Postoperative hormone replacement therapy for epithelial ovarian cancer patients: A systematic review and meta-analysis

doi:10.1016/j.ygyno.2015.07.109

Gynecologic Oncology

Volume 139, Issue 2, November 2015, Pages 355-362

https://doi.org/10.1016/j.ygyno.2015.07.109 Get rights and content

Highlights

•
The first meta-analysis on the effect of HRT on prognosis and recurrence of EOC survivors.
•
Postoperative HRT use is not associated with poorer clinical outcomes of EOC patients.

Abstract

Background

Hormone replacement therapy (HRT) has been proven highly effective for menopausal symptoms caused by radical surgery. However, the impact of postoperative HRT on the clinical outcomes of patients previously treated for epithelial ovarian cancer (EOC) remains unclear.

Objective

To determine whether postoperative HRT use has any positive or negative impacts on prognosis and recurrence among EOC survivors.

Methods

Studies that provided an assessment of postoperative HRT use and prognosis or recurrence in EOC patients were included for analysis. Two reviewers independently evaluated the eligibility of identified studies and abstracted the data. A fixed effects model was used to pool study-specific estimates of hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs).

Results

Two randomized controlled trials (RCTs) and four cohort studies included 419 EOC survivors who used HRT and 1029 non-users. The aggregated HR of overall survival (OS) suggested that HRT use after surgery for EOC had a favorable impact on OS (HR = 0.69, 95% CI: 0.61–0.79), but when these studies were categorized into cohort study and RCT subgroups, not all of them demonstrated positive results (HR = 0.63, 95% CI: 0.49–0.81 and HR = 1.03, 95% CI: 0.58–1.83, respectively). The meta-analysis of EOC recurrence of three available studies demonstrated that postoperative HRT use was not associated with an increased risk of recurrence in EOC survivors (RR = 0.83, 95% CI: 0.64–1.07). This pattern also emerged in the subgroup analysis for the stage and type of HRT.

Conclusions

In EOC patients, postoperative HRT does not have a negative effect on overall survival and tumor recurrence. However, well-designed and large-scale RCTs are needed to verify this relationship in the future.

Introduction

Epithelial ovarian cancer (EOC) is the leading cause of death among patients diagnosed with gynecologic malignancies all over the world [1]. At the time of diagnosis, more than 75% of patients have an advanced stage of disease, and their five-year survival rate is very poor [2]. Although most patients with advanced ovarian cancer respond well to standard management—primary cytoreductive surgery followed by platinum/taxane-based adjuvant chemotherapy—the majority of those patients develop recurrent disease and die of progressive disease.

Although EOC is primarily a disease of postmenopausal women, a small but significant number of EOC patients are premenopausal (approximately 3–17% are under 40 years of age) at the time of diagnosis [3], [4], [5]. After receiving aggressive radical surgery, these patients have to face a sudden onset of menopausal symptoms induced by removal of the ovaries as well as the long term risks of osteoporosis and osteoporotic fractures, resulting from estrogen deficiency [6]. In addition, menopausal symptoms caused by surgery tend to be more intense and may last longer than those of natural menopause [7]. For these reasons, relieving these symptoms has become an important issue for young EOC patients in terms of their quality of life after surgical treatment.

Hormone replacement therapy (HRT) has proven to be highly effective in alleviating menopausal symptoms such as hot flashes, night sweats, dyspareunia, sexual disorders, and insomnia; however, HRT safety in EOC survivors is still a topic of debate. Many clinicians remain reluctant to prescribe HRT for these patients due to the fear of ovarian cancer relapse or the development of breast cancer [8]. To date, studies on HRT use after surgery for EOC are limited, even reaching seemingly contradictory conclusions [9]. It is difficult for EOC survivors and their physicians to weigh the risks and benefits without estimates of the effect of HRT on EOC prognosis and recurrence.

In this regard, the present study aims to evaluate the impact of HRT use on prognosis and recurrence in patients previously treated for EOC by carrying out a systematic review of the literature, followed by a meta-analysis.

Section snippets

Methods

In advance of conducting this review, a protocol was registered on the PROSPERO website (registration no. CRD42015016710). The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and recently published PRISMA-P statement were reviewed when the protocol was developed to ensure optimal quality of reporting of this systematic review and the planned meta-analysis [10], [11].

Study selection

Fig. 1 presents a flow diagram showing how eligible studies were identified. The initial database search yielded 1330 records, of which 296 records were excluded as duplicates and 1022 were excluded based on the titles and abstracts for various reasons (reviews, case reports, or irrelevance to the analysis). Twelve potentially relevant papers were found by focusing on HRT use and EOC patients' clinical outcomes. Among those, six papers were excluded for further analysis, of which four were

Discussion

According to previously published studies, postoperative HRT use had no negative effect on overall survival and recurrence in EOC patients. However, the individual sample size in most studies was not large enough to sufficiently explain that effect, and no quantitative analysis has been conducted to estimate the effect of HRT on clinical outcomes of EOC survivors. The results of the present meta-analysis suggest that HRT use by women with a history of EOC did not lead to a significant increased

Conclusions

In summary, the results suggest that HRT use does not have a detrimental effect on overall survival and recurrence in women with EOC, although they are largely based on cohort studies subject to a variety of unavoidable biases. The selection of healthier and younger patients to begin HRT and potential publication bias might explain the protective effect of HRT on overall survival in EOC survivors. It therefore seems that the positive effect of HRT on maintaining quality of life outweighs the

Conflict of interest statement

i)
I declare that the contents of this paper have not been published or considered for publication elsewhere.
ii)
All authors made substantial contribute to conception and design, and/or extraction of data and/or data analysis; participated in drafting the manuscript and revising it critically for important intellectual content; and gave final approval of the version to be submitted and any revised version to be published.
iii)
There is no financial support or relationship that may pose conflict of interest.

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Hormone replacement in premenopausal women treated with bilateral oophorectomy for ovarian cancer – a nationwide population-based study
2022, Gynecologic Oncology
To study the extent of hormone replacement therapy (HRT) dispensing in premenopausal women after being treated with bilateral salpingo-oophorectomy (BSOE) for ovarian cancer (OC).
Nationwide population- and register-based cohort study including women 18–50 years old, registered in The Swedish Quality Register for Gynecological Cancer (SQRGC), where BSOE was performed due to epithelial (EOC) and non-epithelial ovarian cancers (NEOC) or borderline ovarian tumor (BOT) between 2008 and 2014. Data on HRT dispensing was obtained from the National Prescribed Drug Register analyzed at semi-annual intervals from surgery until end of follow-up December 2015, including a logistic regression analysis.
A cohort of 664 women were identified with OC, whereas 396 women had an EOC, 61 a NEOC and 207 a BOT. At surgery 49% of the women were ≤44 years. HRT dispensed to the total cohort varied between 32% and 41% the first five years after surgery. During follow-up at first 0.5–1 year 51% of the women <40 years were dispensed HRT compared to 25% of women ≥40 years. Of women with EOC, 21% dispensed HRT at first 0.5–1 year. In the multivariable regression analysis; age <40 (OR6.17, p < 0.001) and age 40–44 (OR2.95, p < 0.001) as well as BOT histology (OR3.84, p < 0.001) were found significant variables for dispensing of HRT.
A majority of premenopausal women undergoing BSOE for OC did not use HRT postoperatively. Our study shows that there is a need to address HRT use after OC treatment in young women to prevent from morbidity and a poorer quality of life.
Menopausal hormone therapy in women with benign gynaecological conditions and cancer
2021, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
The remaining ovarian tumours include sex cord stromal, germ cell and borderline tumours. Earlier data suggested the use of MHT following epithelial ovarian cancer conferred no disadvantage to overall or progression-free survival [20,21]. A recent systematic review published in 2020 suggests there may be evidence of MHT providing a slight benefit to overall survival and quality of life, but the quality of evidence available is low.
The efficacy of menopausal hormone therapy for bothersome menopausal symptoms is well established. However, there are a range of benign and malignant gynaecological conditions that pose a challenge in managing menopausal symptoms. Their hormone-dependent nature either raises concerns about symptom recurrence or malignant disease progression making decisions about menopausal hormone therapy complex for both clinicians and patients. It appears there is a small potential for symptom recurrence with menopausal hormone therapy use in menopausal women with a history of severe endometriosis. Malignant transformation of previous endometriotic lesions is likely to be rare but is not adequately understood. In this setting, combined hormone therapy is preferred, including in woman post-hysterectomy. Uterine fibroids are not a contraindication to menopausal hormone therapy use but women with large fibroids at menopause should have regular follow-up of their fibroids. Generally, menopausal hormone therapy is considered appropriate for women with cervical cancer and most ovarian cancers except for low grade serous tumours. Endometrial cancer requires an individualised discussion. The overall quality of data in this area is poor but suggests women with a low risk of recurrence may consider hormonal therapy, balancing symptom impact with prognosis.
Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study
2021, Gynecologic Oncology
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HRT was also associated with a significant decrease in mortality in women treated between the age of 50 to 60 years old in randomized trials [34]. Several studies have demonstrated the safety of HRT in such patients without increase of risk of relapse [8,9,35,36]. In a randomized controlled trial with a median follow-up of 19 years, Eeles et al. observed an improvement in overall survival in EOCS with HRT vs. without [9].
We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS).
166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM).
Mean age at the survey was 62 [21–83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT).
VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.
Parity, menopausal hormone therapy, and risk of ovarian granulosa cell tumor – A population-based case-control study
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The effect of HT use on pure AGCT incidence has, to our knowledge, not been addressed in any previous study, and considering the distinctive nature of AGCT compared to epithelial ovarian carcinoma, findings regarding epithelial tumors cannot be readily applied to AGCT. Numerous recent reports along with a Cochrane Review have concluded that postoperative HT does not have a negative effect on prognosis after epithelial ovarian cancer, although evidence remains limited [19–22]. However, it is recommended that topical or systemic HT should not be advocated to AGCT patients, and non-hormonal options should be used as first-line therapy to treat menopausal symptoms [23–25].
Adult-type ovarian granulosa cell tumors (AGCTs) are hormonally active neoplasms with limited epidemiological data available. We evaluated the effect of parity and postmenopausal hormone therapy (HT) use on the risk of AGCT in a population-based case-control setting.
We identified all women diagnosed with AGCT during 1994–2015 (n = 505) from the Finnish Cancer Registry. For each case, five controls matched for age were selected from the National Population Registry, which also provided data on parity and ages at deliveries. Information on postmenopausal HT by different regimens (estradiol-only, sequential estrogen-progestin and continuous estrogen-progestin) was obtained from nationwide Prescription Register. The association between parity, ages at deliveries, HT use, and AGCT incidence was evaluated by odds ratios (ORs) using a conditional logistic regression model and stratified by age at index date (<55 years or ≥ 55 years).
Parity and age at first or last delivery had no significant effect on AGCT risk. Systemic postmenopausal HT had been used by 20.4% of women who were later diagnosed with AGCT. The risk for subsequent AGCT was significantly decreased among users of estradiol-only therapy for at least five years (OR 0.28; 95% confidence interval 0.08–0.94) and continuous estradiol-progestin therapy for 6 months to 5 years (0.23; 0.08–0.71).
Unlike in epithelial ovarian cancer, AGCT development is not clearly associated with parity, and users of postmenopausal HT do not seem to carry an excess risk for AGCT formation.
Hormone therapy (HT) in women with gynecologic cancers and in women at high risk for developing a gynecologic cancer: A Society of Gynecologic Oncology (SGO) clinical practice statement: This practice statement has been endorsed by The North American Menopause Society
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Authors’ Reply
2020, Journal of Minimally Invasive Gynecology

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Review ArticlePostoperative hormone replacement therapy for epithelial ovarian cancer patients: A systematic review and meta-analysis

Highlights

Abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Study selection

Discussion

Conclusions

Conflict of interest statement

J. Clin. Epidemiol.

Control. Clin. Trials

J. Steroid Biochem. Mol. Biol.

Gynecol. Oncol.

J. Steroid Biochem. Mol. Biol.

Cancer statistics, 2015

CA Cancer J. Clin.

Recent progress in the diagnosis and treatment of ovarian cancer

CA Cancer J. Clin.

Profiles of women age 30–39 and age less than 30 with epithelial ovarian cancer

Obstet. Gynecol.

National survey of ovarian carcinoma XII. Epithelial ovarian malignancies in women less than or equal to 25 years of age

Cancer

Epithelial ovarian carcinoma in the reproductive age group

Cancer

Early menopause: increased fracture risk at older age

Osteoporos. Int.

Managing menopausal symptoms after gynecological cancer

Curr. Opin. Oncol.

Hormonal replacement therapy in ovarian cancer survivors: a survey among Greek gynecologists

Eur. J. Gynaecol. Oncol.

Safety of hormone replacement therapy in gynaecological cancer survivors

J. Obstet. Gynaecol.

Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement

Syst. Rev.

The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Non-randomised Studies in Meta-analysis

Laparoscopic versus open surgery for rectal cancer: a meta-analysis

Ann. Surg. Oncol.

Practical methods for incorporating summary time-to-event data into meta-analysis

Trials

Review Article
Postoperative hormone replacement therapy for epithelial ovarian cancer patients: A systematic review and meta-analysis