discussion about fertility gives patients and families assurance that our goal of treatment is for them to survive and thrive into adulthood.

Success in implementing an oncofertility program requires buy-in at all levels of the institution. In some cases, such as the Knight Cancer Institute at Oregon Health & Science University, institutional policy was prepared around the support of patients’ fertility rights. In other cases, it is driven by departmental or divisional leadership.

Regardless, we appreciate that it takes a team, including — but not limited to — surgeons, gynecologists, urologists, reproductive endocrinologists and other fertility specialists. Although these resources often are available in academic and large urban practices, they may not be readily available in all community-based settings. In addition to the resources referenced above, programs may consider the use of Nicole’s Oncofertility Toolkit, which received the Association of Community Cancer Centers Innovator Award in 2011 (www.accc-cancer.org/oi/MJ2012).

Take-home messages

Common cancer treatment modalities — surgery, chemotherapy, radiation therapy and stem cell transplant — can result in temporary or permanent infertility or early onset menopause.

Fertility preservation is an important component in the care of AYA patients with cancer. It can result in improved psychological outcomes in survivors of cancer.

Currently, there are limited long-term data regarding fertility as it pertains to the use of new targeted therapies.

There are a number of options available for fertility preservation depending on a patient’s age and reproductive status at time of cancer diagnosis. Some options are still only available through research protocols.

Assessment of fertility status should be performed starting at 18 months post-treatment and, if fertility has been restored, patients may not need to incur costs associated with long-term storage of ova, sperm or other tissue.

For most patients, there is time to discuss and address fertility preservation efforts prior to start of treatment. Fertility preservation can be integrated into discussions by many different members of the clinical care team, though a fertility preservation “champion” can facilitate discussions with patients, family members and clinicians. A comprehensive oncofertility program includes a dedicated team of providers outside the field of oncology.

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For more information:

Julie A. Messina, PA-C, is a physician assistant at Hyundai Cancer Institute at Children’s Hospital of Orange County in Orange, Calif.

Keri B. Zabokrtsky, MS, is supervisor of the Hyundai Cancer Genomic Center at Children’s Hospital of Orange County.

Leonard S. Sender, MD, is medical director of the Hyundai Cancer Institute at Children’s Hospital of Orange County, as well as pediatric subspecialty faculty division chief of oncology and director of clinical operations/program development at UC Irvine Health’s Chao Family Comprehensive Cancer Center. He can be reached at UC Irvine Health Chao Family Comprehensive Cancer Center, 101 The City Drive South, Building 23, Orange, CA 92868; email: lsender@uci.edu. 

Disclosure: Messina, Zabokrtsky and Sender report no relevant financial disclosures.