Fertility preservation in patients prior to receiving cancer treatment

The survival rates of young patients suffering from cancer have improved dramatically in recent years due to advances in diagnostic techniques and treatments. With the cure rate for many childhood malignancies now between 70% and 90%, infertility becomes an increasingly important issue.

Quality of life is increasingly important to long-term survivors of cancer, and one of the major quality-of-life issues is the ability to produce and raise children. Both chemotherapy and radiotherapy often cause infertility due to damage to the ovaries in women and to the testicles in men, a combination of chemotherapy and radiotherapy will produce additive damage to ovaries and testicles. The damage could be temporary or permanent, it is impossible to predict who will suffer permanent damage. Approximately one in four younger women who had chemotherapy resumed their menstrual cycle within 3 years following completion of chemotherapy (North America menopause society 2020). Women who have had radiotherapy to their uterus are at a increased risk of miscarriage and premature labour.

Advances in the field of assisted reproductive technology (ART) provide hope that the reproductive impact of cancer therapy can be reduced. A recent study from USA (Cancer 2012) reported that only 4% of young women treated for cancer take steps to preserve their fertility. This is perhaps due to lack of awareness about the impact of cancer treatment on fertility and the efficacy of options to preserve fertility.

When infertility specialist decides to offer fertility preservation to patient diagnosed with cancer, he or she should take into account the following factors: diagnosis, treatment plan, expected outcome of subsequent fertility treatment, the chance of survival following cancer treatment and viability of stored/post-thawed eggs/ embryos.

What are the options for female patients prior to receiving cancer treatment?

• Ovarian tissue freezing
• Mature egg freezing
• Immature egg, in vitro maturation IVM) and freezing mature eggs
• IVF and embryo freezing
• Ovarian transposition
• Treatment of cancer, and see what happens
  • Retain ovarian function - natural conception with fertility treatment as required
  • Loss of ovarian function - IVF with donated eggs
• Surrogacy if the cancer patient's uterus has been surgically removed or the endometrium destroyed by radiotherapy
• Adoption

Ovarian tissue freezing

Ovarian tissue freezing is offered to young girls and single women. Ovarian tissue can be collected by laparoscopy without delaying chemo/ radiotherapy and frozen as small fragments. Tissue can be used either for isolation of follicles or in-vitro culture. After culture, follicles can be isolated, eggs collected for further in-vitro maturation, fertilization with husband/partner sperm. Alternatively, ovarian tissue can be auto-transplanted either in original location (ovary) to allow for natural conception or at a different site (such as an arm) to allow for IVF, egg collection and embryo transfer. Ovarian tissue freezing is still very much a research tool and most work has been done in animal models. To date, about 40 patients around the world have given birth after having their ovaries frozen and re-implanted including one United Kingdom patient. Ovarian tissue freezing has disadvantages such as the inability to assess quantity and quality of the follicle population, follicle death during procedure (about 70% of follicles are lost) and irregular distribution of follicle population in human ovaries which may be a risk when ovarian tissue is cut into 1-2 mm3 fragments and the potential risk of malignancy transmission ( if the ovary contains micrometastases). So far, no reports of relapse caused by transplantation of ovarian tissue. Ovarian tissue freezing is not an option for women with ovarian cancer.

Cryopreservation of isolated immature follicles can avoid transmission of malignant cells as the zona pellucida is impermeable. Unfortunately this technique is also still in research stages with no human pregnancies. Problems include the need for the patient to be fit for the procedue and the high cost.

IVF and mature egg freezing

This is an option for women without a partner or those who do not wish to use donor sperm for IVF provided the following: the patient should be well enough to undergo controlled ovarian stimulation and egg collection, IVF treatment will not worsen their condition and enough time is available before the start of the cancer treatment. (2-3 weeks for ovarian stimulation), It is also important to take into account the cost, and risks associated with egg collection. In addition, both eggs and embryos freezing require ovarian stimulation and the high estradiol concentrations induced during stimulation add extra risk fo women with hormone sensitive cancers. or epithelial ovarian cancers.

There are two methods for freezing eggs:

• The traditional “slow controlled freeze” The eggs are mixed with cryoprotectants and placed in a vial or straw and frozen slowly at a rate of 0.3Ã�°C/min. At -32Ã�° C the straw is put into liquid nitrogen -196Ã�° C. This technique results in one baby per 100 eggs.
• Vitrification “ultrarapid freezing”. This is a new method where the vial or straw is plunged directly into liquid nitrogen, the cooling rates are so rapid that ice crystals does not have a chance to form, and the mixture of cryoprotectant and egg forms a “glass-like” solidification of cells. Vitrifaction method appears to be associated with a significantly higher survival rates compared to slow freezing. Results appear promising approximately 10 babies are born per 100 eggs and it is much simpler technique (Petracco et al ESHRE 2007). Vetrification is recommended by NICE (2013) for freezing eggs and embryos provided the necessary equipment and expertise is available.

Immature eggs, IVM and egg freezing

The immature eggs are collected, and mature in the lab and the matuure eggs are then frozen. A french woman who had cancer breast and had immature eggs harvested before she received chemotherapy. The eggs were then matured in vitro (in vitro maturation) and the mature eggs were frozen using vitrification methods. Five years later the eggs were thawed and fertilized and the resulting embryo was replaced. The woman conceived and delivered a healthy baby (Annals of oncology 2020)

IVF and embryo freezing

This is probably the best option at present given long experience with technique. It can be offered to those in stable heterosexual relationship using controlled ovarian stimulation followed by IVF or ICSI. In single women, IVF with donor sperm is an option. Problems include: time taken (about 2-4 weeks) and cost. In addition, IVF and embryo freezing is a risk in Oestrogen-receptor positive cancers or epithelial ovarian cancer. Also the male partner may subsequently withdraw his consent for the transfer of embryos, so requiring them to be destroyed. This situation can be avoided by the use of egg freezing.

Ovarian transposition

Ovarian transposition is where ovaries are replaced away from the radiation field is an option prior to radiotherapy. If IVF is needed in the future, tranvaginal egg collection will not be possible if ovaries are high up. Laparoscopic collection may be possible though potentially hazardous in the presence of major abdominal scarring (following surgery). Transposition can be performed laparoscopicaly just before the start of radiotherapy.

Current practice

The only technique, which can be arranged and carried out quickly, is ovarian cryopreservation. The procedure does, however, involve a general anaesthetic and an operative laparoscopy. Appropriately skilled medical and laboratory staffs need to be available together with theatre time and equipment. The procedure is only at early research stage in humans with little data on success rates or potential abnormalities in any children, which may result at some time in the future (may be in 5-10 years) when the necessary technology is developed.

Egg freezing has a very poor success rate of about 1 per 100 eggs. Embryo freezing following IVF / ICSI has a better rate of more than 1 per 7 embryos. Both require ovarian stimulation followed by a transvaginal ultrasound egg collection under intra-venous sedation. The process takes about four weeks. The major drawback therefore is an unacceptable delay in starting treatment for the majority of malignancies.

What are the options for male patients prior to receiving cancer treatment?

• Freezing semen: Freezing of the ejaculated sperm is a well established technique. This option should be offered to all post-puberty boys and adults. If the patient is unable to ejaculate, sperm may be recovered by PESA or TESA. About 50% of men with cancer will have reduced sperm quality prior to starting their chemotherapy or radiotherapy. However recent advances in Assisted Reproductive Technology have enabled many men with only a few sperm to father their children. Dr Stahl and colleagues (Journal of the National Cancer Institute,2011) reported a slightly higher but statistically significant incidence of major congenital abnormalities in the offspring of male survivers of cancer when compared to children born to fathers with no history of cancer (3.7% compared to 3.2%). This difference was independent of the mode of conception.The study findings are reassuring but incomplete because of the limited treatment data.
• Fertility preservation in young boys who do not produce sperm is challenging. Freezing of immature testicular tissue with a view of transplantation of the tissue into the testis or in-vitro maturation (IVM) to mature sperm is an option for fertility preservation in young boys. This method is currently successful in animals, and application in humans seems likely in the near future, and if so this would be a milestone in preserving fertility in childhood cancer. Scientists have recently developed a cell culture that could enable development of sperm from testicular stem cells. This could enable fertility preservation for pre-pubertal who undergo chemotherapy for cancer treatment. (Stem Cells and Development 2018)
• Use of donor sperm.
• TESE this is an option for childhood cancer survivors who did not have sperm frozen prior to receiving chemotherapy or radiotherapy. In a recent article publishd in the Journal of Clinical Oncology 2011, sperm were retrieved from 27 of 73 patients resulted in 20 children.

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