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The Cochrane Database of Systematic... Jul 2014Background Prophylactic oophorectomy alongside hysterectomy in premenopausal women is a common procedure. The decision to remove or conserve the ovaries is often based... (Comparative Study)
Comparative Study Review
Background Prophylactic oophorectomy alongside hysterectomy in premenopausal women is a common procedure. The decision to remove or conserve the ovaries is often based on the perceived risk for ovarian cancer and the need for additional gynaecological surgical interventions,and is weighed against the perceived risk of negative health effects caused by surgically induced menopause. The evidence needed to recommend either prophylactic bilateral oophorectomy or conservation of ovaries at the time of hysterectomy in premenopausal women is limited. This is an update of the original version of this systematic review published in 2008.Objectives To compare hysterectomy alone versus hysterectomy plus bilateral oophorectomy in women with benign gynaecological conditions,with respect to rates of mortality or subsequent gynaecological surgical interventions.Search methods We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (December 2005 to January 2014) and the following electronic databases: CENTRAL (The Cochrane Library 2013, Issue 12), MEDLINE (January 1966 to January 2014),EMBASE (January 1985 to January 2014), and PsycINFO (1806 to January 2014).Selection criteria Randomised controlled trials (RCTs) of hysterectomy alone versus hysterectomy with bilateral oophorectomy in premenopausal women with benign gynaecological conditions were eligible. Any surgical approach could be used.Data collection and analysis Three review authors independently assessed trials for inclusion. Study authors were contacted if information was unclear.Main results Only one RCT comparing the benefits and risks of hysterectomy with or without oophorectomy was identified. The results of this pilot RCT have not been published and we have not been able to obtain the results. Therefore, no data could be included in this review. Authors' conclusions The conclusions of this review are limited by a lack of RCTs. Although no evidence is available from RCTs, there is growing evidence from observational studies that surgical menopause may impact negatively on cardiovascular health and all cause mortality.
Topics: Combined Modality Therapy; Female; Genital Diseases, Female; Humans; Hysterectomy; Ovariectomy; Premenopause
PubMed: 25101365
DOI: 10.1002/14651858.CD005638.pub3 -
Osteoarthritis and Cartilage Apr 2023Post-menopausal women are disproportionately affected by osteoarthritis (OA). As such, the purpose of this study was to (1) summarize the state-of-the-science aimed at... (Meta-Analysis)
Meta-Analysis Review
Uncovering the "riddle of femininity" in osteoarthritis: a systematic review and meta-analysis of menopausal animal models and mathematical modeling of estrogen treatment.
OBJECTIVE
Post-menopausal women are disproportionately affected by osteoarthritis (OA). As such, the purpose of this study was to (1) summarize the state-of-the-science aimed at understanding the effects of menopause on OA in animal models and (2) investigate how dosage and timing of initiation of estrogen treatment affect cartilage degeneration.
DESIGN
A systematic review identified articles studying menopausal effects on cartilage in preclinical models. A meta-analysis was performed using overlapping cartilage outcomes in conjunction with a rigor and reproducibility analysis. Ordinary differential equation models were used to determine if a relationship exists between cartilage degeneration and the timing of initiation or dosage of estrogen treatment.
RESULTS
Thirty-eight manuscripts were eligible for inclusion. The most common menopause model used was ovariectomy (92%), and most animals were young at the time of menopause induction (86%). Most studies did not report inclusion criteria, animal monitoring, protocol registration, or data accessibility. Cartilage outcomes were worse in post-menopausal animals compared to age-matched, non-menopausal animals, as evidenced by cartilage histological scoring [0.75, 1.72], cartilage thickness [-4.96, -0.96], type II collagen [-4.87, -0.56], and c-terminal cross-linked telopeptide of type II collagen (CTX-II) [2.43, 5.79] (95% CI of Effect Size (+greater in menopause, -greater in non-menopause)). Moreover, modeling suggests that cartilage health may be improved with early initiation and higher doses of estrogen treatment.
CONCLUSIONS
To improve translatability, animal models that consider aging and natural menopause should be utilized, and more attention to rigor and reproducibility is needed. Timing of initiation and dosage may be important factors modulating therapeutic effects of estrogen on cartilage.
Topics: Humans; Animals; Female; Collagen Type II; Reproducibility of Results; Estrogens; Osteoarthritis; Cartilage Diseases; Disease Models, Animal
PubMed: 36621591
DOI: 10.1016/j.joca.2022.12.009 -
Gynecologic Oncology Jun 2023Increasing evidence suggests the fallopian tube as the site of origin of BRCA1/2-associated high-grade ovarian cancers. Several ongoing trials are evaluating... (Review)
Review
OBJECTIVE
Increasing evidence suggests the fallopian tube as the site of origin of BRCA1/2-associated high-grade ovarian cancers. Several ongoing trials are evaluating salpingectomy with delayed oophorectomy (RRSDO) for ovarian cancer risk reduction and patients are beginning to ask their clinicians about this surgical option. This study sought to systematically review the available literature examining patient preferences regarding RRSDO and risk-reducing salpingo-oophorectomy (RRSO) to provide clinicians with an understanding of patient values, concerns, and priorities surrounding ovarian cancer risk-reducing surgery.
METHODS
We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42023400690). We searched key electronic databases to identify studies evaluating acceptance and surgical decision-making regarding RRSO and RRSDO among patients with an increased risk of ovarian cancer.
RESULTS
The search yielded 239 results, among which six publications met the systematic review inclusion criteria. Acceptance of RRSDO was evaluated in all studies and ranged from 34% to 71%. Factors positively impacting patients' acceptance of RRSDO included: avoidance of surgical menopause, preservation of fertility, concerns about sexual dysfunction, family history of breast cancer, and avoidance of hormone replacement therapy. Factors limiting this acceptance reported by patients included concerns regarding oncologic safety, surgical timing, and surgical complications.
CONCLUSION
To date, few studies have explored patient perspectives surrounding RRSDO. Collectively, the limited data available indicate a high level of acceptance among BRCA1/2 carriers, and provides insight regarding both facilitating and limiting factors associated with patient preferences to better equip clinicians in the counseling and support of their patients.
Topics: Humans; Female; BRCA1 Protein; BRCA2 Protein; Ovariectomy; Salpingectomy; Ovarian Neoplasms; Breast Neoplasms; Risk Reduction Behavior; Mutation; Genetic Predisposition to Disease
PubMed: 37116391
DOI: 10.1016/j.ygyno.2023.04.006 -
Obstetrics and Gynecology Sep 2016To compare the long-term risks associated with salpingo-oophorectomy with ovarian conservation at the time of benign hysterectomy. (Review)
Review
OBJECTIVE
To compare the long-term risks associated with salpingo-oophorectomy with ovarian conservation at the time of benign hysterectomy.
DATA SOURCES
MEDLINE, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials were searched from inception to January 30, 2015. We included prospective and retrospective comparative studies of women with benign hysterectomy who had either bilateral salpingo-oophorectomy (BSO) or conservation of one or both ovaries.
METHODS OF STUDY SELECTION
Reviewers double-screened 5,568 citations and extracted eligible studies into customized forms. Twenty-six comparative studies met inclusion criteria. Studies were assessed for results, quality, and strength of evidence.
TABULATION, INTEGRATION, AND RESULTS
Studies were extracted for participant, intervention, comparator, and outcomes data. When compared with hysterectomy with BSO, prevalence of reoperation and ovarian cancer was higher in women with ovarian conservation (ovarian cancer risk of 0.14-0.7% compared with 0.02-0.04% among those with BSO). Hysterectomy with BSO was associated with a lower incidence of breast and total cancer, but no difference in the incidence of cancer mortality was found when compared with ovarian conservation. All-cause mortality was higher in women younger than age 45 years at the time of BSO who were not treated with estrogen replacement therapy (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.04-1.92). Coronary heart disease (HR 1.26, 95% CI 1.04-1.54) and cardiovascular death were higher among women with BSO (HR 1.84, 95% CI 1.27-2.68), especially women younger than 45 years who were not treated with estrogen. Finally, there was an increase in the prevalence of dementia and Parkinson disease among women with BSO compared with conservation, especially in women younger than age 50 years. Clinical practice guidelines were devised based on these results.
CONCLUSION
Bilateral salpingo-oophorectomy offers the advantage of effectively eliminating the risk of ovarian cancer and reoperation but can be detrimental to other aspects of health, especially among women younger than age 45 years.
Topics: Age Factors; Female; Humans; Hysterectomy; Organ Sparing Treatments; Outcome and Process Assessment, Health Care; Ovarian Neoplasms; Ovariectomy; Patient Selection; Risk Assessment; Salpingectomy
PubMed: 27500347
DOI: 10.1097/AOG.0000000000001592 -
The Cochrane Database of Systematic... Oct 2008Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long... (Review)
Review
BACKGROUND
Among women with early breast cancer, the effects of ovarian ablation on recurrence and death have been assessed by several randomised trials that now have long follow-up.
OBJECTIVES
In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis), now with 15 years' follow-up.
SEARCH STRATEGY
Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module.
SELECTION CRITERIA
All properly randomised trials that began recruiting before 1990 which compared the ablation or suppression of ovarian function, sometimes with the addition of prednisone, versus no such adjuvant treatment for women with operable breast cancer. In practice, all the trials that can be reviewed here began before 1980, and all involved surgical or therapeutic ablation.
DATA COLLECTION AND ANALYSIS
In 1995, information was sought on each patient in any randomised trial of ovarian ablation or suppression versus control that began before 1990. Data were obtained for 12 of the 13 studies that assessed ovarian ablation by irradiation or surgery, all of which began before 1980, but not for the four studies that assessed ovarian suppression by drugs, all of which began after 1985. Menopausal status was not consistently defined across trials; therefore, the main analyses are limited to women aged under 50 (rather than "premenopausal") when randomised. Oestrogen receptors were measured only in the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone.
MAIN RESULTS
Among 2102 women aged under 50 when randomised, most of whom would have been premenopausal at diagnosis, 1130 deaths and an additional 153 recurrences were reported. 15-year survival was highly significantly improved among those allocated ovarian ablation (52.4 vs 46.1%, 6.3 [SD 2.3] fewer deaths per 100 women, logrank 2p=0.001), as was recurrence-free survival (45.0 vs 39.0%, 2p=0.0007). The numbers of events were too small for any subgroup analyses to be reliable. The benefit was, however, significant both for those with ("node positive") and for those without ("node negative") axillary spread when diagnosed. In the trials of ablation plus cytotoxic chemotherapy versus the same chemotherapy alone, the benefit appeared smaller (even for women with oestrogen receptors detected on the primary tumour) than in the trials in the absence of chemotherapy (where the observed survival improvements were about six per 100 node-negative women and 12 per 100 node-positive women). Among 1354 women aged 50 or over when randomised, most of whom would have been perimenopausal or postmenopausal, there was only a non-significant improvement in survival and recurrence-free survival.
AUTHORS' CONCLUSIONS
In women aged under 50 with early breast cancer, ablation of functioning ovaries significantly improves long-term survival, at least in the absence of chemotherapy. Further randomised evidence is needed on the additional effects of ovarian ablation in the presence of other adjuvant treatments, and to assess the relevance of hormone-receptor measurements.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Meta-Analysis as Topic; Neoplasms, Hormone-Dependent; Ovariectomy; Randomized Controlled Trials as Topic
PubMed: 18843610
DOI: 10.1002/14651858.CD000485.pub2 -
PloS One 2016Biomechanical tests are widely used in animal studies on osteoporotic fracture healing. However, the biomechanical recovery process is still unknown, leading to... (Meta-Analysis)
Meta-Analysis Review
Biomechanical tests are widely used in animal studies on osteoporotic fracture healing. However, the biomechanical recovery process is still unknown, leading to difficulty in choosing time points for biomechanical tests and in correctly assessing osteoporotic fracture healing. To determine the biomechanical recovery process during osteoporotic fracture healing, studies on osteoporotic femur fracture healing with biomechanical tests in ovariectomized rat (OVX) models were collected from PUBMED, EMBASE, and Chinese databases. Quadratic curves of fracture healing time and maximum load were fitted with data from the analyzed studies. In the fitted curve for normal fractures, the predicted maximum load was 145.56 N, and the fracture healing time was 88.0 d. In the fitted curve for osteoporotic fractures, the predicted maximum load was 122.30 N, and the fracture healing time was 95.2 d. The maximum load of fractured femurs in OVX rats was also lower than that in sham rats at day 84 post-fracture (D84 PF). The fracture healing time was prolonged and maximum load at D84 PF decreased in OVX rats with closed fractures. The maximum load of Wister rats was higher than that of Sprague-Dawley (SD) rats, but the fracture healing time of SD and Wister rats was similar. Osteoporotic fracture healing was delayed in rats that were < = 12 weeks old when ovariectomized, and at D84 PF, the maximum load of rats < = 12 weeks old at ovariectomy was lower than that of rats >12 weeks old at ovariectomy. There was no significant difference in maximum load at D84 PF between rats with an osteoporosis modeling time <12 weeks and > = 12 weeks. In conclusion, fracture healing was delayed and biomechanical property decreased by osteoporosis. Time points around D95.2 PF should be considered for biomechanical tests of osteoporotic femur fracture healing in OVX rat models. Osteoporotic fracture healing in OVX rats was affected by the fracture type but not by the strain of the rat.
Topics: Animals; Biomechanical Phenomena; Female; Femur; Fracture Healing; Osteoporotic Fractures; Ovariectomy; Rats
PubMed: 27055104
DOI: 10.1371/journal.pone.0153120 -
International Urogynecology Journal Jun 2021We aimed to summarize the knowledge on the pathogenesis of pelvic organ prolapse (POP) generated in animal models.
INTRODUCTION AND HYPOTHESIS
We aimed to summarize the knowledge on the pathogenesis of pelvic organ prolapse (POP) generated in animal models.
METHODS
We searched MEDLINE, Embase, Cochrane and the Web of Science to establish what animal models are used in the study of suggested risk factors for the development of POP, including pregnancy, labor, delivery, parity, aging and menopause. Lack of methodologic uniformity precluded meta-analysis; hence, results are presented as a narrative review.
RESULTS
A total of 7426 studies were identified, of which 51 were included in the analysis. Pregnancy has a measurable and consistent effect across species. In rats, simulated vaginal delivery induces structural changes in the pelvic floor, without complete recovery of the vaginal muscular layer and its microvasculature, though it does not induce POP. In sheep, first vaginal delivery has a measurable effect on vaginal compliance; measured effects of additional deliveries are inconsistent. Squirrel monkeys can develop POP. Denervation of their levator ani muscle facilitates this process in animals that delivered vaginally. The models used do not develop spontaneous menopause, so it is induced by ovariectomy. Effects of menopause depend on the age at ovariectomy and the interval to measurement. In several species menopause is associated with an increase in collagen content in the longer term. In rodents there were no measurable effects of age apart of elastin changes. We found no usable data for other species.
CONCLUSION
In several species there are measurable effects of pregnancy, delivery and iatrogenic menopause. Squirrel monkeys can develop spontaneous prolapse.
Topics: Animals; Delivery, Obstetric; Female; Models, Animal; Parity; Pelvic Floor; Pelvic Organ Prolapse; Pregnancy; Rats; Sheep
PubMed: 33484287
DOI: 10.1007/s00192-020-04638-1 -
The Cochrane Database of Systematic... Aug 2018The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The presence of deleterious mutations in breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2) significantly increases the risk of developing some cancers, such as breast and high-grade serous cancer (HGSC) of ovarian, tubal and peritoneal origin. Risk-reducing salpingo-oophorectomy (RRSO) is usually recommended to BRCA1 or BRCA2 carriers after completion of childbearing. Despite prior systematic reviews and meta-analyses on the role of RRSO in reducing the mortality and incidence of breast, HGSC and other cancers, RRSO is still an area of debate and it is unclear whether RRSO differs in effectiveness by type of mutation carried.
OBJECTIVES
To assess the benefits and harms of RRSO in women with BRCA1 or BRCA2 mutations.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 7) in The Cochrane Library, MEDLINE Ovid, Embase Ovid and trial registries, with no language restrictions up to July 2017. We handsearched abstracts of scientific meetings and other relevant publications.
SELECTION CRITERIA
We included non-randomised trials (NRS), prospective and retrospective cohort studies, and case series that used statistical adjustment for baseline case mix using multivariable analyses comparing RRSO versus no RRSO in women without a previous or coexisting breast, ovarian or fallopian tube malignancy, in women with or without hysterectomy, and in women with a risk-reducing mastectomy (RRM) before, with or after RRSO.
DATA COLLECTION AND ANALYSIS
We extracted data and performed meta-analyses of hazard ratios (HR) for time-to-event variables and risk ratios (RR) for dichotomous outcomes, with 95% confidence intervals (CI). To assess bias in the studies, we used the ROBINS-I 'Risk of bias' assessment tool. We quantified inconsistency between studies by estimating the I statistic. We used random-effects models to calculate pooled effect estimates.
MAIN RESULTS
We included 10 cohort studies, comprising 8087 participants (2936 (36%) surgical participants and 5151 (64%) control participants who were BRCA1 or BRCA2 mutation carriers. All the studies compared RRSO with or without RRM versus no RRSO (surveillance). The certainty of evidence by GRADE assessment was very low due to serious risk of bias. Nine studies, including 7927 women, were included in the meta-analyses. The median follow-up period ranged from 0.5 to 27.4 years.
MAIN OUTCOMES
overall survival was longer with RRSO compared with no RRSO (HR 0.32, 95% CI 0.19 to 0.54; P < 0.001; 3 studies, 2548 women; very low-certainty evidence). HGSC cancer mortality (HR 0.06, 95% CI 0.02 to 0.17; I² = 69%; P < 0.0001; 3 studies, 2534 women; very low-certainty evidence) and breast cancer mortality (HR 0.58, 95% CI 0.39 to 0.88; I² = 65%; P = 0.009; 7 studies, 7198 women; very low-certainty evidence) were lower with RRSO compared with no RRSO. None of the studies reported bone fracture incidence. There was a difference in favour of RRSO compared with no RRSO in terms of ovarian cancer risk perception quality of life (MD 15.40, 95% CI 8.76 to 22.04; P < 0.00001; 1 study; very low-certainty evidence). None of the studies reported adverse events.Subgroup analyses for main outcomes: meta-analysis showed an increase in overall survival among women who had RRSO versus women without RRSO who were BRCA1 mutation carriers (HR 0.30, 95% CI 0.17 to 0.52; P < 0001; I² = 23%; 3 studies; very low-certainty evidence) and BRCA2 mutation carriers (HR 0.44, 95% CI 0.23 to 0.85; P = 0.01; I² = 0%; 2 studies; very low-certainty evidence). The meta-analysis showed a decrease in HGSC cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.10, 95% CI 0.02 to 0.41; I² = 54%; P = 0.001; 2 studies; very low-certainty evidence), but uncertain for BRCA2 mutation carriers due to low frequency of HGSC cancer deaths in BRCA2 mutation carriers. There was a decrease in breast cancer mortality among women with RRSO versus no RRSO who were BRCA1 mutation carriers (HR 0.45, 95% CI 0.30 to 0.67; I² = 0%; P < 0.0001; 4 studies; very low-certainty evidence), but not for BRCA2 mutation carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; 3 studies; very low-certainty evidence). One study showed a difference in favour of RRSO versus no RRSO in improving quality of life for ovarian cancer risk perception in women who were BRCA1 mutation carriers (MD 10.70, 95% CI 2.45 to 18.95; P = 0.01; 98 women; very low-certainty evidence) and BRCA2 mutation carriers (MD 13.00, 95% CI 3.59 to 22.41; P = 0.007; very low-certainty evidence). Data from one study showed a difference in favour of RRSO and RRM versus no RRSO in increasing overall survival (HR 0.14, 95% CI 0.02 to 0.98; P = 0.0001; I² = 0%; low-certainty evidence), but no difference for breast cancer mortality (HR 0.78, 95% CI 0.51 to 1.19; P = 0.25; very low-certainty evidence). The risk estimates for breast cancer mortality according to age at RRSO (50 years of age or less versus more than 50 years) was not protective and did not differ for BRCA1 (HR 0.85, 95% CI 0.64 to 1.11; I² = 16%; P = 0.23; very low-certainty evidence) and BRCA2 carriers (HR 0.88, 95% CI 0.42 to 1.87; I² = 63%; P = 0.75; very low-certainty evidence).
AUTHORS' CONCLUSIONS
There is very low-certainty evidence that RRSO may increase overall survival and lower HGSC and breast cancer mortality for BRCA1 and BRCA2 carriers. Very low-certainty evidence suggests that RRSO reduces the risk of death from HGSC and breast cancer in women with BRCA1 mutations. Evidence for the effect of RRSO on HGSC and breast cancer in BRCA2 carriers was very uncertain due to low numbers. These results should be interpreted with caution due to questionable study designs, risk of bias profiles, and very low-certainty evidence. We cannot draw any conclusions regarding bone fracture incidence, quality of life, or severe adverse events for RRSO, or for effects of RRSO based on type and age at risk-reducing surgery. Further research on these outcomes is warranted to explore differential effects for BRCA1 or BRCA2 mutations.
Topics: Adult; Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Heterozygote; Humans; Mastectomy; Middle Aged; Mutation; Ovarian Neoplasms; Quality of Life; Salpingo-oophorectomy
PubMed: 30141832
DOI: 10.1002/14651858.CD012464.pub2 -
Journal of Musculoskeletal & Neuronal... Jun 2023Axial loading in rodents provides a controlled setting for mechanical loading, because load and subsequent strain, frequency, number of cycles and rest insertion between...
Axial loading in rodents provides a controlled setting for mechanical loading, because load and subsequent strain, frequency, number of cycles and rest insertion between cycles, are precisely defined. These methodological aspects as well as factors, such as ovariectomy, aging, and disuse may affect the outcome of the loading test, including bone mass, structure, and bone mineral density. This review aims to overview methodological aspects and modifying factors in axial loading on bone outcomes. A systematic literature search was performed in bibliographic databases until December 2021, which resulted in 2183 articles. A total of 144 articles were selected for this review: 23 rat studies, 74 mouse studies, and 47 knock out (KO) mouse studies. Results indicated that peak load, frequency, and number of loading cycles mainly affected the outcomes of bone mass, structure, and density in both rat and mouse studies. It is crucial to consider methodological parameters and modifying factors such as age, sex-steroid deficiency, and disuse in loading protocols for the prediction of loading-related bone outcomes.
Topics: Female; Rats; Mice; Animals; Rodentia; Tibia; Bone and Bones; Bone Density; Weight-Bearing; Stress, Mechanical
PubMed: 37259664
DOI: No ID Found -
The Cochrane Database of Systematic... Oct 2009Approximately 60% of breast cancers amongst premenopausal women express the nuclear oestrogen receptor (ER+ breast cancer). Adjuvant endocrine therapy is an integral... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Approximately 60% of breast cancers amongst premenopausal women express the nuclear oestrogen receptor (ER+ breast cancer). Adjuvant endocrine therapy is an integral component of care for ER+ breast cancer, exerting its effect by reducing the availability of oestrogen to micrometastatic tumour cells. Endocrine strategies in premenopausal women include oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, or permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Aromatase inhibitors are also available with concurrent suppression of ovarian oestrogen synthesis, either through LHRH agonists, surgery, or radiotherapy. Chemotherapy can also have an endocrine action in premenopausal women by interrupting ovarian oestrogen production, either temporarily or permanently. International consensus statements recommend single agent tamoxifen as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy), and the role of LHRH agonists remains under active investigation.
OBJECTIVES
To assess LHRH agonists as adjuvant therapy for women with early breast cancer.
SEARCH STRATEGY
The Cochrane Breast Cancer Group Specialised Register was searched on 19 February 2009. This register incorporates references from CENTRAL (The Cochrane Library) (to 2002), MEDLINE (1966 to July 2008), EMBASE (until 2002); and handsearches of abstracts from the San Antonio Breast Cancer Symposium, American Society of Clinical Oncology Annual Meeting, and the Clinical Oncological Society of Australia Annual Meeting. MEDLINE references (from August 2008 to 19th February 2009) were checked by the authors. The reference lists of related reviews were checked. A final check of the list of trials maintained by the Early Breast Cancer Trialists' Collaborative Group was made in January 2008.
SELECTION CRITERIA
All randomised trials assessing LHRH agonists as adjuvant treatment in premenopausal women with early stage breast cancer were included. Specifically, we included trials that compared:(A) LHRH agonists (experimental arm) versus another treatment;(B) LHRH agonists + anti-oestrogen (experimental arm) versus another treatment;(C) LHRH agonists + chemotherapy (experimental arm) versus another treatment;(D) LHRH agonists + anti-oestrogen + chemotherapy (experimental arm) versus another treatment.
DATA COLLECTION AND ANALYSIS
Data were collected from trial reports. We reported estimates for the differences between treatments on recurrence free survival, overall survival, toxicity and quality of life using data available in the reports of each trial. Meta-analyses were not performed because of variability in the reporting of the trials.
MAIN RESULTS
We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were:(A) i. LHRH versus tamoxifen (three trials),ii. LHRH versus chemotherapy (four trials);(B) i. LHRH + tamoxifen versus tamoxifen (two trials),ii. LHRH + tamoxifen versus LHRH (three trials),iii. LHRH + tamoxifen versus chemotherapy (two trials),iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial);(C) i. LHRH + chemotherapy versus LHRH (one trial),ii. LHRH + chemotherapy versus chemotherapy (five trials);(D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials).The LHRH agonist in most of these trials was goserelin.For most of the treatment comparisons there are too few trials, too few randomised patients, or too little follow up to draw reliable estimates of the relative effects of different treatments.(A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival.(B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive.(C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone.(D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone.There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen.Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear.
AUTHORS' CONCLUSIONS
Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Ovariectomy; Premenopause; Randomized Controlled Trials as Topic; Survival Analysis; Tamoxifen
PubMed: 19821328
DOI: 10.1002/14651858.CD004562.pub4