Fertility preservation in patients with cancer: What the surgeon needs to know

As surgeons, we often are the first physicians to diagnose and treat cancer, which gives us a unique opportunity to direct cancer care. As more people choose to delay childbearing, and as younger patients are diagnosed with advanced cancers, we need to include fertility preservation in our initial patient discussions. The American Society of Clinical Oncology published evidence-based clinical practice guidelines on fertility preservation, which were most recently updated in 2018. The goal of this article is to summarize the recommendations that are most relevant to surgical practice so we, as surgeons, may help our young cancer patients navigate complex cancer treatment decisions. Any cost and fertility success rates discussed in this article are estimates and vary significantly between programs and patient factors.

Many cancer patients fail to mention fertility concerns for a variety of reasons. They are overwhelmed by the cancer diagnosis, worried about delays in cancer treatment, or unaware of the potential for fertility loss. However, if offered, many patients keep in mind fertility concerns when making treatment decisions. Surgeons can initiate the fertility discussion, which should include patient preferences and any potential risk to fertility with the proposed treatment. Surgeons should involve appropriate psychosocial providers if the patient is distressed about any risk of infertility and document these discussions in the electronic health record. Having the fertility discussion with patients early, ideally before the start of treatment, can reduce patient distress and, ultimately, improve quality of life. Patients interested in learning more about their fertility options or who are ambivalent about these decisions should be referred to reproductive specialists.

Surgeons should understand which oncologic treatments present the highest risk to fertility. Any treatments containing high doses of alkylating agents and/or high doses of radiation to the testes, abdomen/pelvis, or hypothalamic axis present the highest level of risk for gonadal impact for either future sperm production or immediate amenorrhea. Lower levels of alkylating agents and/or radiation reduce but do not eliminate the risk of sterility. Nonalkylating agents are a lower risk to fertility; however, patients may want to consider fertility preservation due to the potential for relapse and/or additional treatment. Certain monoclonal antibodies or tyrosine kinase inhibitors lack conclusive fertility data, and patients should be counseled about the unknown fertility risk.

Male fertility preservation

For postpubertal males receiving cancer treatment, sperm cryopreservation is effective, and sperm banking should be discussed with the patient. Sperm collected after initiation of chemotherapy has a high risk of genetic damage. A single cancer treatment may affect the quality of sperm DNA; therefore, sperm should be collected before the initiation of treatment. Sperm are typically obtained through self-stimulation, then frozen. Multiple samples can be collected over several days to be used in intrauterine insemination or in vitro fertilization (IVF) cycles. Estimated cost is $1,000 to $1,500 for sperm analysis and three years of storage, then $300 per year for storage thereafter. If necessary, sperm can be extracted through aspiration under sedation with an additional varied cost. Intracytoplasmic sperm injection allows fertility preservation with a very limited amount of sperm; therefore, patients with limited time should still be encouraged to consider sperm cryopreservation.

For prepubertal males, options are limited to testicular tissue cryopreservation and reimplantation or grafting of human testicular tissue. These are considered experimental and should ideally be performed as part of a clinical trial or experimental protocol. Tissue is harvested via an incisional biopsy, which can be bundled safely with other procedures such as port-a-catheter placement. There are no available human success rates for testicular cryopreservation for prepubertal cancer patients and cost increases to an estimated $2,500 for surgery with $300 for annual storage.

For postpubertal males that are postcancer treatment, sperm extraction and freezing can be used, with approximately 37 percent sperm retrieval rate. Cost significantly increases to estimates of $6,000 to $16,000, which does not include the added cost of IVF. Donor sperm (estimated cost of $300 to $750 per vial) can be used, with variable success rates. Adoption can have variable costs, and cancer history may be a factor in the adoption process.

Female fertility preservation

Fertility options for female cancer patients can be complex and depend on multiple factors, including the following:

• Age
• Diagnosis
• Type of treatment
• Participation of male partner
• Preference regarding use of donor sperm
• Time available
• Potential for delay in cancer treatment
• Likelihood of cancer involving ovaries

For postpubertal women receiving cancer treatment, embryo cryopreservation is the most established technique, and requires participating partner or donor sperm. Intact embryos after thawing have similar implantation potential as fresh embryos. Cost can be substantial—$12,000 per cycle, with $400 per year for storage. Success rates (30 to 40 percent) will vary by maternal age and other factors. Unfertilized oocyte cryopreservation is no longer considered experimental, which is a good option for women without a participating partner or who have religious or ethical objections to embryo cryopreservation. Costs and success are similar to embryo cryopreservation.

Both embryo and oocyte cryopreservation require controlled ovarian stimulation and vaginal ultrasound-guided oocyte retrieval. More flexible random start ovarian stimulation protocols are now available, and these require approximately two weeks resulting in less treatment delay. Patients with estrogen-sensitive breast and gynecologic malignancies can consider a natural IVF cycle (without stimulation), which will yield one egg per cycle, or they can use aromatase inhibitors such as letrozole with the ovarian stimulation, which will act as an ovarian stimulant yet keep estrogen levels near physiologic with similar pregnancy outcomes. Short-term follow-up indicates this has no impact on cancer-free survival.

For prepubertal females, ovarian tissue cryopreservation for the purpose of future transplantation does not require sexual maturity and is considered safe. Tissue is harvested laparoscopically/robotically and can be bundled safely with other procedures such as port-a-catheter placement. For some malignancies, this will be contraindicated, and tissue should be screened for neoplasia. There have been no reports of cancer recurrence with ovarian tissue freezing and transplantation. This method also may restore global ovarian function; however, it remains experimental in the U.S.

For postpubertal women, ovarian suppression during chemotherapy remains the subject of ongoing research. Suppressing ovarian function during chemotherapy hypothetically could prevent ovarian follicle destruction by maintaining follicles dormant and may also prevent menorrhagia, a potential complication of chemotherapy. When proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, ovarian suppression during chemotherapy may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. However, this should not be used in place of proven fertility preservation methods.

Other options for females’ postcancer treatment include using donor eggs, which can be costly ($22,000) or donor embryos ($5,000). Surrogacy has significant costs as well ($60,000–$80,000). Adoption can have varying costs, and cancer history may be a factor in the adoption process.

For breast cancer patients, the longer duration of hormone-blocking therapy for estrogen-sensitive breast cancer has a higher risk of infertility at completion of therapy. Breast cancer gene carriers have diminished ovarian reserve and a higher risk of postchemotherapy infertility, and preimplantation genetic diagnosis can be considered for patients with inherited cancers (with an additional estimated cost of $3,550).

Special considerations in children

Fertility preservation in children undergoing cancer treatment should include both the parent/guardian and the child in the consent process. Postpubertal children should consider established methods of fertility preservation (semen or oocyte cryopreservation). Prepubertal children only have investigational methods (ovarian or testicular cryopreservation) available and may be considered for referral for clinical trials.

Barriers

Barriers to fertility preservation are many. Many states do not require insurance coverage for fertility preservation in cancer patients. Access to reproductive specialists can be limited by distance and time, as these often require multiple visits. Worry about delay in cancer care for fertility preservation or ethical/religious concerns also are potential barriers. Overall, IVF has a low rate of live births with significant costs for these patients. Discussion of costs can be part of shared decision-making, and less expensive alternatives should be discussed when practical and feasible. Reproductive care is part of the standard of care for all oncology patients though many barriers exist and can result in significant health disparities for vulnerable populations.

Conclusion

Surgeons should be prepared to discuss infertility as a potential risk of cancer treatment during the formulation of the treatment plan. We should refer patients who express an interest in fertility, as well as those who are ambivalent or uncertain about available options, to reproductive specialists as soon as possible. We should refer any patients distressed about potential infertility to appropriate psychosocial providers and encourage participation in registries and clinical studies when available. Ultimately, surgeons should initiate the discussion on fertility as early as possible in all patients for whom it is appropriate.

Bibliography

Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2013;31(19):2500-2510.

Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36(19):1994-2001.

RESOLVE: The National Infertility Association. Making infertility affordable. Available at: http://www.resolve.org/family-building-options/making-treatment-affordable/the-costs-of-infertility-treatment.html. Accessed September 23, 2021.