Fertility Treatment

Undergoing a cancer diagnosis is hugely stressful. Preparing for chemotherapy with the concerns of hair loss and fear of side effects, allow patients little time to further contemplate the possibility of infertility as a result of their treatment. At times, possible conflicting advice from your treating team, doctors, friends, family and partner can result in confusing options and difficult choices. Finding a member of your multi-disciplinary team to discuss these options with is essential.

The responsibility of your health care provider is to address the possibility of infertility with patients treated during their reproductive years, or with parents and guardians of those under age. Health care providers should advise potential threats to fertility as early as possible in the treatment process, so as to allow for the widest array of options for fertility preservation, while informing patients families and partners of the potential risks

The essential principles around fertility are sperm and embryo cryopreservation – freezing – as well as oocyte cryopreservation. These options are considered standard practice and are widely available. Other fertility preservation methods should be considered investigational and detailed discussions around their benefits should take place with every patient.

Ethically, all patients of reproductive age undergoing oncology treatment should have a detailed discussion and documentation around fertility if infertility is a potential risk of therapy.

Questions should be asked irrespective of whether patients with cancer are interested in interventions to preserve fertility or not. Discussions around the quality of evidence supporting current and forthcoming options for preservation of fertility in both males and females should be explained.

Post discussion with their oncologist, all patients who express an interest in fertility preservation, as well as patients who are ambivalent, should have a referral to reproductive specialists. Fertility preservation should be addressed as early as possible, preferably even before treatment starts. Documentation of fertility preservation discussions should be placed in the medical record. Patients should be referred to psycho-social providers or onco-psychologists if they experience distress about potential infertility. Patients should be encouraged to participate in registries and clinical studies.

Discussions should be honest, so as to not create unattainable expectations with poor clinical outcomes both in terms of fertility and patient outcome. The often difficult role of the oncologist in advising patients about fertility preservation options, must also be taken into account, as the oncologist’s primary goal is to treat malignancy. Their responsibility is in preserving the life of the person with cancer, therefore delays in cancer treatment in order to undergo fertility treatment, may not sit comfortably with them, however necessary it may be.

Male fertility

• Present sperm cryopreservation (sperm banking) is the only established fertility preservation method available.

• Hormonal therapy in men is not recommended.

• Testicular tissue cryopreservation – which does not require sexual maturity – for the purpose of future reimplantation or grafting of human testicular tissue, is experimental.

• Men must be advised of a potentially higher risk of genetic damage in sperm collected after initiation of chemotherapy.

Female 

• Both embryo  (fertilized egg and sperm) and oocyte (egg) cryopreservation are acknowledged as established fertility preservation methods.

• Option of ovarian transposition (oophoropexy) when pelvic radiation therapy is performed can be offered in certain centers.

• Discuss conservative gynecologic surgery and radiation therapy options.

• There is insufficient evidence regarding the effectiveness of ovarian suppression as a fertility preservation method.

• Inform patients that other methods like ovarian tissue cryopreservation, which does not require sexual maturity for the purpose of future transplantation, are still experimental.

Are Patients With Cancer Interested in Interventions to Preserve Fertility?

The failure of patients to mention infertility is multifactorial. Patients are often overwhelmed by and focused exclusively on the cancer diagnosis. They may be totally unaware that potential fertility loss may occur.

Concerns that pursuing fertility preservation will delay their treatment, leading to increased morbidity or mortality are also real. Patients may make cancer treatment decisions based on fertility concerns and thus decide not to undergo oncology therapy, further jeopardizing their health.

Principles

Fertility preservation options in females depend on patient age, diagnosis, type of treatment, presence or participation of a male partner and patient preferences regarding the use of banked donor sperm, time available, and likelihood that cancer has metastasized to her ovaries.

Some, but not all, interventions may entail a delay in cancer treatment and it must be emphasized that early referral to a subspecialist can minimize this delay.

Letrozole can be used for ovulation induction in infertility patients, for the purpose of ovarian stimulation for fertility preservation via oocyte or embryo cryopreservation in women with estrogen-sensitive cancer.

When combined with standard fertility drugs, letrozole enhances ovarian stimulation while keeping estrogen levels near physiologic levels.

Cryopreservation of unfertilized oocytes 

The freezing of unfertilized eggs results in similar numbers of eggs and embryos, and similar pregnancy outcomes in most international fertility units. Discussions with your fertility specialist as to what their success rate is, should be undertaken.

Success rates for this procedure have improved significantly with studies and some reproductive specialty centers have reported success rates comparable to those obtained using unfrozen eggs, especially in younger women.

Like embryo cryopreservation, this technique also requires ovarian stimulation and ultrasound-guided oocyte retrieval. Oocyte cryopreservation is of particular importance for women who do not have a male partner or prefer not to use donor sperm.

Embryo cryopreservation

It is ideal to stimulate ovaries within three days of the start of the menstrual cycle, random stimulation can be successful as well, but not as ideal. Newer hormonal stimulation regimens may be as effective as traditional methods, and their use may be preferred in women with hormone-sensitive cancers. Although aromatase inhibitors are primarily used as adjuvant treatment of hormone-positive breast cancers – especially in premenopausal women – they can act as ovarian stimulants, but also suppress estrogen levels.

Ovarian suppression

Ovarian suppression is a term that means keeping the ovarian tissue in a state of non-function on ice. The effectiveness of GnRHa is still not resolved, as there were no differences observed in the menstruation resumption rates or in hormonal and ultrasound markers of fertility between GnRHa-treated patients, versus the control group twelve months after termination of chemotherapy.

A recent meta-analysis, which updates an earlier one, included 24 months of follow-up in the ZORO (Zoladex Rescue of Ovarian Function). The study failed to demonstrate a possible beneficial effect of GnRHa use on either maintenance of menstruation, or fertility.

Speaking to your treating oncologist about using these drugs is beneficial to your fertility quest, but understand that there is not definitive data that show that GnRHa preserves fertility.

Ovarian tissue cryopreservation and transplantation

Although this process is still considered experimental, successful pregnancies have been reported. There is a theoretic concern with re-implanting ovarian tissue and the potential for reintroducing cancer cells, depending on the type and stage of cancer.

Other considerations

With recent data supporting a longer duration of hormonal therapies for estrogen and progesterone receptor-positive breast cancer, larger numbers of women will be affected by the risk of compromised fertility. These women will be older and at higher risk for infertility by the time that their hormonal therapy is completed. This needs to be discussed with women on hormonal treatment for breast cancer.

BRCA and High Risk families

BRCA mutation carriers, especially those with BRCA1, have diminished ovarian reserve. Carriers may be more prone to chemotherapy-induced infertility with a higher likelihood of low response to ovulation induction. Embryos can be tested for these mutations by embryo biopsy and pre-implantation genetic diagnosis techniques can be considered

Considerations for Patients Receiving Targeted and Biologic Therapies

Ovarian failure occurred in 34% of women receiving a bevacizumab-containing regimen for colorectal cancer, with only one fifth of these women recovering ovarian function. Tyrosine kinase inhibitors (TKIs), such as imatinib, may affect fertility, with no significant higher risk of congenital abnormalities in offspring.

A small reminder here; oncology care is for the preservation of a persons life, and although the importance of fertility treatment cannot be emphasised enough, the importance of taking the suggested oncological agents are often critical to a patients survival from the malignancy.

PROVIDER AND PATIENT COMMUNICATION

Discussions with medical insurance providers around payment for oncology related fertility treatment should be openly discussed and advocacy groups for this should address the need.

Conversely, fertility issues are not without a minefield of potential concerns regarding use of embryos from relationships that no longer exist, as well as the potential that due to they may not be able to utilise the preserved eggs or sperm or embryos due to the malignancy of the patient, so patients should each be informed of their individual risk. Risks can be stratified into high, medium, low or nonexistent.

Risks of pregnancy and children after cancer

There seems to be no increased risk of cancer recurrence from fertility preservation methods or pregnancy, even in hormonally sensitive tumors. There is also no known risk of passing cancer along to children. Aside from hereditary genetic syndromes and in utero exposure to some chemotherapy treatments, there is no evidence that a history of cancer, cancer therapy, or fertility interventions increases the risk of cancer or congenital abnormalities in the progeny.

State Practice

Few fertility units are operational in our government health set up. However, this should not preclude the discussion around fertility in patients. It may be that the only option is the use of a GnRHa in young women?

Conclusions

There are many available fertility preservation and parenthood after cancer options to consider. For men, the most common and successful option is sperm banking. For women, the most established options are embryo and egg freezing. A referral should be made to an appropriate reproductive specialist for a consultation.

Time is of the essence. Fertility preservation treatments need to be completed before you start chemotherapy or irradiation. For men, sperm banking can be done quickly and can be done every 24 hours, for as long as necessary, to collect the desired number of samples.

For women, fertility preservation may take 2 to 4 weeks for established techniques.

Data supplements, clinical tools and resources can be found at http://www.asco.org/guidelines/fertility.

Patient information is also available at http://www.cancer.net

• ASCO: www.asco.org

• Fertile Hope: www.fertilehope.org

• Lance Armstrong Foundation: www.livestrong.org

MEET THE EXPERT

Prof Carol-Ann Benn heads up breast cancer centres at Helen Joseph Hospital and Netcare Milpark Hospital. She lectures at Wits University and, in 2002, established the Breast Health Foundation.

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