Fertility preservation for cancer patients

What is oncofertility?

Significant advances in cancer therapeutics in the past decade have contributed to an increase in survivorship among young people with cancer. According to the National Cancer Institute, nearly 80% of pediatric cancer patients (aged: 0–14 years) will survive their disease, and there are approximately 600,000 cancer survivors under the age of 40 years in the USA today [1,101]. These individuals expect to enjoy a high quality of life after cancer, which may include having a family. Unfortunately, although today’s cancer therapies are highly effective, they can also adversely impact fertility, denying the choices associated with family planning. The discipline of oncofertility was created at the intersection of oncology and reproductive medicine in order to inform patients, their families and their partners regarding the potential impact of cancer therapy on fertility and the fertility-preservation options that are available to them at the time of diagnosis [2].

How does oncofertility impact current fertility clinical practice?

Oncofertility seeks to integrate fertility management into cancer care at the time of diagnosis, before patients initiate potentially fertility-threatening cancer treatments [3–6]. For all patients, the fertility management plan should include a discussion of the immediate and long-term fertility risks associated with the cancer treatment, a discussion of the symptoms associated with a steroid hiatus (either short- or long-term loss of estrogen requires a robust symptom management plan) and appropriate contraceptive choices during chemotherapy or radiation treatment. For certain female cancer patients, embryo or egg banking may be an option to preserve their ability to have children after cancer. Embryo or egg banking requires several weeks of hormonal stimulation before eggs can be retrieved. Women who have a partner or source of sperm can bank embryos while women without a partner can bank eggs. Rapid assimilation into an IVF program for emergent treatment is required to minimize delays in beginning cancer treatments. Immediate navigation of young men to sperm banking centers provides a reliable option for gamete preservation with no impact on cancer care.

For patients who cannot delay treatment, ovarian tissue cryopreservation (OTC) can be performed within days of diagnosis and cancer treatment can begin immediately. Similar to sperm banking, which is the best option for fertility preservation in men and pubertal boys, OTC is an option for girls or female patients who do not have access to a sperm donor or who are not able to delay cancer treatment in order to undergo embryo or egg banking. Current efforts are focused on the optimization of OTC and thawing techniques, as well as development of methods to mature thawed follicles in vivo or in vitro for use at a later date.

How does oncofertility impact current oncology practice?

While sperm cryopreservation is widely available to men and postpubertal boys faced with potentially fertility-threatening cancer diagnoses, there have been fewer fertility-sparing options and few programs ready to meet the challenges (specifically, the time constraints and invasive nature of the technology involved) of young women, and particularly girls, with cancer [7,8]. For this reason, oncologists are less inclined to discuss fertility issues with their female patients or their parents. A key goal of oncofertility is to help clinicians communicate effectively with their patients regarding the potential effects of cancer and its treatment on fertility and discuss available fertility preservation options at a time when these issues are not likely to be people’s top priorities.

Optimal patient management requires that fertility issues be addressed quickly after diagnosis so that the patient can resume oncology care as rapidly as possible. Close collaboration and interaction between fertility specialists and oncologists is essential in this regard. Ultimately, a new type of clinician – the oncofertility specialist – will emerge to bridge the gap between the two disciplines and facilitate the delivery of individualized and comprehensive fertility preservation information and resources to cancer patients.

New tools and resources must be developed to help physicians navigate patients through the sometimes bewildering number of issues and available options by providing the oncologists, in particular, a ready referral to a skilled oncofertility specialist. This specialist can discuss the full range of options with the patient – from sperm cryopreservation and intracytoplasmic sperm injection for men, to embryo and egg banking and OTC for women, to adoption, use of donor eggs or gestational surrogacy for couples based on each patient’s unique circumstances and personal preferences. Clinicians must be able to make appropriate referrals to specialists who keep up-to-date on the latest advancements in reproductive medicine and are able to discuss the full range of options with their patients. To facilitate the transfer of information and identification of the best options the Oncofertility Consortium™ has established websites [102,103] that are authoritative and up-to-date and a national oncofertility hotline [phone] FERT [3378]). These navigation tools were created to ensure a rapid-action referral network using the most current and sound scientific and clinical data available to the clinician.

In addition, the field of oncofertility challenges the idea that fertility options are only available to the upper middle class. Cancer does not discriminate, and individual patients (particularly young patients) may not have the financial resources or sufficient medical insurance to pursue fertility preservation procedures prior to initiating cancer therapy. It is imperative that patients be provided with information on the opportunities for financial assistance for fertility preservation in order to give every patient the possibility of having a family after cancer. Fertile Hope, a nonprofit organization that advocates for cancer patients seeking fertility preservation options, has developed the first need-based program that provides financial support to women with cancer [104]. Certainly, long-term strategies, including third-party payer reimbursements, legislative mandates and financial aid, are needed; the Oncofertility Consortium is working on a broad-based national initiative in this regard.

What are the expectations of the patient?

A cancer diagnosis represents a very complex emotional fulcrum for young cancer patients. Oncofertility asks that these patients consider issues of fertility, the hopeful prospect of survival and a possible future family at the same time that they are dealing with devastating news and unexpectedly facing their mortality. Nevertheless, a recent survey of pediatric cancer survivors found that the majority wished that they had been given the opportunity to preserve their fertility at the time of diagnosis [9]. While some patients and their families may choose to focus on treating the cancer, others may want to consider the impact of therapy on fertility and what options may be available before treatment is started, as long as this process does not negatively affect cancer care. The oncofertility specialist will be trained to recognize, assess and balance each patient’s medical needs with their personal wishes, and will be able to work with the patient to identify and implement the best course of action.

What contributions do ethics, law, economics, communication & decision-making disciplines have on oncofertility?

In order to communicate effectively with patients, the oncofertility specialist must appreciate the various factors that influence how cancer patients, their families and their partners make decisions regarding fertility preservation. Thus, oncofertility is not limited to the fields of oncology and reproductive medicine. Understanding the needs and expectations of cancer patients and their clinicians requires interdisciplinary scholarship including ethics, law, the social sciences and economics. As new fertility-preservation techniques are translated to the cancer clinic, they are expected to raise multiple ethical and legal issues [10–12]. Particularly for pediatric cancer patients, questions of informed consent and benefits versus risks will need to be discussed and clarified [13,14].

What do we expect over the next 5 years?

Interest in fertility issues and options for fertility preservation are expected to grow among cancer patients and advocates, and this in turn will stimulate change in clinical practice patterns of both oncologists and fertility specialists. Within the next few years, the line between these two disciplines is expected to blur with the rise of the new oncofertility specialist, versed in both cancer and reproductive biology and capable of providing patients with the information they need to make informed decisions regarding fertility at the time of cancer diagnosis.

At the bench, it is hoped that the first live birth will be achieved using in vitro-matured and in vitro-fertilized eggs retrieved from frozen ovarian tissue [15–17]. Live births from tissue transplants provide significant hope for the utility of the cortical tissue pieces to preserve the reproductive potential of the individual at the time of a cancer diagnosis [18]. Current efforts are focused on translational research in the rhesus monkey model and in human ovarian tissues collected through the National Physicians Cooperative of the Oncofertility Consortium [102]. In particular, the goal is to optimize methods to preserve ovarian tissue at a young age to ensure availability of biologically ‘young’ eggs if and when these patients are ready to start a family later in life. The ability to ‘bank’ ovarian tissue and use it successfully to achieve a pregnancy would represent a significant leap forward in reproductive medicine; it will extend fertility preservation options to even the youngest cancer patients.

Future challenges

There are several scenarios that are expected to pose significant challenges to the practice of oncofertility. For example, high-risk patients, such as those who are BRCA-1 positive, may wish to have their ovaries removed to reduce their cancer risk. Normally, the oncologist would want to examine the tissue for occult cancer, but if these patients do not have a partner, they may want to store their ovarian tissue for later use. While this tissue would probably not be considered for use in autotransplantation, it may one day be possible to retrieve follicles from the thawed tissue for in vitro follicle maturation and IVF. Prophylactic, elective removal of breasts and ovaries to reduce the lifetime risk of cancer is a very challenging and emotionally charged decision for many women in this category. In the modern era of advanced genomic diagnostics, daughters of BRCA mothers are aware of their genetic destiny at an early age. This permits proactive decision-making and expectant management of cancer onset and progression; however, it may also disrupt the individual’s family planning. Embryo selection following preimplantaiton genetic diagnosis can eliminate the transmission of the gene and removal of affected tissues reduces the long-term risk of cancer in the offspring. In some sense, if a BRCA-positive individual makes the choice early enough to bank embryos (perhaps with donor sperm) and eggs, followed by prophylactic removal of the ovaries, she has the opportunity to both manage her own fertility and reduce her lifetime risk of cancer. Managing the complexities of the BRCA-affected individual and providing national guidelines is one goal of this program.

Another challenge to the application of fertility preservation techniques for cancer patients is the storied history of IVF, which appeared to move from the bench to the bedside at a record-breaking pace [18]. A majority of IVF research occurred outside of the peer-reviewed, NIH-funded environment, simply because there were no good preclinical models for human IVF, and research on human gametes and fertilization is strictly regulated in the USA and cannot be carried out using NIH funding. The basic and translational aspects of oncofertility research have adopted a rigorous, empirical methodology. Moreover, we invited peer and community review from its nascent stages. This interdisciplinary engagement raises three intrinsic challenges; the first is that scholars from different disciplines speak different professional lexicons that must be managed to ensure a clear understanding of the principles and the concerns each group brings to the table; second, the broad engagement model may encourage a radical difference of opinion regarding how (and indeed whether) the research should go forward; which, finally, may seem to slow translational initiatives and the clinical application of new procedures. Despite these challenges, the universal scholar engagement model is, in our expert opinion, the best way to bring new, advanced reproductive technologies to the public.

As these technologies become more routine, we predict they will be used outside the cancer community to provide fertility-sparing options to other iatrogenic or disease-mediated fertility threats. Eventually, there may be interest in banking a piece of ‘young’ ovarian tissue, eggs or embryos early in life to provide a ‘reproductive piggy bank’. While perhaps controversial in human applications, this concept is a viable one in endangered species conservation where the inability to preserve the female germ line threatens a large number of animals with which we share this planet. Clearly, the engagement of a large number of voices in the conversation, as has been the case since the inception of this program, is a vital, albeit challenging, necessity.

Conclusion

Since its inception, the discipline of oncofertility set out to fulfill an important unmet need in cancer care: gaining a deeper understanding and addressing the impact of cancer and cancer therapy on fertility with the goal of providing patients with the possibility of having a family after cancer. Meeting this need requires a truly interdisciplinary effort, one that brings together not only oncology and fertility specialists, but also scholarship in ethics, law, social science, health economics and education. Ultimately, the successful practice of oncofertility will require the creation of a new kind of specialist who can bridge these disciplines and communicate effectively with patients about personalized fertility strategies, even amidst the stress of a new cancer diagnosis.

Acknowledgements

The authors acknowledge the members of the Oncofertility Consortium for their thoughtful participation in this project.

Financial & competing interests disclosure

This work is done under the auspices of the Oncofertility Consortium, an interdisciplinary team funded through NIH Roadmap Initiative UL1 RR024926. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.