Being diagnosed with breast cancer is already devastating for young women. If frontline chemotherapy could possibly push their ovaries into failure and result in infertility, their life is further made desolate.
Premature ovary failure (POF) is associated with several health-related consequences such as infertility, hot flashes, sleep disturbance, sexual dysfunction, and osteoporosis, as well as potentially influences the development of cardiovascular disease and dementia as women age.1,2 As a consequence, POF can cause psychological distress and negative impact on short- and long-term global health of young breast cancer survivors.
Recently, two high quality randomized controlled trials3-4 have shown reduced occurrence of ovarian failure and possible benefit on fertility preservation when temporal ovarian suppression was exercised during cancer therapy. Upon these new evidences, Dr. Matteo Lambrtini, MD, a medical oncologist from the IRCCS AOU San Martino-IST from Genoa in Italy, and his colleagues re-assessed all the available RCTs – the largest scale meta-analysis so far- and the results supporting the use of ovarian suppression in early breast cancer. The ovarian suppression is medically done by adding a luteinizing hormone-releasing hormone analogue (LHRHa) to the cytotoxic therapy for the breast cancer.
This meta-analysis was published online 7-September-2015 in the Annals of Oncology5 and was presented in European Cancer Congress (ECC) 20156.
“Temporary ovarian suppression with LHRHa during chemotherapy is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate in young breast cancer patients”, concluded by the lead author Dr. Lambrintin. Importantly, this comes with no apparent negative impact on patients’ prognosis. “The use of LHRHa during chemotherapy might be considered as an option for women interested in preserving their ovarian function, thus reducing the chance of developing the negative consequences of early menopause, and might also play a role in increasing the likelihood of becoming pregnant after cessation of chemotherapy”, he said.
Most updated meta-analysis that included recent trials
This meta-analysis included 12 RCTs with a total of 1,231 breast cancer patients receiving chemotherapy with or without LHRHa.
Most notably, two recent major trials were included. One was the POEMS trial (n=218), which demonstrated adding goserelin to chemotherapy protecting against ovarian failure, reducing risk of early menopause, improving prospects for fertility and boosting disease-free survival in premenopausal women with operable hormone-receptor negative breast cancer. This study is regarded as potentially practice changing when presented at 2014 annual meeting of ASCO and was subsequently published in the New England Journal of Medicine early this year4. Another study, conducted by Dr. Lambertini and his colleagues, provided reassuring updates for the long-term outcome of a Phase III PROMISE-GIM6 trial with median follow-up duration of 7.3 years (n=281) that adding LHRHa to chemotherapy was associated with occurrence of more pregnancies on top of less events of chemotherapy-induced early menopause in premenopausal women with stage 1-3 cancer, despite no difference of disease-free survival.3
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Overall, the use of LHRHa was associated with a significant 64% reduction in risk of POF (OR 0.36, 95%CI: 0.23–0.57; p<0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026) which might be attributed to different POF definitions of different studies. To address this issue, Dr. Lambertini evaluated the benefit by restricting the analysis to the 8 studies with reported rate of amenorrhea one year after the end of chemotherapy, and confirmed beneficial effect of adding LHRHa (OR = 0.55; 95%CI: 0.41–0.73, p<0.001), with no heterogeneity (I2 = 0.0%, p=0.936).
In the five studies reporting pregnancies, patients treated with LHRHa achieved more pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02–3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In the three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49–2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044).
Ready to be standard of care?
“With a rising trend of delaying childbearing, more breast cancer patients are diagnosed without having completed their families, and thus, it is vital to provide reliable fertility preservation methods for these young female patients”, Dr. Lambertini stated.
In response to the new data on ovarian suppression, the 2015 ST. Gallen International Expert Consensus and National Compression Cancer Network (NCCN) guidelines have been updated to acknowledge the role of LHRHa in preventing chemotherapy-induced POF, but this is limited to hormone receptor negative breast cancer. However, NCCN panellists still believe that there is no high-level evidence to support ovarian suppression or other interventions could decrease the toxicity of cytotoxic chemotherapy on the premenopausal ovary, though many women, especially <35 years, regain menstrual function within 2 years of completing chemotherapy. The resumption of menses does not necessarily correlate with fertility and fertility may be preserved without menses.7
“Other guidelines are still hesitating to recommend this technique”, wrote Dr. Lambertini, “To date, the role of this approach in fertility preservation remains controversial for the conflicting results in several RCTs”. Another recent meta-analysis of 10 RCTs covering 907 patients, published in July 2015 version of Obstetrics and Gynecology analyzing the effect of LHRHa on resumption of ovarian function, however, reached a different conclusion (RR=1.12, 95%CI:0.77-12.7, p=0.07) and claimed that adding LHRHa to chemotherapy is not a reliable method for fertility preservation”.8
The ASCO and EMSO guidelines on fertility conservation have not been updated since 2013 and both considered this approach as experimental due to the lack of data on subsequent pregnancy outcome. It would not be likely that a small but statistically significant difference in occurrence of pregnancy observed in the most updated meta-analysis may lead ovarian suppression during chemotherapy becoming standard of care. However, this technique might be considered as an option for women interested in preserving their ovarian function and might play a role in increasing the likelihood of becoming pregnant after the cessation of chemotherapy, according to Dr. Lambertini.