Table 1 Use of GnRHa in patients with breast cancer

Del Maestro et al. [22]

Investigating the effect of triptorelin-induced temporary ovarian suppression during chemotherapy on the occurrence of chemotherapy-induced early menopause

100 mg/m² of oral cyclophosphamide on days 1–14 or 600 mg/m² of intravenous cyclophosphamide on days 1 and 8, 40 mg/m² of methotrexate on days 1 and 8, and 600 mg/m² of fluorouracil on days 1 and 8 chemotherapy

The rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group (P = 0.001) thus an attributable risk reduction of 17% (95% confidence interval, − 26% to − 7.9%; P < .001).

In a multivariate analysis, only the treatment with triptorelin was associated with a significant reduction of the risk of developing early menopause with an odds ratio for treatment-related early menopause of 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).

Lack of follow-up to assess the end points.

Moore et al. [23]

Effect of using Goserelin on the incidence of ovarian failure

Outcomes of pregnancy after 5 years

3 to 4 cycles [about 3 months] or 6 to 8 cycles [about 6 months] and anthracycline-based vs nonanthracycline-based

Ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; P = 0.04)

Among the 218 patients who could be evaluated, 34 (16%) had at least one pregnancy: 12 of 113 (11%) in the chemotherapy-alone group and 22 of 105 (21%) in the goserelin group (odds ratio, 2.45; 95% CI, 1.09 to 5.51; P = 0.03).

The study included only patients with ER-negative disease.

Munster et al. [24]

Effect of triptorelin on the preservation of ovarian function through and after receiving chemotherapy

Four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide

Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P = .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after the completion of chemotherapy in the triptorelin vs 5.0 months (range, 0 to 28 months) in the control arm (P = .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries.

After patient stratification for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group (10% vs 12% hazard ratio of 0.76; 95% CI, 0.40 to 1.46) indicating no statistically significant advantage of adding triptorelin.

Small sample size.

Leonard, et al. [25]

Assess amenorrhoea between 12 and 24 months after the use of goserelin

Six to eight cycles of cyclophosphamide and/or anthracycline-containing regimens with or without a taxane

Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% vs 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% vs 34.8% in the control group, respectively (P = 0.048). Follicle-stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). However, the use in women above the age of 40 proved to be non-significant.

Small sample size.

Lambertini et al. [26]

Effect of use of triptorelin on the risk of premature ovarian failure and number of pregnancies after breast cancer treatment

N/A

A significant reduction in the risk of POF (OR 0.36, 95% CI 0.23–0.57, P < 0.001) was observed in patients receiving the agonist during chemotherapy, although with significant heterogeneity (I² = 47.1%, P (heterogeneity) = 0.026).

Of the 359 patients treated with GnRH analog during chemotherapy, 33 (9.2%) became pregnant, compared with 19 (5.5%) among 347 women undergoing chemotherapy alone which was statistically significant (OR 1.83, 95% CI 1.02–3.28, P = 0.041) with no heterogeneity.

Different definitions of premature ovarian failure used, few studies including end point data, and data analyzed not from individual patient-level data.

Lambertini et al. [27]

Effect of use of GnRHa on chemotherapy-induced premature ovarian failure

N/A

In the GnRHa group, 51 (14.1%) of 363 patients developed premature ovarian insufficiency (POI), as compared with 111 (30.9%) of 359 in the control group (adjusted OR, 0.38; 95% CI, 0.26–0.57; P < 0.001) without any heterogeneity. The multivariate analysis showed that only treatment with GnRHa (adjusted OR, 0.38; 95% CI, 0.26–0.57; P < 0.001) and younger age at diagnosis (< 40 years) (adjusted OR, 0.35; 95% CI, 0.24–0.52; P < 0.001) were significantly associated with a reduced risk of developing chemotherapy-induced POI.

Individual patient-level data from only five major randomized trials were included.

Lambertini et al. [28]

Effect of administration of triptorelin on ovarian function recovery and rate of pregnancy

FE60-75-100C every 21–28 days

CMF every 28 days

A—>CMF

EC—>paclitaxel

FE—>paclitaxel

EC—>docetaxel

Premenopausal women do actually benefit from the administration of triptorelin along with chemotherapy specifically in terms of higher long-term probability of ovarian function recovery; however, without a statistically significant difference in pregnancy rate, the incidence of menstrual resumption at 5 years was 72.6% (95% CI, 65.7–80.3%) among the 148 patients in the GnRHa group and 64.0% (95% CI, 56.2–72.8%) among the 133 patients in the control group (hazard ratio (HR), 1.28; 95% CI, 0.98–1.68; P = 0.07).

Analyses not prespecified in the study protocol, long-term outcome collection was planned at the time of primary end point analysis.