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IMR Press / EJGO / Volume 42 / Issue 5 / DOI: 10.31083/j.ejgo4205155
Open Access Systematic Review
The use of menopausal hormone therapy in women survivors of gynecological cancer: safety report based on systematic reviews and meta-analysis
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1 Spanish Menopause Society, 28036 Madrid, Spain
2 Spanish Society of Medical Oncology, 28011 Madrid, Spain
3 Spanish Society of Gynaecology and Obstetrics, 28036 Madrid, Spain

§MHT Eligibility Criteria Group: Laura Baquedano, Joaquín Calaf, Mª Jesús Cancelo, Antonio Cano, Camil Castelo Branco, Rafael Comino, Pluvio Coronado, Ester de la Viuda, José Luis Doval, Maria Fasero, Javier Ferrer, Gabriel Fiol, Ana Gómez, Mª Ángeles Gómez, Silvia González, Misericordia Guinot, Eva Iglesias, Ana Rosa Jurado, Plácido Llaneza, Iñaki Lete, Paloma Lobo, Dani Lubián, Montserrat Manubens, Milagros Martínez, Marina Mazheika, Nicolás Mendoza, Aníbal Nieto, Laura Nieto, Borja Otero, Santiago Palacios, María Jesús Plá, Ezequiel Pérez-Campos, Jesús Presa, Francisco Quereda, Isabel Ramírez, Miriam Ribes, Beatriz Roca, Sonia Sánchez, Rafael Sánchez-Borrego, Ana Santaballa.

Eur. J. Gynaecol. Oncol. 2021, 42(5), 1058–1067; https://doi.org/10.31083/j.ejgo4205155
Submitted: 10 February 2021 | Revised: 22 March 2021 | Accepted: 31 March 2021 | Published: 15 October 2021
Abstract

The data collected during the last two decades on the effects of menopausal hormone therapy (MHT) could help to provide a safer and more effective long term-treatment of menopause symptoms and possible complications such as osteoporotic fractures, cognitive impairment, or cardiovascular conditions, as well as an improved quality of life. Having a history of suffering from gynecological cancer (endometrial, cervical or ovarian) is one of the conditions that most strongly determines the use of any form of MHT due to the concerns associated with a possible recurrence of the disease. Objective: To create a set of eligibility criteria for the use of MHT in gynecological cancer patients. Methods: The study was registered in PROSPERO (registration number CRD42020166658). Results: Ovarian cancer survivors who use MHT have better overall survival, disease-free survival, and lower recurrence rates than women survivors who do not use MHT. Endometrial cancer survivors who use MHT do not have a higher rate of disease recurrence than those survivors who do not use MHT. Cervical cancer survivors who use MHT do not have a higher rate of disease recurrence than those survivors who do not use MHT. Conclusion: MHT is safe in women who have suffered from most of non-advanced gynecological cancers.

Keywords
Menopausal hormone therapy
Gynecological cancer survivors
1. Introduction

The data collected during the last two decades on the effects of menopausal hormone therapy (MHT) could help to provide a safer and more effective long term-treatment of menopause symptoms and possible complications such as osteoporotic fractures, cognitive impairment, or cardiovascular conditions, as well as an improved quality of life [1-4]. Based on all of this information, international societies have concluded that the benefits of MHT outweigh the risks in healthy symptomatic postmenopausal women when MHT is initiated within 10 years of the menopause or when younger than 60 years of age [5,6].

However, there are currently no guidelines available that provide recommendations on the prescription of MHT in postmenopausal women with any medical condition that could compromise its use. In the case of contraceptive methods, there is a globally available document that provides information for this purpose. Thus, the “WHO Medical Eligibility Criteria” classifies the various medical conditions of women into four categories, providing the scientific community with recommendations for the safe use of any contraceptive method [7].

Having a history of suffering from gynecological cancer (endometrial, cervical or ovarian) is one of the conditions that most strongly determines the use of any form of MHT due to the concerns associated with a possible recurrence of the disease. Moreover, the majority of women survivors of these cancers have received treatments that have sharply increased their menopausal symptoms, due to oophorectomy or the effects of QT and RT, which further increases the need to treat them with effective remedies, one of the most notable being MHT [8].

The objective of this report is to create a set of eligibility criteria for the use of MHT in gynecological cancer patients, similar to those established for contraceptive methods. A consortium of scientific societies coordinated by the Spanish Menopause Society met to develop guidelines for the use of MHT in patients with medical conditions, based on the best available evidence.

2. Methods

The study was registered in PROSPERO (registration number CRD42020166658) and is part of the “Eligibility criteria for MHT project” (Supplementary material 1).

2.1 Selection of studies

We conducted an exhaustive literature searches in the following databases: MEDLINE (via PubMed), The Cochrane Library (CENTRAL), and EMBASE (via embase.com), from their inception until the most recent date. We will design a search strategy that is tailored to the requirements of each database, which will include a combination of controlled vocabulary and search terms related to each gynecological cancer. Appendix displays an exploratory search strategy for MEDLINE. When necessary, we will use validated filters to retrieve the appropriate study designs.

Two independent researchers screened the references yielded by the search to reach an agreement on the inclusion of studies.

The PICOS (Population, Intervention, Comparators, Outcomes, Study Design) criteria are developed a priori to guide the scope of the review, along with the procedures, selection, and synthesis of the literature search. The selection criteria were as follows:

(Population) menopausal women of any age with gynecological cancer receiving HMT; (Intervention) any MHT preparation (oestrogens alone or combined with a progestogen, tibolone or tissue selective oestrogen complex) or any route of administration (oral, transdermal, vaginal or intra-nasal); (Outcome) recurrence and mortality; (Study Design) randomized controlled trials, and related extension studies or follow-up reports. Any complete article that met the inclusion criteria was reviewed in detail.

2.2 Data extraction and risk of bias assessment

We described the synthesis of the evidence following the PRISMA guidelines [9]. We assessed the risk of bias of the eligible studies using the Cochrane tool for clinical trials, which takes into account the evaluation of five possible sources of bias (selection, performance, detection, attrition and report bias) [10]. For observational studies, we adapted the ROBINS I tool, focusing on the evaluation of the impact of the confounding variables, selection bias, outcome measures, and attrition [11]. Pooled analyses were conducted using the Mantel-Haenszel method and the random effects model included within the RevMan software statistical package (v 5.3.5) [12].

We made explicit judgements on the certainty of the evidence for each outcome of interest according to GRADE criteria [13]. Quality will be classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias).

3. Results

The quality of the studies is described in Tables 1-3 (Ref. [14-32]) and in the Supplementary material provided.

Table 1. Ovarian cancer. Summary of findings.
 Certainty evaluation Impact Certainty No of studies Study design Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Mortality 3 Randomized trials [14, 15, 16] Serious${}^{a}$ Not serious Not serious Not serious None RR 0.90, 95% CI: 0.73 to 1.10 $\bigoplus$$\bigoplus$$\bigoplus$$\bigcirc$ MODERATE Mortality 9 Randomized trials [14, 15, 16] and retrospective cohorts [17, 18, 19, 20, 21, 22] Very serious${}^{b}$ Serious${}^{c}$ Not serious Not serious None RR 0.76, 95% CI: 0.58 to 1.00 $\bigoplus$$\bigcirc$$\bigcirc$$\bigcirc$ VERY LOW Overall survival 3 Randomized trials [14, 15, 16] Serious${}^{a}$ Serious${}^{c}$ Not serious Not serious None HR 0.71, 95% CI: 0.54 to 0.93 $\bigoplus$$\bigoplus$$\bigcirc$$\bigcirc$ 120 less per 1000 (84 to 220 less)${}^{d}$ LOW Recurrence-free survival 2 Randomized trials [14, 15] Serious${}^{a}$ Not serious Not serious Not serious None HR 0.72, 95% CI: 0.58 to 0.90 $\bigoplus$$\bigoplus$$\bigoplus$$\bigcirc$ MODERATE Recurrence of ovarian cancer 2 Randomized trials [14, 16] Serious${}^{a}$ Not serious Not serious Not serious None RR 0.81, 95% CI: 0.70 to 0.93 $\bigoplus$$\bigoplus$$\bigoplus$$\bigcirc$ 147 less per 1000 (54 to 232 less) MODERATE Recurrence of ovarian cancer 8 Randomized trials [14, 16] and retrospective cohorts [18, 20, 22] Very serious${}^{b}$ Not serious Not serious Not serious None RR 0.81, 95% CI: 0.71 to 0.92 $\bigoplus$$\bigoplus$$\bigcirc$$\bigcirc$ LOW ${}^{a}$ Lack of blinding, with an impact on the loss of participants. ${}^{b}$ Retrospective studies with selection and confounding bias. ${}^{c}$ Inconsistency (presence of notable statistical heterogeneity not explained by the characteristics of the studies). ${}^{d}$ Data taken from the Cochrane review by Saeaib [34].
Table 2.Endometrial cancer. Summary of findings.
 Certainty evaluation Impact Certainty No of studies Study design Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Recurrence 1 Randomized trial [23] Serious${}^{a}$ Not serious Not serious Serious${}^{b}$ None RR 1.17, 95% CI: 0.54 to 2.50${}^{c}$ $\bigoplus$$\bigoplus$$\bigcirc$$\bigcirc$ LOW Recurrence 9 Randomized trial [23], prospective [24] and retrospective [25, 26, 27, 28, 29, 30, 31] cohorts Very serious${}^{d}$ Not serious Not serious Not serious Publication bias${}^{e}$ RR 0.64, 95% CI: 0.50 to 0.82 $\bigoplus$$\bigcirc$$\bigcirc$$\bigcirc$ 28 less for every 1000 women treated rather than untreated (38 to 14 less) VERY LOW ${}^{a}$ Limitations in study design and execution: lack of information on sequence generation and allocation masking; in addition, the trial was stopped early without completion of recruitment. ${}^{b}$ Interruption of the trial before completion of planned recruitment affects the accuracy of the effect estimator. ${}^{c}$ Median follow-up of 37.5 months. ${}^{d}$ Most retrospective cohort studies showed a high risk of confounding bias. ${}^{e}$ Publication bias of retrospective studies with negative results (analysis 02.05 in Annex 2).
Table 3.Cervico-uterine cancer. Summary of findings.
 Certainty evaluation Impact Certainty No of studies Study design Risk of bias Inconsistency Indirect evidence Imprecision Other considerations Cervical-uterine cancer. Mortality (Hormonal replacement therapy versus symptomatic management without hormonal treatment) 1 Randomized trial [32] Very serious${}^{a}$ No Not serious Serious${}^{b}$ None OR 0.46, 95% CI: 0.20 to1.09${}^{c}$ $\bigoplus$$\bigcirc$$\bigcirc$$\bigcirc$ VERY LOW Cervical-uterine cancer. Recurrence (Hormonal replacement therapy versus symptomatic management without hormonal treatment) 1 Randomized trial [32] Very serious${}^{a}$ No Not serious Serious${}^{b}$ None OR 0.52, 95% CI: 0.22 to 1.23${}^{c}$ $\bigoplus$$\bigcirc$$\bigcirc$$\bigcirc$ VERY LOW ${}^{a}$ Lack of information on sequence generation, allocation masking, blinding, selective reporting of results, failure to specify the role of industry. ${}^{b}$ A single clinical trial of low methodological quality. ${}^{c}$ Follow-up at least 5 years.
3.1 Ovarian cancer

Three randomized clinical trials (RCTs) were included on the impact of MHT on ovarian cancer recurrence and mortality [14-16]. Six retrospective observational studies were also considered [17-22]. Most patients received combined oral MHT, primarily with equine conjugated estrogens (ECE) 0.625–1.25 mg/day plus medroxyprogesterone 4 mg/day.

There were no differences in overall survival when all studies were pooled (RR 0.90, 95% CI: 0.73 to 1.10; Fig. 1a), but differences emerged when only RCTs were analyzed [14-16] indicating improvement after MHT (HR 0.71, 95% CI: 0.54 to 0.93; Fig. 1b).

One of the cohort studies [21] presented the results according to the age of the participants. Survival in women under 55 years was higher when using MHT, according to a univariate analysis (HR 0.41, 95% CI: 0.19 to 0.89, p = 0.023), but not in the multivariate model (according to disease stage and chemotherapy administration; HR 0.49, 95% CI: 0.23 to 1.09, p = 0.08). For patients over 55 years old, MHT did not affect survival.

Combined data from two RCTs [14,16] showed an increase in recurrence-free survival with MHT (HR 0.72, 95% CI: 0.58 to 0.90; Fig. 1c), and a reduction in the risk of recurrence (RR 0.81, 95% CI: 0.70 to 0.93; Fig. 1d). These results were maintained when data from retrospective studies were added (RR 0.81, 95% CI: 0.71 to 0.92; Fig. 1d).

Disease-free survival was also higher for MHT users younger than 55 years in the Power 2016 study [21], both in the univariate (HR 0.34, 95% CI: 0.17 to 0.69; p = 0.003) and multivariate models (adjusted HR 0.35, 95% CI: 0.17 to 0.74; p = 0.006). For women over 55 years of age, the use of MHT was not associated with increased disease-free survival.

Fig. 1.

Ovarian cancer. (a) Mortality (data from clinical trials and retrospective studies). (b) Overall survival (data from clinical trials). (c) Recurrence-free survival (data from clinical trials). (d) Recurrence (data from clinical trials and retrospective studies).

3.2 Endometrial cancer

One RCT was identified [23] with 1236 participants where neither the dose nor the route of administration of MHT is described, with a mean follow-up of 35.7 months. Eight observational studies were also included, one prospective [24] and seven retrospective studies [25-31] with a total of 1801 endometrial cancer survivors who received MHT and 6015 who did not. Almost all were limited to patients with early stages of the disease.

The RCT [23] found no difference in recurrence according to MHT use (RR 1.17, 95% CI: 0.54 to 2.50), the same being true for the combined analysis of the RCT and the prospective study (RR 1.08, 95% CI: 0.52 to 2.24; Fig. 2a). However, when adding the results of the retrospective studies, a significant reduction in recurrence was observed with the use of MHT (RR 0.64, 95% CI: 0.50 to 0.82; Fig. 2b). In particular, recurrence was reduced with combined MHT (RR 0.31, 95% CI: 0.13 to 0.73; Fig. 2c) but not with estrogen alone (RR 0.57, 95% CI: 0.30 to 1.10). These results were found to be independent of the stage of the disease (RR for Stage I 0.14, 95% CI: 0.03 to 0.70; RR for Stage I–II 0.70, 95% CI: 0.54 to 0.90; Fig. 2d).

Fig. 2.

Endometrial cancer. (a) Recurrence (data from clinical trials and prospective studies). (b) Recurrence (data from clinical trials and prospective and retrospective studies). (c) Recurrence (by type of treatment). (d) Recurrence (by stage of disease). (e) Recurrence (analysis of publication bias).

3.3 Cervical cancer

One RCT was identified [32] with 120 patients under 45 years of age with Stage I and II cancer. Oral MHT was combined with different formulations over an observation period of more than 5 years. This RCT found no significant differences in either mortality (RR 0.62, 95% CI: 0.33 to 1.15; Fig. 3a) or recurrence (RR 0.57, 95% CI: 0.31 to 1.15; Fig. 3b).

Fig. 3.

Cervical cancer. (a) Mortality. (b) Recurrence.

4. Discussion

Taken together, analysis of the researched literature leads to the conclusion that MHT is probably safe in terms of recurrence and/or mortality, in patients who have suffered from non-advanced gynecological cancer, but this affirmation should be interpreted with caution mostly after ovarian cancer.

4.1 Why is this report important?

There is considerable confusion regarding the appropriateness of prescribing MHT in women with gynecological cancer, particularly because of the fear of recurrence or increased mortality that may occur with its use.

Women who have suffered from gynecological cancer often present earlier and more intense menopausal symptoms due to ovarian surgery or the effects of certain treatments (RT, QT), which have a severe impact on their quality of life. These long-term risks often overlap with those suffered by women with premature ovarian failure (POF), thus extending the suitability of MHT [8].

This report complements the recommendations contained in a recent position paper published by EMAS and IGCS [33].

4.2 Strengths

This is the first published work where several systematic reviews and meta-analyses are gathered to analyze the recurrence and mortality associated with MHT use in women survivors of gynecological cancer (endometrial, ovarian, or cervical).

This is also the first time that categories of evidence (eligibility criteria) have been distinguished for the use of MHT in these patients, using the strictest methodological tools.

Other systematic reviews have been included [34,40,41] as sources of studies relevant to this report.

4.3 Limitations

The quality of evidence is low overall. Many studies include the generic use of MHT without distinguishing between dose, formulation, or route of administration.

4.4 Special considerations
4.4.1 Ovarian cancer

The recommendation is based on the analysis of three RCTs and six retrospective observational studies. One of the major limitations of these studies is the use of different compounds, guidelines, and routes of administration of MHT. Most ovarian cancer survivors in these studies used oral equine conjugated estrogens, alone if they had been hysterectomized, and in combination with a progestogen (usually medroxyprogesterone acetate) when the women retained their uterus. In addition, no conclusions can be drawn about the different types of ovarian carcinomas. MHT may slightly improve overall survival in women who have undergone surgical treatment for epithelial ovarian cancer, but the certainty of the evidence is low. Respecting other types of ovarian cancer, the evidence in this review is limited by imprecision and incompleteness of reported relevant outcomes and therefore the results should be interpreted with caution.

4.4.2 Endometrial cancer

The recommendation is based on the analysis of one RCT and eight observational studies (one prospective cohort study and seven retrospective studies). The studies included only patients in the early stages of endometrial cancer (I and II) and the treatments used differed in terms of composition, pattern, and route of administration.

The advantage of administering MHT to these patients is the improvement of their quality of life without compromising their survival. No recommendations can be made on the use of HMT in patients with stage III and IV.

Analysis of these studies, however, suggests the existence of a publication bias in retrospective studies with negative results (Fig. 2e).

4.4.3 Cervical cancer

This recommendation is based on a single RCT with several biases and limitations. The advantage of administering MHT to these patients is the improvement of their quality of life without compromising their survival.

4.4.4 Vulval and vaginal cancer

Regarding cancers of the vulva and vagina, although we have not found studies that measure the safety of HMT, most of them are squamous cell carcinomas not hormone-dependent, so we agree that there should be no contraindication to the use of HMT, whether systemic or local, when is indicated [38,39,41].

4.5 Cancer risk in healthy MHT users
4.5.1 Ovarian cancer

The literature review has revealed an increased risk of ovarian cancer in case-control and cohort studies with both estrogen therapy alone and combined with progestogen.

The global RR is between 1.29 (95% CI: 1.19 to 1.40, I2 = 57.4%) [42] and 1.37 (95% CI: 1.29 to 1.46; p $<$ 0.0001) [43]. This difference is maintained regardless of the time of administration of the treatment and is similar in both Europe and North America, whilst the results obtained in Australia were not significant [42]. Evidence for an increased risk was found only for serous and endometrioid tumors, but not for other histological subtypes. It is not established if there are differences according to guidelines and types of treatment.

4.5.2 Endometrial cancer

Exposure of the endometrium to estrogen has been associated with an increased risk of developing endometrial cancer, which is why progestogen is recommended as opposed to estrogenic treatment.

The Women Health Initiative study showed a non-significant risk reduction with continuous in comparison with cyclic MHT [44]. The Million Women Study reported the protective effect of continuous combination treatment (RR 0.71, 95% CI: 0.56 to 0.90), while the use of tibolone and estrogen alone was associated with an increased risk [45,46]. Other studies have pointed to an increased risk in combination therapy with synthetic progestogens, and even micronized progesterone [47].

These differences in the effects of using estrogens alone and those combined with progestogens appear to be more marked in obese women, where the risk of estrogen treatment is higher and progestogen protection seems to be increased [46].

4.5.3 Cervical cancer

The literature provides little information regarding the effect of MHT on the development of cervical cancer. The EPIC study (European Prospective Investigation into Cancer and Nutrition), on 308,036 women revealed a significant risk reduction (RR 0.5, 95% CI: 0.4 to 0.8), particularly if the treatment duration exceeds five years. While it has been suggested that estrogens may promote cervical carcinogenesis with a protective effect of progestogens, risk reduction seems to be evident in both estrogenic treatment and the combined use of estrogens [48].

4.6 Future research

Our report, however, has identified some important areas of improvement for future research. It is expected that the results will contribute to the development of studies that further examine the safety and efficacy of MHT for treating menopausal symptoms in gynecological cancer survivors. Larger RCTs should be conducted, and over a longer follow-up period, to evaluate the various MHT strategies.

5. Conclusions

Non-advanced ovarian cancer survivors who use MHT have better overall survival, disease-free survival, and lower recurrence rates than women survivors who do not use MHT.

Endometrial cancer survivors who use MHT do not have a higher rate of disease recurrence than those survivors who do not use MHT.

Cervical cancer survivors who use MHT do not have a higher rate of disease recurrence than those survivors who do not use MHT.

Author contributions

IL, GF, NM—conception and design of the idea. IL, GF, NM—preparation of manuscript. LN, AS, MJP—review of information, selection of valuable articles, critical reading of articles. All authors participated in data interpretation, statement and approved the final version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

Supplementary material associated with this article can be found, in the online version, at https://ejgo.imrpress.com/EN/10.31083/j.ejgo4205155.

Appendix

Search strategy:

(“Hormone Replacement Therapy”[Mesh] OR hormone replacement[tiab] OR hormonal replacement[tiab] OR estrogen replacement[tiab] OR hormone therapy[tiab] OR hormonal therapy[tiab]) AND (prognos*[ti] OR survivor*[ti] OR postoperative[ti] OR adjuvant[ti] OR after[ti] OR (after[tiab] AND diagnos*[tiab]) OR following[ti]) AND (endometrial[ti] OR “Endometrial Neoplasms”[Majr] OR ovarian[ti] OR “Uterine Cervical Neoplasms”[Mesh] OR cervical[ti]).

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