Interventions for fertility preservation in women with cancer undergoing chemotherapy.

Abstract

Background: Anti-cancer drugs can be toxic to healthy cells in the body and have the potential to cause irreversible damage to ovarian tissue. This may lead to premature ovarian insufficiency. There are two main strategies to preserve fertility in women undergoing chemotherapy treatment for cancer. One is controlled ovarian hyperstimulation with gonadotropins and a protective agent for safety, followed by freezing of oocytes or embryos; the other is ovarian suppression using gonadotropin-releasing hormone agonists (GnRH agonists). This review aims to gain an understanding of the best way to support women with cancer to preserve their fertility. As breast cancer is the most common cancer in women worldwide, it is the primary focus of this review.

Objectives: To determine the effectiveness and safety of the two main fertility preservation strategies used in premenopausal women with cancer undergoing chemotherapy. One strategy is controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes/embryos, and the other is ovarian suppression using GnRH agonists.

Search methods: We searched the Cochrane Gynaecology and Fertility (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO on 27 November 2023. To identify additional studies, we also checked reference lists and contacted study authors and experts in the field.

Selection criteria: We included randomised controlled trials (RCTs) that evaluated protective agents used in combination with controlled ovarian hyperstimulation with gonadotropins and followed by freezing of oocytes or embryos, and RCTs that evaluated the use of GnRH agonists to suppress the ovaries. The comparator could be placebo, usual care, no treatment or another agent in the same group (e.g. ovarian suppression using goserelin versus using leuprolide acetate). We also looked for studies that compared the two main fertility preservation methods against each other.

Data collection and analysis: We used the standard methodological procedures recommended by Cochrane. The primary review outcomes were ovarian insufficiency, live birth and overall survival. We had a number of secondary outcomes, including non-pregnancy-related adverse events.

Main results: We included 23 RCTs (2647 women analysed). We judged the certainty of the evidence to be very low to moderate. The main limitations in the evidence were serious risk of bias in multiple domains for several studies, publication bias due to early termination of three studies and very serious imprecision. Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients There was no evidence available for our primary outcomes: ovarian insufficiency, live birth and overall survival. Nor was there any evidence for disease-free survival, pregnancy-related adverse events or non-pregnancy-related adverse events. Compared to standard controlled ovarian hyperstimulation, the evidence is very uncertain about the effect of controlled ovarian hyperstimulation with gonadotropins plus a protective agent on the number of oocytes retrieved (letrozole: mean difference (MD) 0.70 (95% confidence interval (CI) -2.60 to 4.00; 1 study, 108 women); tamoxifen: MD 0.70 (95% CI -3.05 to 4.45; 1 study, 109 women) (both very low-certainty evidence). There is probably little to no difference between the use of letrozole or tamoxifen as the protective agent added to controlled ovarian hyperstimulation with gonadotropins (MD -0.04, -2.72 to 2.64; 2 studies, 203 women; I² = 0%; moderate-certainty evidence). Ovarian suppression using GnRH agonists versus placebo, usual care, no treatment or another agent in the same group in breast cancer patients Ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency (relative risk (RR) 0.43, CI 0.31 to 0.59; P < 0.001; 5 studies, 811 women; I² = 0%; low-certainty evidence). The evidence is very uncertain about the effect of ovarian suppression using GnRH agonists on live birth (RR 1.60, CI 0.89 to 2.87; P = 0.12; 3 studies, 599 women; I² = 0%; very low-certainty evidence). Ovarian suppression using GnRH agonists may have little to no effect on overall survival over 10 years (hazard ratio (HR) 1.17, CI 0.67 to 2.04; P = 0.58; 1 study, 281 women) and disease-free survival over 10 years (HR 1.16, CI 0.76 to 1.77; P = 0.5; 1 study; 281 women), but the evidence is of low certainty. Only evidence that we judged to have very low certainty was available for pregnancy-related adverse events (4 studies, 648 women), including induced abortion, miscarriage, preterm delivery, delivery complications and elective termination. Moderate-certainty evidence was available for non-pregnancy-related adverse events (4 studies; 744 women), which showed that study participants in both groups experienced chemotherapy-related adverse events (e.g. fatigue, nausea, leukopenia) and non-pregnancy-related adverse events (e.g. sweating, hot flushes, headache); however, ovarian suppression might increase the likelihood of non-pregnancy-related adverse events. Controlled ovarian hyperstimulation with gonadotropins and a protective agent followed by freezing of oocytes or embryos versus ovarian suppression using GnRH agonists No evidence was available for this comparison. Women with cancers other than breast cancer For women with other cancers, the evidence is inconclusive and of very low certainty, and it is not possible to draw conclusions and implications for practice.

Authors' conclusions: In women with breast cancer being treated with chemotherapy, the evidence is very uncertain about controlled ovarian hyperstimulation using gonadotropins plus a protective agent (letrozole or tamoxifen) compared to controlled ovarian hyperstimulation with gonadotropins in terms of the number of oocytes obtained. When comparing letrozole versus tamoxifen used as the protective agent, there is probably little to no difference in the number of oocytes retrieved. There is no evidence available for the long-term implications of controlled ovarian hyperstimulation protocols, such as their effects on live births or overall survival of women with breast cancer. In women with breast cancer, ovarian suppression using GnRH agonists may result in a large reduction in ovarian insufficiency caused by chemotherapy, but the certainty of the evidence is low. Evidence for other outcomes is of low or very low certainty. We are not able to reach any conclusions concerning the choice of controlled ovarian hyperstimulation versus ovarian suppression because there are no data available comparing these fertility preservation interventions.