Can Fertility Be Preserved In Female Cancer Survivors?

Fertility preservation in essence means preserving the ability of an individual or couple to start a family at a time of their choosing. Oncofertility is a term coined for fertility preservation in cancer patients. Improvement in cancer management and increasing survival rates has created a need for oncofertility. Unfortunately, fertility preservation services are rarely offered or even discussed with the patient before starting cancer therapy. Studies have shown that infertility is a significant survival concern. Patients who receive information regarding their sexual and reproductive health have lower levels of psychological distress than patients who do not receive this information. Informed decision reduces reproductive regret in these young men and women.

Chemotherapy and radiotherapy remain the mainstay of cancer treatments. Both can be damaging to the ovary depending on the agent used, dose given, and age of the patient. The prepubertal ovary is less susceptible to damage by chemotherapeutic agents while older women have a lower ovarian reserve and hence are more susceptible to premature ovarian failure. Alkylating agents have an extremely damaging effect and are responsible for high ovarian failure rates. Platinum‑based compounds such as cisplatin cause DNA damage. They carry a medium risk of amenorrhea. Anthracycline antibiotics such as doxorubicin (DXR) induce oxidative stress. The amenorrhea and fertility risk is medium to low with this group of drugs.

Live birth rates from pregnancies in cancer survivors are similar to those of siblings. No significant increase in miscarriage, congenital malformations, genetic abnormalities, or malignant neoplasms has been found when conception has taken place long after completion of therapy. Risk of mutagenesis is maximum during the maturation phase of the oocyte, which is approximately 6 months and minimum during the dormant stage. It is, therefore, recommended that patients be asked to delay conception for 6 months after completing the treatment and fertility preservation techniques such as oocyte and embryo cryopreservation are carried out 6 months after treatment and not between treatments.

Unlike chemotherapy, radiotherapy affects both the ovary and the uterus. Human oocyte is sensitive to radiation, with an estimated median lethal dose (LD50) of <2 Gy. Damage to the ovary by radiotherapy is dependent on the age of the patient and dose of the ovarian exposure. The effective sterilizing dose (ESD) is the dose of fractionated radiotherapy (Gy) at which POF occurs immediately after treatment in 97.5% of patients. ESD decreases with increasing age, being 18.4 Gy at 10 years, with only 6 Gy being required to cause permanent ovarian failure (POF) in women over 40. Ovarian failure has been reported in 90% of patients following total body irradiation (TBI) (10–15.75 Gy) and in 97% of females treated with total abdominal irradiation (20–30 Gy) during childhood. In adults, an exposure to TBI of 12 Gy is associated with significant uterine damage. Radiation doses of >25 Gy directly to the uterus in childhood appears to induce irreversible damage. Increased rates of infertility, miscarriage, preterm labor, intra‑uterine growth retardation and low birth weight have been reported especially if conception occurs within a year of radiotherapy. It is suggested that patients receiving>45Gy during adulthood and >25 Gy in childhood should be counseled to avoid attempting pregnancy.

In colorectal cancers, radiation damage to the gonads and uterus is inevitable, hence fertility preservation techniques should be strongly advised. Ovarian transposition needs to be performed to get the ovary out of the radiation field. Standard management for cervical cancer is radical hysterectomy with lymph node dissection for early disease. Radical trachelectomy can be performed for women with early‑stage cervical cancer (<2 cm in size) who have not yet completed their childbearing. No significant difference is noted between two surgical procedures in rates of recurrence, mortality, 5 years recurrence‑free survival. Traditional management for ovarian cancer is total hysterectomy with bilateral salpingo‑oophorectomy. Type of fertility‑sparing surgery (FSS) depends upon the histology, stage of disease and preexisting ovarian reserve. Nonepithelial malignant ovarian tumors, particularly germ‑cell tumors, do well with fertility‑sparing surgery. Unilateral salpingo‑oophorectomy or in some cases cystectomy is done with extensive staging and subsequent follow‑up. Recurrence after cystectomy is high 25%. FSS has also been tried for early stage epithelial ovarian malignancy. Prerequisites for conservative surgery include well‑differentiated unilateral disease, with no sign of extra‑ovarian metastasis. Patients need to understand the risk of recurrence and give consent knowing this potential risk.

“Ferto‑protective adjuvant therapy” is a term used for administration of adjuvant therapy during or prior to chemotherapy with an agent that can prevent loss of ovarian reserve. The list of drugs under investigation are sphingosine‑1‑phosphate (S1P) and imatinib that inhibit apoptosis, thalidomide and granulocyte colony‑stimulating factor, mechanism of their action is unclear, tamoxifen which works as an antioxidant, and AS101 which causes modulation of follicle activation pathway.So far, the only drug used in clinical practice is the gonadotropin‑releasing hormone (GnRH) agonist. Patients with leukemia may be good candidates for GnRH agonist co‑administration in order to manage the ovulation and menstrual bleeding during chemotherapy.

Fertility preservation techniques in females include Embryo cryopreservation, Oocyte cryopreservation, Ovarian tissue cryopreservation (OTC) and In vitro maturation (IVM). Patients with breast cancer can undergo IVF while waiting for chemotherapy after surgery. The challenge here is the hyperestrogenemia. Aromatase inhibitors, mild stimulation protocols have been used to avoid high estradiol levels. IVM or ovarian tissue preservation can be offered to patients not willing for OS. They can have multiple OR’s to preserve oocytes/embryos before BSO. OTC for transplantation is not advisable in patients carrying a BRCA mutation given the increased risk of ovarian cancer in this population. Parents have to be given full information of the process, associated risks and success rates. Thorough psychological counseling is required, and ethical considerations have to be kept in mind. Postpubertal girls under the age of 18 may be candidates for mature oocyte cryopreservation following OS. In prepubertal girls, OTC is currently the only way to cryopreserve gametes.

Careful counselling and informed consent is strongly recommended. Oocyte and embryo cryopreservation are now established techniques but have their limitations. OTC has a wider application and the advantage of keeping the fertility window open for a longer time. The need for fertility preservation has to be weighed against morbidity and mortality associated with cancer. There is thus a need for a multidisciplinary collaboration between oncologists and reproductive specialists to improve awareness and availability.

Dr. A.K. Dewan
Director – Surgical Oncology