The management of ovarian malignancies in young female patients carries a significant risk of compromise to their menstrual function and fertility. In the first 2 decades of life, almost 70% of ovarian tumours are of germ cell in origin, and one-third of these are malignant. Germ cell tumours account for the majority of the ovarian malignancies in this age group. Fortunately, the previously dismal prognosis of malignant ovarian germ cell tumours (MOGCT) has improved dramatically with the use of combination chemotherapy, thus allowing for conservative, fertility-sparing surgery in these young patients.

Today the standard of care for MOGCT in a patient desirous of fertility preservation comprises a unilateral salpingo-oophorectomy and appropriate surgical staging. MOGCT are almost always unilateral, except for dysgerminomas, where a careful inspection and palpation of the contralateral ovary is important. Patients with FIGO Stage IA pure dysgerminomas and low grade immature teratomas can be observed and followed up while all other patients will require adjuvant chemotherapy, of which the most widely used regimen comprises Bleomycin, Etoposide and Cisplatin.

Although radiosensitive, adjuvant radiation is rarely used in MOGCT, because the radiation doses with standard pelvic radiation will uniformly induce ovarian failure, the breakpoint for radiation-induced ovarian failure being approximately 300 cGy to the ovaries.

Chemotherapy-induced infertility has been studied extensively. Microscopic exam of ovaries after chemotherapy reveals cortical fibrosis, reduction in the number of follicles, and impaired follicular maturation. Incidence of ovarian failure after chemotherapy is determined by the age of the patient, class of drug and cumulative dose. Advanced age is more prone due to lesser number of residual oocytes. Alkylators such as cyclophosphamide, nitrogen mustard etc cause more amenorrhoea, where as certain short term intensive protocols particularly using antimetabolites, vinca alkaloids and anthracyclines affect ovarian function less commonly.

In a reported series of adjuvant BEP for MOGCT, 62% were amenorrhoiec during chemotherapy, and 92% resumed regular menses on completion of treatment. In our local experience, the mean time to resumption of menses after completion of chemotherapy was 2.5 months, and the mean duration when menses became regular was 3.5 months.

Several studies have shown that the prepubertal ovary is more resistant to the adverse effects of chemotherapy, likely due to larger ovarian reserve. It is unclear at present whether therapy with gonadotrophin-releasing hormone agonists, oral contraceptives or progestins are effective in preventing ovarian failure.

Successful pregnancies after cancer-chemotherapy have been documented for Hodgkin disease (using ABVD regimen), non-Hodgkin lymphoma and leukaemia. Many papers have reported unaffected reproductive capacity and healthy life births after MOGCT chemotherapy. The true reproductive potential in all these cohorts is difficult to ascertain because of short duration of follow-up of these young patients, many of whom may not be desirous of fertility immediately after treatment.

The risk of congenital malformations in the offspring of patients treated with chemotherapy is a real concern. The risk is highest if chemotherapy is administered during the first trimester of pregnancy especially when antimetabolites and alkylating agents are used. Chemotherapy administered during the second and third trimesters generally is not associated with an increase in foetal anomalies although to our knowledge, the number of patients studied to date is relatively small. In our local experience, 5 patients had 8 healthy life births after chemotherapy for MOGCT.

In patients where premature ovarian failure is a possibility, pre-treatment harvesting and preservation ex-vivo with assisted reproductive technology appears to be a logical strategy. Although the human oocyte appears to be very sensitive to cryopreservation damage leading to low pregnancy rates after IVF, recent studies have suggested increased success through vitrification and the use of intracytoplasmic sperm injection. This was achieved successfully in Singapore in the year 2000. For women already with partners at the time of cancer treatment, embryo cryopreservation may be the best option, as delivery rates of 18-20% have been reported, and this is available in all IVF centres in Singapore, including KKIVF. Finally, experimental work is also underway on cryopreservation of ovarian tissue for subsequent transplantation and stimulation. This is being investigated at Singapore General Hospital’s Centre for Assisted Reproduction.

 

Jeffrey Low
Head & Consultant
Gynaecological Oncology Unit
KK Women’s and Children’s Hospital