Ovarian suppression with GnRH analogues

Does ovarian suppression with gonadotropin releasing hormone (GnRH) analogues or antagonists during chemotherapy in women with cancer reduce the risk of primary ovarian insufficiency?

Primary ovarian insufficiency (POI) is a serious, irreversible adverse effect of chemotherapy for pre-menopausal women. POI results in infertility, and increases the risk of osteoporosis, cardiovascular disease and cognitive dysfunction.^[1][2] Prevention of POI is therefore very important to preserve the fertility of young Australian women after cancer.

Randomised studies, predominantly in pre-menopausal women with breast cancer, have shown that concurrent administration of gonadotropin releasing hormone agonists (GnRHa) with chemotherapy reduces the risk of POI compared to no GnRHa. As a result, use of GnRHa in this setting is recommended in the European St Gallen and U.S. National Comprehensive Cancer Network guidelines for premenopausal women with breast cancer.^[3][4] However, studies in other malignancies, such as lymphoma, comparing chemotherapy with or without concurrent GnRHa have shown mixed results.^[5][6][7]

In 2017 the GnRHa goserelin, was listed on the Australian Pharmaceutical Benefits Scheme (PBS) for premenopausal women receiving treatment with an alkylating agent for any malignancy or autoimmune disorders (Australian Government Department of Health 2017).

Breast cancer

The majority of evidence for the efficacy of GnRHa in prevention of POI comes from studies of premenopausal breast cancer patients. Recent meta-analysis assessing the efficacy of GnRHa in prevention of POI in premenopausal patients with early breast cancer concluded that concurrent GnRHa (goserelin, triptorelin or leuprolide) administration resulted in lower rates of chemotherapy induced POI.^[8][9][10] The most recent of these meta-analyses, by Lambertini and colleagues, included five randomised controlled studies (RCT) using individual patient data. The primary endpoint was study defined chemotherapy-induced POI. POI rates were lower in those who received concurrent GnRHa compared to those who did not (14.1% versus 30.9%, adjusted OR 0.38; 95% CI, 0.26 to 0.57; P<0.001).^[8]

With regards to the potential impact of GnRHa given during chemotherapy on breast cancer outcomes, Lambertini et al concluded that the five-year overall survival (OS) was similar between those who received GnRH agonist and those who did not.^[8] An exploratory analysis of patients with estrogen receptor negative breast cancer in the POEMS trial showed better four-year estimated disease free survival (DFS) and overall survival in the goserelin arm (HR 0.49, 95% CI 0.24 – 0.97, p = 0.04 and HR 0.43, 95% CI 0.18 – 1.0, p = 0.05 respectively).[11] The PROMISE trial, which included patients with both oestrogen receptor negative and oestrogen receptor positive breast cancer showed no difference in 5-year DFS between the GnRHa and control arms (HR 1.17, 95% CI: 0.72-1.92, p=0.52).^[12] These results are reassuring regarding the safety of GnRHa use in both oestrogen-receptor positive and negative breast cancer.

Other malignancies

Studies exploring the efficacy of GnRHa in haematological and solid malignancies other than breast cancer are mostly limited to lymphoma patients. These studies show mixed results. A recent 2018 meta-analysis by Senra and colleagues, which included three studies of 109 patients with lymphoma and 10 studies of 1099 patients with breast cancer, demonstrated a lower rate of POI in women receiving GnRHa compared to chemotherapy alone overall (RR, 0.60; 95% CI, 0.45–0.79). However, subgroup analysis showed the benefit was only seen in patients with breast cancer (RR, 0.57; 95% CI, 0.43–0.77) but not patients with lymphoma (RR, 0.70; 95% CI, 0.20–2.47).^[13]

Similarly, the rate of spontaneous pregnancy after completion of treatment was higher in women receiving GnRHa compared to chemotherapy alone (RR, 1.43; 95% CI, 1.01–2.02). However this benefit was again only seen for breast cancer patients (RR, 1.78; 95% CI, 1.09–2.90) and not lymphoma patients. (RR, 1.13; 95% CI, 0.66–1.93).^[13] This difference in outcomes between breast cancer and lymphoma studies may be due to the heterogeneous chemotherapy regimens prescribed, the lower median age and the smaller sample sizes in the lymphoma trials compared to breast cancer trials.

The largest randomised control trial in patients with lymphoma included in this study was performed by Demeestrere and colleagues in 129 women with Hodgkin and non-Hodgkin lymphoma.^[5] In 63 evaluable women, the POI rate, defined as an elevated FSH level, was 19% in the GnRHa group versus 25% in the control group (P = 0.763) (Demeestere 2016).^[5] Pregnancy occurred in 53% of the GnRHa group compared to 43% of the control cohort (P = 0.467), with five pregnancies occurring in those with protocol defined POI, suggesting that defining POI by elevated FSH alone is not adequate.^[5]