The importance of fertility preservation in cancer patients

Abstract

The potential risks of anti-cancer therapy for male and female fertility are well understood, yet evidence suggests that fewer patients than predicted actually preserve their fertility before therapy begins. Studies of post-pubertal males and females suggest that the approach of health professionals in oncology is vital in facilitating successful sperm and egg banking. For men, this seems to be compounded by a general lack of understanding about their personal risk of infertility. Those involved in delivering anticancer therapy therefore have a vital role to play in providing timely information and facilitating efficient referral to fertility services. In the future, this is likely to become more important if new fertility preservation strategies such as ovarian and testicular tissue banking become more routinely used, with implications for both pre- and post-pubertal individuals.

Keywords::

• cancer
• cryopreservation
• egg
• fertility
• sperm

A recognized ‘late-effect’ of anticancer therapy is infertility, although exact risk estimates vary with age, gender, disease and the type and dose of treatment administered [1]. For example, men who survived cancer as children are about half as likely to achieve a pregnancy in comparison with their brothers [2], whereas a surprising number of those diagnosed and treated as adults go on to father children successfully [3]. Conversely, women who survive childhood cancer are about 80% as fertile as their sisters [4] and those diagnosed and treated as young adults have noticeably reduced fertility in comparison with the general population as well as being at increased risk of early pregnancy loss if they do become pregnant [3], or at risk of delivering a child prematurely and underweight. Women who survive cancer are also at risk of an early menopause [5], which will shorten their reproductive years even if they are initially fertile following anti-cancer treatment.

Given the risks of infertility, and importantly the uncertainty of prediction for any one individual, guidelines for clinicians and other healthcare professionals have been established in many countries with regard to the provision of fertility preservation prior to anti-cancer therapy [6–8]. However, little is currently known about the extent to which these are followed and whether or not cancer patients of either sex are actually offered the opportunity to preserve their fertility. In addition, research is beginning to show that for patients the decision-making process is sometimes far from straightforward, with a complex interplay between the views of patients, family members and health professionals. To date, fertility preservation has been largely delivered and managed by specialists in reproductive medicine, but in this paper we argue that oncologists and those delivering anti-cancer treatment have a significant role to play in providing timely information and facilitating appropriate referral to fertility services.

For post-pubertal males, the recognized approach to preserve fertility is to bank samples of ejaculated sperm [1], or occasionally sperm recovered from surgical aspirations. It has been possible to bank sperm successfully since the 1950s, although it was only demonstrated to be effective as fertility preservation for cancer patients in the 1970s [9]. In spite of this long history, and the relative ease and speed with which it can be performed, studies continue to show that relatively few men actually bank sperm before anti-cancer treatment begins. For example, in a recent review, we showed that in seven studies from five countries this was lower than 30% [10]. For some men, this may be because their oncologist did not give them the opportunity to bank sperm, or the cost, if not state funded, was not covered by health insurance. For others, the decision seems to be to deliberately decline the offer. In a recent prospective study in the UK, where we know that oncologists were offering sperm banking according to the relevant guidelines [7] and where sperm banking was available free of charge through the UK National Health Service, only 56% took up the offer to bank sperm [11]. There is evidence to suggest that this may be because men are overwhelmed with information at the time of diagnosis and fail to understand the effect of anti-cancer treatment and their personal risk of infertility [12]. In addition, those who do successfully bank report that a major enabling factor was that health professionals made it easy for them to do so by making all necessary arrangements, in the same way that they would for blood tests and scans [12]. This suggests that barriers can exist to effective sperm banking and health professionals should do all they can to facilitate efficient sperm banking as a routine part of the package of tests and investigations that are undertaken before anti-cancer treatment begins. Interestingly, it seems that barriers to engagement with fertility issues can exist in the longer-term with some men seemingly reluctant to agree to semen analysis once anti-cancer treatment is over [13]. In this context, it is interesting that information provided on-line about sperm banking and subsequent fertility recovery, use or disposal of banked sperm is often written at a level too advanced for an average member of the general public to understand [14]. These findings make us wonder if, in spite of the long history of sperm banking, there is scope to radically improve how the service is provided.

In contrast to sperm banking for males, fertility preservation options for post-pubertal females have not been available for as long and are certainly not as easy to undertake. Although the freezing of human embryos has been technically possible since the mid-1980s, it is often an inadequate solution for many women since it requires a long-term partner who is willing to provide the sperm to fertilize their eggs and with whom they feel sufficiently secure to entrust their reproductive future [15]. However, more recently, freezing technology has advanced sufficiently to allow post-pubertal females to bank unfertilized eggs that can be thawed and fertilized at a later date when the woman was ready to start a family. In contrast to banking sperm, the timescales involved in both egg and embryo banking are significantly longer, as several weeks are required to administer the gonadotrophins necessary to obtain a reasonable number of eggs, although some alternative strategies have been attempted [16]. However, for the most part, this means that egg and embryo banking are not always possible for women with aggressive tumors requiring urgent treatment. However, for women whose anti-cancer treatment can be delayed, this is often the first option. A number of pregnancies have now been reported and the pregnancy rates using frozen-thawed eggs appear to be comparable with that achieved using fresh eggs [17].

Exactly how women feel about delaying anti-cancer treatment for several weeks in order to undergo fertility preservation is not clear, but we know that the way in which health professionals present information to women has a significant bearing on how they view their fertility preservation options and whether they are ready to accept them [18]. Often health professionals stress the life-saving nature of treatment and paint a picture of survival as the paramount objective, with future fertility of secondary importance. It seems relatively few women are currently given the opportunity for a discussion about fertility and this may explain why young women seem consistently dissatisfied with the fertility discussions provided by their oncologist at the time of diagnosis [19]. We know that reproductive health is important to female cancer survivors and irregular menstrual function or early menopause can lead to reduced quality of life [20]. In comparison with the relatively easy fertility options for males, it is clear that we need better options for women facing anti-cancer treatment.

A potential solution to these dilemmas for women has been proposed through the removal and long-term storage of ovarian tissue prior to anti-cancer treatment, with a view to replacing it later to restore natural fertility if required. The beauty of this approach is that tissue can be removed at any time in a relatively minor surgical procedure and therefore not delay the start of anti-cancer treatment. Moreover, the same technique could also be used to preserve the fertility of pre-pubertal girls, who currently have no options available to them. While the theory is robust, there is currently no consensus on how much tissue to take, the technical aspects of storage or the site of re-implantation [21]. In addition, there are genuine concerns about the possibility of re-introducing cancer cells back into the survivor if tissue taken and stored before anti-cancer treatment is reintroduced into the woman later to restore fertility. For this reason, some have suggested that the safest route by which this tissue might be used to restore fertility would be to grow eggs in the laboratory that can be fertilized in vitro and then any embryos returned to the woman's uterus. However, although eggs have been successfully matured and fertilized after extraction from ovarian tissue of cancer patients, to our knowledge no pregnancies have resulted [22]. For this reason, this approach is still considered experimental. By contrast, a limited number of births have been reported worldwide following the re-transplantation of ovarian tissue into the body, but it is not currently known how many failed attempts have been unreported. Thus, the efficacy of this approach is unquantified and remains experimental.

Finally, there are currently no proven fertility preservation options for pre-pubertal boys, although it has been suggested that an experimental approach might be to collect and freeze pieces of testicular tissue before anti-cancer treatment begins with a view to re-transplanting spermatogonial stem cells into the testis at a later date to restore fertility [23]. Similar concerns apply concerning the dangers of re-populating the testis with cancer cells at a later date, but arguably it is easier to isolate and remove them from a suspension of spermatogonial stem cells than it would be from a solid piece of ovarian cortex in the case of female fertility preservation. To our knowledge, there are no published examples of successful re-population of the human testis with spermatogonial stem cells taken prior to anti-cancer therapy, and similarly there are to our knowledge no reported paternities from sperm generated in this way. Therefore, this approach remains at the experimental stage and should only be offered in the context of an approved clinical trial.

In conclusion, in the last 20 years we have seen major advances in the provision of fertility preservation options for men and women about to begin anti-cancer therapy. Moreover, strategies for fertility preservation for pre-pubertal males and females are currently in development and may become mainstream in the next few years. Oncologists and those delivering anti-cancer treatment have a significant role to play in providing timely, accessible and impartial information as well as facilitating appropriate referral at the right time. As new technologies emerge, clear and unambiguous information for patients will become increasingly important.

Acknowledgements

The author would like to thank D Saxton and K Williams for their help in proof reading the manuscript.

Financial & competing interests disclosure

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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