Cochrane Database of Systematic Reviews

Preoperative medical therapy before surgery for uterine fibroids

Uterine fibroids occur in up to 40% of women over 35 years of age. Up to 50% of uterine fibroids cause symptoms that warrant treatment: anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and poor quality of life. Surgery is the first choice of treatment, but medical therapies have been used prior to surgery to improve outcomes. Gonadotropin-hormone-releasing analogues (GnRHa) induce a low-oestrogen state that shrinks fibroids, but they have unacceptable side effects if used long-term. Other potential hormonal treatments include progestins and selective progesterone-receptor modulators (SPRMs). This updates a Cochrane review published in 2017. To assess the benefits and risks of medical treatments prior to surgery for uterine fibroids. We searched the Cochrane Gynaecology and Fertility Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL on 8 August 2024. We also searched trials registers (ClinicalTrials.gov; WHO ICTRP), theses and dissertations, and grey literature, as well as handsearching reference lists of retrieved articles and contacting pharmaceutical companies. We included randomised controlled trials of premenopausal women receiving medical therapy before myomectomy, hysterectomy or hysteroscopic resection for uterine fibroids versus placebo, no pretreatment or another medical therapy. We used standard Cochrane methods. We assessed the certainty of the evidence using GRADE. We included 41 RCTs, which involved 3982 women. Thirty-six studies evaluated GnRHa: the comparators were no pretreatment (19 studies), placebo (9 studies), or other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (8 studies). Five studies evaluated SPRMs versus placebo. Most results provided low-certainty evidence due to poor reporting of randomisation procedures, lack of blinding, imprecision and inconsistency. Some outcomes were not measured or did not have usable data. The use of ulipristal acetate (an SPRM) is suspended at this time (March 2025) because of an association with cases of liver failure. GnRHa versus placebo or no pretreatment before surgery for uterine fibroids GnRHa pretreatment may reduce uterine volume (mean difference (MD) -175.34 mL, 95% confidence interval (CI) -219.04 to -131.65; 13 studies, 858 participants; I² = 67%; low-certainty evidence) and fibroid volume (MD range 5.7 mL to 155.4 mL; 5 studies to heterogeneous to pool, 427 participants; low-certainty evidence), and probably increases preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.68 to 1.08; 10 studies, 834 participants; I² = 0%; moderate-certainty evidence). However, there is probably a greater likelihood of adverse events with GnRHa (odds ratio (OR) 2.78, 95% CI 1.77 to 4.36; 5 studies, 755 participants; I² = 28%; moderate-certainty evidence). No usable data were available for preoperative bleeding. Hysterectomy Duration of hysterectomy may be reduced amongst women who receive GnRHa treatment (-10.11 minutes, 95% CI -16.96 to -3.25; 6 studies, 617 participants; I² = 57%; low-certainty evidence). Results are uncertain for intraoperative blood loss (4 heterogeneous studies, 258 participants; MD range 25 mL to 148 mL, in favour of GnRHa; very low-certainty evidence). There are probably fewer blood transfusions with GnRHa (OR 0.54, 95% CI 0.29 to 1.01; 6 studies, 601 participants; I² = 0%; moderate-certainty evidence) and less postoperative morbidity (OR 0.54, 95% CI 0.32 to 0.91; 7 studies, 772 participants; I² = 28%; moderate-certainty evidence). Myomectomy There is uncertainty about the effects of GnRHa pretreatment on surgery duration (7 heterogeneous studies, 443 participants) (very low-certainty evidence) and intraoperative blood loss during myomectomy (11 studies too heterogenous to pool, 549 participants; very low-certainty evidence). GnRHa may make little to no difference to blood transfusions (OR 0.85, 95% CI 0.26 to 2.75; 4 studies, 121 participants; I² = 0%; low-certainty evidence) or postoperative morbidity (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies, 190 participants; low-certainty evidence). Hysteroscopic resection GnRHa treatment before hysteroscopic resection of uterine myomas may result in little to no difference in surgery duration (2 studies,123 participants; low-certainty evidence). One study reported no cases of postoperative morbidity in either group (84 participants; low-certainty evidence). GnRHa versus other medical therapies before surgery - preoperative outcomes GnRHa may be associated with a greater reduction in uterine volume than other medical therapies (-47% compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate, respectively; low-certainty evidence). There may be little to no difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.30 to 1.68; 1 study, 199 participants; low-certainty evidence), and there is probably little to no difference in preoperative haemoglobin (MD -0.02, 95% CI -0.41 to 0.37; 242 participants; moderate-certainty evidence). We are uncertain whether there is any difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.92 to 31.34; 2 studies, 110 participants; I² = 0%; low-certainty evidence). Adverse events such as hot flushes may be more likely with GnRHa (OR 2.83, 95% CI 1.68 to 4.77; 6 studies, 507 participants; I² = 59%; low-certainty evidence). SPRMs versus placebo before surgery - preoperative outcomes SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) before surgery probably reduce uterine volume (2 heterogenous studies, 275 participants; moderate-certainty evidence) and may reduce fibroid volume (5 heterogeneous studies, 451 participants; low-certainty evidence). SPRMs probably increase preoperative haemoglobin (MD 0.93 g/dL, 95% CI 0.52 to 1.34; 2 studies, 173 participants; I² = 0%; moderate-certainty evidence), and they may reduce bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.26 to 112.38; 1 study, 143 participants; asoprisnil: MD -166.9 mL; 95% CI -277.60 to -56.20; 1 study, 22 participants; low-certainty evidence). Results were very imprecise for adverse events (low-certainty evidence). Pretreatment with gonadotropin-hormone-releasing analogues may reduce uterine and fibroid volume and probably increases preoperative haemoglobin levels, but probably also increases the number of adverse events. Blood transfusions and operation time during hysterectomy may be reduced, with fewer women experiencing postoperative morbidity. SPRMs, such as ulipristal acetate, seem to offer similar advantages: they probably reduce uterine volume and increase haemoglobin level before surgery, and may reduce fibroid volume and fibroid-related bleeding. However, replication of these studies is advised as the certainty of the evidence is moderate to low.

Metformin versus the combined oral contraceptive pill for hirsutism, acne, and menstrual pattern in polycystic ovary syndrome

Metformin has been proposed as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome (PCOS). It is important to directly compare the efficacy and safety of metformin versus OCP in the long-term treatment of women with PCOS. This is an update of a Cochrane Review comparing insulin sensitising agents with the OCP and only includes studies on metformin. To assess the effectiveness and safety of metformin versus the OCP (alone or in combination) in improving clinical, hormonal, and metabolic features of PCOS. In August 2019 we searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL, the trial registers, handsearched references of the identified articles, and contacted experts in the field to identify additional studies. We included randomised controlled trials (RCTs) of the use of metformin versus the OCP (alone or in combination) for women with PCOS. We used standard methods recommended by Cochrane. The primary review outcomes were the clinical parameters of hirsutism and adverse events, both severe (requiring stopping of medication), and minor. In the presence of substantial heterogeneity (I This is a substantive update. We identified 38 additional studies. We included 44 RCTs (2253 women), which comprised 39 RCTs on adult women (2047 women) and five RCTs on adolescent women (206 women). Evidence quality ranged from very low to low. The main limitations were risk of bias, imprecision and inconsistency. Metformin versus the OCP In adult women, we are uncertain of the effect of metformin compared to the OCP on hirsutism in subgroup body mass index (BMI) < 25 kg/m In adult women with PCOS, metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m

Health education interventions to promote early presentation and referral for women with symptoms of endometrial cancer

Diagnosis of endometrial (womb) cancer is normally made at an early stage, as most women with the disease experience abnormal vaginal bleeding, which prompts them to seek medical advice. However, delays in presentation and referral can result in delay in diagnosis and management, which can lead to unfavourable treatment outcomes. This is particularly a problem for pre- and peri-menopausal women. Providing educational information to women and healthcare providers regarding symptoms relating to endometrial cancer may raise awareness of the disease and reduce delayed treatment. To assess the effectiveness of health education interventions targeting healthcare providers, or individuals, or both, to promote early presentation and referral for women with endometrial cancer symptoms. We searched CENTRAL, MEDLINE and Embase. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. We planned to include randomised controlled trials (RCTs), both individually randomised and cluster-RCTs. In the absence of RCTs we planned to include well-designed non-randomised studies (NRS) with a parallel comparison assessing the benefits of any type of health education interventions. Two review authors independently evaluated whether potentially relevant studies met the inclusion criteria for the review, but none were found. A comprehensive search of the literature yielded the following results: CENTRAL (1022 references), MEDLINE (2874 references), and Embase (2820 references). After de-duplication, we screened titles and abstracts of 4880 references and excluded 4864 that did not meet the review inclusion criteria. Of the 16 references that potentially met the review inclusion, we excluded all 16 reports after reviewing the full texts. We did not identify any ongoing trials. There is currently an absence of evidence to indicate the effectiveness of health education interventions involving healthcare providers or individuals or both to promote early presentation and referral for women with endometrial cancer symptoms. High-quality RCTs are needed to assess whether health education interventions enhance early presentation and referral. If health education interventions can be shown to reduce treatment delays in endometrial cancer, further studies would be required to determine which interventions are most effective.

Factors that influence caregivers’ and adolescents’ views and practices regarding human papillomavirus (HPV) vaccination for adolescents: a qualitative evidence synthesis

Human papillomavirus (HPV) vaccination in adolescents provides a powerful tool for preventing cervical cancer in women and other HPV-associated diseases in people of all genders. HPV vaccines have been progressively introduced in many countries. However, worldwide, many adolescents do not receive HPV vaccination, for various reasons. The HPV vaccine might be costly or unavailable, healthcare systems might lack capacity for its delivery, or adolescent health might not be prioritised. Some caregivers and adolescents may not accept available HPV vaccines and vaccination services. We currently lack a comprehensive understanding of the factors that influence HPV vaccination views and practices, and why some caregivers and adolescents may be less accepting of the vaccine. Qualitative research can contribute to this understanding and help inform policy and practice, including the development of more relevant, acceptable and effective interventions to promote public acceptance and uptake of HPV vaccination in adolescents. This qualitative evidence synthesis supplements a Cochrane review of the effectiveness of interventions to improve uptake of adolescent vaccination, including HPV vaccination. The objectives of the review are to identify, appraise, and synthesise qualitative studies that explore caregivers' or adolescents' views, experiences, practices, intentions, decision-making, acceptance, hesitancy, or nonacceptance of HPV vaccination; to gain an understanding of the factors that influence caregiver and adolescent views and practices regarding HPV vaccination for adolescents; and to explore how the findings of this review can enhance our understanding of the related Cochrane intervention review. We searched MEDLINE, Embase, CINAHL, PsycInfo, and Scopus for eligible studies (February 2023). We updated this search in October 2024, but these results have not yet been fully incorporated. We included studies that utilised qualitative methods for data collection and analysis; focused on caregivers' or adolescents' views, practices, acceptance, hesitancy, or refusal of HPV vaccination for adolescents aged 9 to 19 years of age; and were from any setting globally where HPV vaccination is provided. We used a prespecified sampling frame to capture a sample of eligible studies that were from a range of geographical and income-level settings, were conceptually rich in relation to the review's phenomenon of interest, and included HPV vaccination for diverse genders. We extracted contextual and methodological data from each sampled study. We used a thematic synthesis approach to analyse the evidence. We assessed methodological limitations using a list of criteria used in previous Cochrane reviews and originally based on the Critical Appraisal Skills Programme quality assessment tool for qualitative studies. We used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each review finding. We integrated the findings of this review with those from the related Cochrane review of intervention effectiveness (by Abdullahi and colleagues), by mapping whether the trial interventions reflected or targeted the factors identified by this review as influencing caregivers' or adolescents' views and practices regarding HPV vaccination. We included 206 studies in the review and sampled 71 of these for our synthesis. Of these, 35 studies were conducted in high-income countries, 26 studies in middle-income countries, 8 studies in low-income countries, and 2 studies in multiple-income settings. Studies came from all six World Health Organization (WHO) regions and included urban and rural settings. We downgraded our confidence in several findings, mainly due to concerns about how the studies were conducted (methodological limitations), concerns about perspectives lacking from some types of participants or in some settings (relevance), or because of variability in the data or insufficient evidence to support all aspects of a review finding (coherence). Many complex factors were found to influence caregivers' and adolescents' HPV vaccination views and practices, which we categorised into eight overarching themes: 1) A lack of biomedical knowledge; 2) Perceptions of a range of interrelated risks and benefits (or lack thereof) associated with HPV vaccination; 3) Routine responses to vaccination generally or more specific views or experiences of other vaccines and vaccination programmes; 4) Complex nuclear familial decision-making dynamics; 5) Extended familial and social relations and networks, particularly extended family members, peers, traditional or religious leaders, and the media; 6) Interrelated socio-cultural beliefs and practices regarding adolescence, sexuality, gender, parenting and health; 7) Trust or distrust in the institutions, systems or experts associated with vaccination, most particularly teachers and the school, the pharmaceutical industry, government, science and biomedicine, and healthcare professionals; and 8) Access to, and experiences of, HPV vaccination programmes and delivery services, such as the convenience (or lack thereof) of HPV vaccination services, the cost of the vaccine, language barriers, the feminisation of HPV vaccination programmes and procedural aspects of school-based vaccination delivery. We did not identify any major differences in the occurrence of these overarching themes between subgroups. However, for various subthemes certain differences emerged in relation to place, gender and socio-economic status, and between caregivers and adolescents. The interventions tested in the related Cochrane review of intervention effectiveness most commonly targeted caregivers' and adolescents' lack of biomedical knowledge and their perceptions of the risks and benefits of HPV vaccination, with the other influencing factors identified by our review being underrepresented. Our review reveals that caregivers' and adolescents' HPV vaccination views and practices are not only influenced by issues related to individual knowledge and perceptions of the vaccine, but also an array of more complex, contextual factors and meanings: social, political, economic, structural, and moral. Successful development of interventions to promote the acceptance and uptake of HPV vaccination for adolescents requires an understanding of the context-specific factors that influence HPV vaccination views and practices in the target setting. Through this, more tailored and in turn more relevant, acceptable, and effective responses could be developed. The eight overarching themes that emerged from our review could serve as a basis for gaining this understanding.

Surgery and minimally invasive treatments for uterine fibroids

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of surgery and minimally invasive treatments for uterine fibroids.

Evaluation of follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment

This is an update of a previous Cochrane Review, last updated in 2014. Ovarian cancer is the eighth most common cancer and seventh most common cause of death due to cancer in women worldwide. Traditionally, most women who have been treated for cancer undergo long-term follow-up in secondary care. However, it has been suggested that the use of routine review may not be effective in improving survival, or health-related quality of life (HRQOL), or relieving anxiety. In addition, traditional follow-up may not be cost-effective. To compare the potential effects of different strategies of follow-up in women with epithelial ovarian cancer, following completion of primary treatment. For this update, we searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL 2022, Issue 11, MEDLINE, and Embase from August 2013 to November 2022. We also searched review articles and contacted experts in the field. All randomised controlled trials (RCTs) that evaluated follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment. We followed standard Cochrane methodology. Two review authors independently selected potentially relevant trials, extracted data, and assessed risk of bias. They compared results, and resolved disagreements by discussion. We assessed the certainty of evidence, using the GRADE approach, for the outcomes of interest: overall survival (OS), health-related quality of life (HRQOL), psychological effects, and cost analysis. For this update, we included one new RCT, including 112 women with ovarian, fallopian tube, or peritoneal cancer, who had completed primary treatment by surgery, with or without chemotherapy. This study reported the effect of individualised, i.e. individually tailored, nurse-led follow-up versus conventional medical follow-up on HRQOL, psychological outcomes, and cost-analysis. Individualised follow-up improved HRQOL in one of the two scales, with a decrease in mean difference (MD) in the QLQ-C30 discomfort scale following 12 months of individualised treatment compared to 12 months of conventional treatment (MD -5.76 points, 95% confidence interval (CI) -10.92 to -0.60; 1 study, 112 participants; low-certainty evidence; minimal important difference 4 to 10 points). There may be little or no difference in the other HRQOL scale (QLQ-Ov28, MD -0.97 points, 95% CI -2.57 to 0.63; 1 study, 112 participants: low-certainty evidence); psychological outcome, measured with the hospital anxiety and depression scale (HADS; MD 0.10 point, 95% CI -0.81 to 1.02; 1 study, 112 participants: low-certainty evidence), or cost analysis (MD -GBP 695.00, 95% CI -1467.23 to 77.23; 1 study, 112 participants: moderate-certainty evidence). Our previous review included one RCT, with 529 women in a confirmed remission, with normal CA125 concentration and no radiological evidence of disease, after surgery and first-line chemotherapy for ovarian cancer. This study evaluated immediate treatment of ovarian cancer relapse following a rise of serum CA125 levels versus delaying treatment until symptoms developed for OS, and HRQOL. There was little or no difference in OS between the immediate and delayed arms after a median follow-up of 56.9 months (unadjusted hazard ratio (HR) 0.98, 95% CI 0.80 to 1.20; 1 study, 529 participants; moderate-certainty evidence). Time from randomisation to first deterioration in global health score or death was shorter in the immediate treatment group than in the delayed treatment group (HR 0.71, 95% CI 0.58 to 0.88). Limited evidence from one trial suggests that routine surveillance with CA125 in asymptomatic women and treatment at CA125-defined relapse does not seem to offer survival advantage when compared to treatment at symptomatic relapse. However, this study pre-dates the use of PARPi maintenance treatment and the increased use of secondary cytoreductive surgery, so the results may be limited in their applicability to current practice. Limited evidence from one trial suggests that individualised nurse-led follow-up may improve HRQOL in women with ovarian cancer following completion of primary treatment. Large RCTs are needed to compare different types of follow-up, looking at survival, HRQOL, psychological effects, and cost as outcomes.

Interventions targeted at women to encourage the uptake of cervical screening

This is an update of the Cochrane review published in Issue 5, 2011. Worldwide, cervical cancer is the fourth commonest cancer affecting women. High-risk human papillomavirus (HPV) infection is causative in 99.7% of cases. Other risk factors include smoking, multiple sexual partners, the presence of other sexually transmitted diseases and immunosuppression. Primary prevention strategies for cervical cancer focus on reducing HPV infection via vaccination and data suggest that this has the potential to prevent nearly 90% of cases in those vaccinated prior to HPV exposure. However, not all countries can afford vaccination programmes and, worryingly, uptake in many countries has been extremely poor. Secondary prevention, through screening programmes, will remain critical to reducing cervical cancer, especially in unvaccinated women or those vaccinated later in adolescence. This includes screening for the detection of pre-cancerous cells, as well as high-risk HPV. In the UK, since the introduction of the Cervical Screening Programme in 1988, the associated mortality rate from cervical cancer has fallen. However, worldwide, there is great variation between countries in both coverage and uptake of screening. In some countries, national screening programmes are available whereas in others, screening is provided on an opportunistic basis. Additionally, there are differences within countries in uptake dependent on ethnic origin, age, education and socioeconomic status. Thus, understanding and incorporating these factors in screening programmes can increase the uptake of screening. This, together with vaccination, can lead to cervical cancer becoming a rare disease. To assess the effectiveness of interventions aimed at women, to increase the uptake, including informed uptake, of cervical screening. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 6, 2020. MEDLINE, Embase and LILACS databases up to June 2020. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Randomised controlled trials (RCTs) of interventions to increase uptake/informed uptake of cervical screening. Two review authors independently extracted data and assessed risk of bias. Where possible, the data were synthesised in a meta-analysis using standard Cochrane methodology. Comprehensive literature searches identified 2597 records; of these, 70 met our inclusion criteria, of which 69 trials (257,899 participants) were entered into a meta-analysis. The studies assessed the effectiveness of invitational and educational interventions, lay health worker involvement, counselling and risk factor assessment. Clinical and statistical heterogeneity between trials limited statistical pooling of data. Overall, there was moderate-certainty evidence to suggest that invitations appear to be an effective method of increasing uptake compared to control (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.49 to 1.96; 141,391 participants; 24 studies). Additional analyses, ranging from low to moderate-certainty evidence, suggested that invitations that were personalised, i.e. personal invitation, GP invitation letter or letter with a fixed appointment, appeared to be more successful. More specifically, there was very low-certainty evidence to support the use of GP invitation letters as compared to other authority sources' invitation letters within two RCTs, one RCT assessing 86 participants (RR 1.69 95% CI 0.75 to 3.82) and another, showing a modest benefit, included over 4000 participants (RR 1.13, 95 % CI 1.05 to 1.21). Low-certainty evidence favoured personalised invitations (telephone call, face-to-face or targeted letters) as compared to standard invitation letters (RR 1.32, 95 % CI 1.11 to 1.21; 27,663 participants; 5 studies). There was moderate-certainty evidence to support a letter with a fixed appointment to attend, as compared to a letter with an open invitation to make an appointment (RR 1.61, 95 % CI 1.48 to 1.75; 5742 participants; 5 studies). Low-certainty evidence supported the use of educational materials (RR 1.35, 95% CI 1.18 to 1.54; 63,415 participants; 13 studies) and lay health worker involvement (RR 2.30, 95% CI 1.44 to 3.65; 4330 participants; 11 studies). Other less widely reported interventions included counselling, risk factor assessment, access to a health promotion nurse, photo comic book, intensive recruitment and message framing. It was difficult to deduce any meaningful conclusions from these interventions due to sparse data and low-certainty evidence. However, having access to a health promotion nurse and attempts at intensive recruitment may have increased uptake. One trial reported an economic outcome and randomised 3124 participants within a national screening programme to either receive the standard screening invitation, which would incur a fee, or an invitation offering screening free of charge. No difference in the uptake at 90 days was found (574/1562 intervention versus 612/1562 control, (RR 0.94, 95% CI: 0.86 to 1.03). The use of HPV self-testing as an alternative to conventional screening may also be effective at increasing uptake and this will be covered in a subsequent review. Secondary outcomes, including cost data, were incompletely documented. The majority of cluster-RCTs did not account for clustering or adequately report the number of clusters in the trial in order to estimate the design effect, so we did not selectively adjust the trials. It is unlikely that reporting of these trials would impact the overall conclusions and robustness of the results. Of the meta-analyses that could be performed, there was considerable statistical heterogeneity, and this should be borne in mind when interpreting these findings. Given this and the low to moderate evidence, further research may change these findings. The risk of bias in the majority of trials was unclear, and a number of trials suffered from methodological problems and inadequate reporting. We downgraded the certainty of evidence because of an unclear or high risk of bias with regards to allocation concealment, blinding, incomplete outcome data and other biases. There is moderate-certainty evidence to support the use of invitation letters to increase the uptake of cervical screening. Low-certainty evidence showed lay health worker involvement amongst ethnic minority populations may increase screening coverage, and there was also support for educational interventions, but it is unclear what format is most effective. The majority of the studies were from developed countries and so the relevance of low- and middle-income countries (LMICs), is unclear. Overall, the low-certainty evidence that was identified makes it difficult to infer as to which interventions were best, with exception of invitational interventions, where there appeared to be more reliable evidence.

Ultra-radical (extensive) surgery versus standard surgery for the primary cytoreduction of advanced epithelial ovarian cancer

Ovarian cancer is the seventh most common cancer among women and the leading cause of death in women with gynaecological malignancies. Opinions differ regarding the role of ultra-radical (extensive) cytoreductive surgery in ovarian cancer treatment. To evaluate the effectiveness and morbidity associated with ultra-radical/extensive surgery in the management of advanced-stage epithelial ovarian cancer. We searched CENTRAL (2021, Issue 11), MEDLINE Ovid and Embase Ovid up to November 2021. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. Randomised controlled trials (RCTs) or non-randomised studies (NRS), analysed using multivariate methods, that compared ultra-radical/extensive and standard surgery in women with advanced primary epithelial ovarian cancer. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria, abstracted data and assessed the risk of bias. We identified three NRS and conducted meta-analyses where possible. We identified three retrospective observational studies for inclusion in the review. Two studies included women exclusively undergoing upfront primary debulking surgery (PDS) and the other study including both PDS and interval debulking surgical (IDS) procedures. All studies were at critical risk of bias due to retrospective and non-randomised study designs. Meta-analysis of two studies, assessing 397 participants, found that women who underwent radical procedures, as part of PDS, may have a lower risk of mortality compared to women who underwent standard surgery (adjusted HR 0.60, 95% CI 0.43 to 0.82; I We found only very low-certainty evidence comparing ultra-radical surgery and standard surgery in women with advanced ovarian cancer. The evidence was limited to retrospective, NRSs and so is at critical risk of bias. The results may suggest that ultra-radical surgery could result in improved OS, but results are based on very few women who were chosen to undergo each intervention, rather than a randomised study and intention-to-treat analysis, and so the evidence is very uncertain. Results for progression/DFS were inconsistent and evidence was sparse. QoL and morbidity was incompletely or not reported in the three included studies. A separate prognostic review assessing residual disease as a prognostic factor in this area has been addressed elsewhere, which demonstrates the prognostic effect of macroscopic debulking to no macroscopic residual disease. In order to aid existing guidelines, the role of ultra-radical surgery in the management of advanced-stage ovarian cancer could be addressed through the conduct of a sufficiently powered, RCT comparing ultra-radical and standard surgery, or well-designed NRSs, if this is not possible.

Hormone replacement therapy after surgery for epithelial ovarian cancer

Women who have undergone surgical treatment for epithelial ovarian cancer (EOC) may develop menopausal symptoms due to immediate loss of ovarian function following surgery and chemotherapy. Women may experience vasomotor symptoms, sleep disturbance, difficulty concentrating, sexual dysfunction, vaginal symptoms and accelerated osteoporosis. Although hormone replacement therapy (HRT) is the most effective treatment to relieve these symptoms, its safety has been questioned for women with EOC. To assess the safety and efficacy of HRT for menopausal symptoms in women surgically treated for EOC. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 6), MEDLINE via Ovid (1946 to 12 June 2019) and Embase via Ovid (1980 to 2019, week 23). We also handsearched conference reports and trial registries. There was no language restriction. We included randomized controlled trials (RCTs) with participants of any age and menopausal status who had undergone surgery for EOC and, after diagnosis and treatment, used any regimen and duration of HRT compared with placebo or no hormone therapy. We also included trials comparing different regimens or duration of administration of HRT. Two review authors independently identified studies that met the inclusion criteria. They used Covidence to extract study characteristics, outcome data and to assess methodological quality of the included studies. Our search strategy identified 2617 titles, of which 2614 titles were excluded. Three studies, involving 350 women, met our inclusion criteria. Two of the studies included pre and postmenopausal women, and the third only included premenopausal women. The overall age range of those women included in the studies was 20 to 89.6 years old, with a median follow-up ranging from 31.4 months to 19.1 years. The geographical distribution of participants included Europe, South Africa and China. All stages and histological subtypes were included in two of the studies, but stage IV disease had been excluded in the third. The three included studies used a variety of HRT regimens (conjugated oestrogen with or without medroxyprogesterone and with or without nylestriol) and HRT administrations (oral, patch and implant), In all studies, the comparisons were made versus women who had not received HRT. The studies were at low or unclear risk of selection and reporting bias, and at high risk of performance, detection and attrition bias. The certainty of the evidence was low for overall survival and progression-free survival, and very low for quality-of-life assessment, incidence of breast cancer, transient ischaemic attack (TIA), cerebrovascular accident (CVA) and myocardial infarction (MI). Meta-analysis of these studies showed that HRT may improve overall survival (hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.54 to 0.93; 350 participants, 3 studies; low-certainty evidence). Quality-of-life assessment by use of the EORTC-C30 questionnaire was performed only in one study. We are uncertain whether HRT improves or reduces quality of life as the certainty of the evidence was assessed as very low (mean difference (MD) 13.67 points higher, 95% CI 9.26 higher to 18.08 higher; 1 study; 75 participants; very low-certainty evidence). Likewise, HRT may make little or no difference to progression-free survival (HR 0.76, 95% CI 0.57 to 1.01; 275 participants, 2 studies; low-certainty evidence). We are uncertain whether HRT improves or reduces the incidence of breast cancer (risk ratio (RR) 2.00, 95% CI 0.19 to 21.59; 225 participants, 2 studies; very low-certainty evidence); TIA (RR 5.00, 95% CI 0.24 to 102.42; 150 participants, 1 study; very low-certainty evidence); CVA (RR 0.67, 95% CI 0.11 to 3.88; 150 participants, 1 study; very low-certainty evidence); and MI (RR 0.20, 95% CI 0.01 to 4.10; 150 participants, 1 study; very low-certainty evidence). The incidence of gallstones was not reported in the included studies. Hormone replacement therapy may slightly improve overall survival in women who have undergone surgical treatment for EOC, but the certainty of the evidence is low. HRT may make little or no difference to quality of life, incidence of breast cancer, TIA, CVA and MI as the certainty of the evidence has been assessed as very low. There may be little or no effect of HRT use on progression-free survival. The evidence in this review is limited by imprecision and incompleteness of reported relevant outcomes and therefore the results should be interpreted with caution. Future well-designed RCTs are required as this is an important area to women experiencing menopausal symptoms following surgical treatment for ovarian cancer, especially as doctors are often reluctant to prescribe HRT in this scenario. The evidence in this review is too limited to support or refute that HRT is very harmful in this population.

Exercise interventions for the treatment of lower limb lymphoedema after treatment for gynaecological cancers

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of load exercise therapy with complex decongestive therapy compared with complex decongestive therapy alone for lower limb lymphoedema after gynaecological cancer treatment.

Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced ovarian epithelial cancer

Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). We searched the following databases up to 9 October 2020: the Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. Two review authors independently extracted data and assessed risk of bias in each included trial. We extracted data of overall (OS) and progression-free survival (PFS), adverse events, surgically-related mortality and morbidity and quality of life outcomes.  We used GRADE methods to determine the certainty of evidence. We identified 2227 titles and abstracts through our searches, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1774 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the four studies where data were available and found little or no difference with regard to overall survival (OS) (Hazard Ratio (HR) 0.96, 95% CI 0.86 to 1.08; participants = 1692; studies = 4; high-certainty evidence) or progression-free survival in four trials where we were able to pool data (Hazard Ratio 0.98, 95% CI 0.88 to 1.08; participants = 1692; studies = 4; moderate-certainty evidence). Adverse events, surgical morbidity and quality of life (QoL) outcomes were variably and incompletely reported across studies. There are probably clinically meaningful differences in favour of NACT compared to PDS with regard to overall postoperative serious adverse effects (SAE grade 3+): 6% in NACT group, versus 29% in PDS group, (risk ratio (RR) 0.22, 95% CI 0.13 to 0.38; participants = 435; studies = 2; heterogeneity index (I The available high to moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT probably reduces the risk of serious adverse events, especially those around the time of surgery, and reduces the risk of postoperative mortality and the need for stoma formation. These data will inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer

Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)). We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information. Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. Two review authors independently extracted data and assessed risk of bias in each included trial. We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; Hazard Ratio (HR) 0.95, 95% CI 0.84 to 1.07; I The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Government regulation of private health insurance

The strain on public resources to meet the healthcare needs of populations through publicly-provided health insurance programmes is increasing and many governments turn to private health insurance (PHI) to ease the pressure on government budgets. With the goal of improving access to basic health care for citizens through PHI programmes, several high-income countries have developed strong regulations for PHI schemes. Low- and middle-income countries have the opportunity to learn from this experience to optimise PHI. If poorly regulated, PHI can hardly achieve an adequate quantity or quality of population coverage, as can be seen in the USA where a third of adults younger than 65 years of age have no insurance, sporadic coverage or coverage that exposes them to high out-of-pocket healthcare costs. To assess the effects of policies that regulate private health insurance on utilisation, quality, and cost of health care provided. In November 2019 we searched CENTRAL; MEDLINE; Embase; Sociological Abstracts and Social Services Abstracts; ICTRP; ClinicalTrials.gov; and Web of Science Core Collection for papers that have cited the included studies. This complemented the search conducted in February 2017 in IBSS; EconLit; and Global Health. We also searched selected grey literature databases and web-sites.  SELECTION CRITERIA: Randomised trials, non-randomised trials, interrupted time series (ITS) studies, and controlled before-after (CBA) studies conducted in any population or setting that assessed one or more of the following interventions that governments use to regulate private health insurance: legislation and licensing, monitoring, auditing, and intelligence. Two review authors independently assessed study eligibility, extracted data, and assessed risk of bias and certainty of the evidence resolving discrepancies by consensus. We planned to summarise the results (using random-effects or fixed-effect meta-analysis) to produce an overall summary if an average intervention effect across studies was considered meaningful, and we would have discussed the implications of any differences in intervention effects across studies. However, due to the nature of the data obtained, we have provided a narrative synthesis of the findings. We included seven CBA studies, conducted in the USA, and that directly assessed state laws on cancer screening. Only for-profit PHI schemes were addressed in the included studies and no study addressed other types of PHI (community and not for-profit). The seven studies were assessed as having 'unclear risk' of bias. All seven studies reported on utilisation of healthcare services, and one study reported on costs. None of the included studies reported on quality of health care and patient health outcomes. We assessed the certainty of evidence for patient health outcomes, and utilisation and costs of healthcare services as very low. Therefore, we are uncertain of the effects of government mandates on for-profit PHI schemes. Our review suggests that, from currently available evidence, it is uncertain whether policies that regulate private health insurance have an effect on utilisation of healthcare services, costs, quality of care, or patient health outcomes. The findings come from studies conducted in the USA and might therefore not be applicable to other countries; since the regulatory environment could be different. Studies are required in countries at different income levels because the effects of government regulation of PHI are likely to differ across these income and health system settings. Further studies should assess the different types of regulation (including regulation and licensing, monitoring, auditing, and intelligence). While regulatory research on PHI remains relatively scanty, future research can draw on the rich body of research on the regulation of other health financing interventions such as user fees and results-based provider payments.

Postoperative interventions for preventing bladder dysfunction after radical hysterectomy in women with early-stage cervical cancer

Bladder dysfunction is a common complication following radical hysterectomy, caused by the damage to pelvic autonomic nerves that innervate the muscles of the bladder, urethral sphincter, and pelvic floor fasciae. Bladder dysfunction increases the rates of urinary tract infection, hospital visits or admission, and patient dissatisfaction. In addition, bladder dysfunction can also negatively impact patient quality of life (QoL). Several postoperative interventions have been proposed to prevent bladder dysfunction following radical hysterectomy. To our knowledge, there has been no systematic review evaluating the effectiveness and safety of these interventions for preventing bladder dysfunction following radical hysterectomy in women with cervical cancer. To evaluate the effectiveness and safety of postoperative interventions for preventing bladder dysfunction following radical hysterectomy in women with early-stage cervical cancer (stage IA2 to IIA2). We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) in the Cochrane Library, MEDLINE via Ovid (1946 to April week 2, 2020), and Embase via Ovid (1980 to 2020, week 16). We also checked registers of clinical trials, grey literature, conference reports, and citation lists of included studies. We included randomised controlled trials (RCTs) evaluating the effectiveness and safety of any type of postoperative interventions for preventing bladder dysfunction following a radical hysterectomy in women with stage IA2 to IIA2 cervical cancer. Two review authors independently selected potentially relevant RCTs, extracted data, assessed risk of bias, compared results, and made judgments on the quality and certainty of the evidence. We resolved any disagreements through discussion or consultation with a third review author. Outcomes of interest consisted of spontaneous voiding recovery one week after the operation, quality of life (QoL), adverse events, post-void residual urine volume one month after the operation, urinary tract infection over the one month following the operation, and subjective urinary symptoms. We identified 1464 records as a result of the search (excluding duplicates). Of the 20 records that potentially met the review criteria, we included five reports of four studies. Most of the studies had unclear risks of selection and reporting biases. Of the four studies, one compared bethanechol versus placebo and three studies compared suprapubic catheterisation with intermittent self-catheterisation. We identified two ongoing studies. Bethanechol versus placebo The study reported no information on the rate of spontaneous voiding recovery at one week following the operation, QoL, adverse events, urinary tract infection in the first month after surgery, and subjective urinary symptoms for this comparison. The volume of post-void residual urine, assessed at one month after surgery, among women receiving bethanechol was lower than those in the placebo group (mean difference (MD) -37.4 mL, 95% confidence interval (CI) -60.35 to -14.45; one study, 39 participants; very-low certainty evidence). Suprapubic catheterisation versus intermittent self-catheterisation The studies reported no information on the rate of spontaneous voiding recovery at one week and post-void residual urine volume at one month following the operation for this comparison. There was no difference in risks of acute complication (risk ratio (RR) 0.77, 95% CI 0.24 to 2.49; one study, 71 participants; very low certainty evidence) and urinary tract infections during the first month after surgery (RR 0.77, 95% CI 0.53 to 1.13; two studies, 95 participants; very- low certainty evidence) between participants who underwent suprapubic catheterisation and those who underwent intermittent self-catheterisation. Available data were insufficient to calculate the relative measures of the effect of interventions on QoL and subjective urinary symptoms. None of the included studies reported rate of spontaneous voiding recovery one week after surgery, time to a post-void residual volume of urine of 50 mL or less, or post-void residual urine volume at 6 and 12 months after surgery, all of which are important outcomes for assessing postoperative bladder dysfunction. Limited evidence suggested that bethanechol may minimise the risk of bladder dysfunction after radical hysterectomy by lowering post-void residual urine volume. The certainty of this evidence, however, was very low. The effectiveness of different types of postoperative urinary catheterisation (suprapubic and intermittent self-catheterisation) remain unproven.

Debulking hysterectomy followed by chemoradiotherapy versus chemoradiotherapy for FIGO stage (2019) IB3/II cervical cancer

With an estimated 570,000 new cases reported globally in 2018, and increasing numbers of new cases in countries without established human papillomavirus (HPV) vaccination programmes, cervical cancer is the third most common cancer in women worldwide. The majority of global disease burden (around 85%) is in low-and middle-income countries (LMICs), with estimates of cervical cancer being the second most common cancer in women in such regions. As it commonly affects younger women, cervical cancer has the greatest impact on years of life lost (YLL) and adverse socioeconomic outcomes compared to all other cancers in women. Management of cervical cancer depends on tumour stage. Radical hysterectomy with lymphadenectomy is the standard primary treatment modality for International Federation of Gynecology and Obstetrics (FIGO) stage (2019) 1B1 to 1B3 disease. However, for larger primary tumours, radical hysterectomy is less commonly recommended. This is mainly due to a high incidence of unfavourable histopathological parameters, which require adjuvant concurrent chemoradiotherapy (CCRT) (chemotherapy given with radiotherapy treatment). CCRT is the standard of care and is widely used as first-line treatment for cervical cancer considered to be not curable with surgery alone (i.e.those with locally advanced disease). However, a sizable cohort of women managed with primary CCRT will have residual disease within the cervix following treatment. Debulking' hysterectomy to remove (debulk) the primary tumour in locally advanced disease, prior to CCRT, may be an alternative management strategy, avoiding the potential need for surgery for residual cervical disease following CCRT, which may be more extensive, or have increased morbidity due to CCRT. However, this strategy may subject more women to unnecessary surgery and its inherent risks. To assess the efficacy and harms of debulking hysterectomy (simple or radical) followed by chemoradiotherapy (CCRT) versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer. We systematically searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 4), MEDLINE via Ovid (1946 to 12 April 2021) and Embase via Ovid (1980 to 12 April 2021). We also searched other registers of clinical trials, abstracts of scientific meetings and reference lists up to 12 April 2021. We searched for randomised controlled trials (RCTs), quasi-RCTs or non-randomised studies (NRSs) comparing debulking hysterectomy followed by CCRT versus CCRT alone for locally advanced FIGO (2019) stage IB3/II cervical malignancy. We applied Cochrane methodology, with two review authors independently assessing whether potentially relevant studies met the inclusion criteria. We planned to apply standard Cochrane methodological procedures to analyse data and risk of bias. We did not find any evidence for or against debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer. We did not identify any studies assessing the validity of debulking hysterectomy for these women.  AUTHORS' CONCLUSIONS: There was no evidence for or against debulking hysterectomy followed by CCRT versus CCRT alone for FIGO (2019) stage IB3/II cervical cancer.

Effects of human papillomavirus (HPV) vaccination programmes on community rates of HPV-related disease and harms from vaccination

Human papillomavirus (HPV) vaccination has the potential to enhance prevention of cervical cancer, especially in countries where screening programmes are currently unaffordable or impractical. Rare adverse events and longer-term benefits of HPV vaccination, such as effects on cancer rates, are difficult to examine in randomised controlled trials (RCTs) and require large data from population-level studies to inform decision-making. We aimed to assess population-level effects of HPV vaccination programmes on HPV-related disease and harms from vaccination. We conducted electronic searches on 11 September 2024 in CENTRAL (Cochrane Library), Ovid MEDLINE and Ovid Embase. We also searched vaccine manufacturer websites and checked reference lists from an index of HPV studies and other relevant systematic reviews. We included studies that assessed the impact of HPV vaccination on the general population. This included population-level studies comparing outcomes before and after the introduction of HPV vaccine. We also included individual-level, non-randomised comparative studies, such as cohort studies, case-control studies, cross-sectional studies and self-controlled case series. We used methods recommended by Cochrane. Two review authors carried out data extraction independently using pretested data extraction forms. We assessed the risk of bias of all included effect estimates using different tools according to study design. We carried out quantitative and qualitative data synthesis separately by outcome and study design. We performed meta-analysis on studies that reported effect estimates adjusted for confounding, with a focus on those receiving HPV vaccination at or before the age of 16 years (the target age group for vaccination). We rated the certainty of the evidence with GRADE. We included 225 studies from 347 records in this review, evaluating over 132 million people. We included 86 cohort studies, four case-control studies, 46 cross-sectional studies, 69 pre-post vaccine introduction studies, five RCT extensions and two self-controlled case series. Thirteen additional studies reported on more than one type of analysis. Of the included studies, 177 reported only on females, 11 only males and 37 a combination of males and females. Risk of bias ranged from overall moderate risk to critical risk. Clinical outcomes There was moderate-certainty evidence from 20 studies that HPV vaccination reduces the incidence of cervical cancer. Five cohort studies including 4,390,243 females reported adjusted estimates showing a reduced risk of cervical cancer following HPV vaccination in the long term (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.25 to 0.56; I There are now long-term outcome data from different countries and from different study designs that consistently report a reduction in the development of high-grade CIN and cervical cancer in females vaccinated against HPV in early adolescence. Data show that there is greater benefit to vaccinating younger adolescents prior to becoming sexually active. There is evidence that HPV vaccination does not increase the risk of the most common adverse events reported on social media.

Hormone therapy in postmenopausal women and risk of endometrial hyperplasia or endometrial cancer

Reduced circulating estrogen levels around the time of menopause can induce symptoms that affect health and well-being. Estrogen therapy is the most effective treatment, but may be associated with some adverse health outcomes, including endometrial pathology. This is an update of a review first published in 1999 and last updated in 2012. • To assess the effects of hormone therapy regimens for protecting postmenopausal women against endometrial hyperplasia and endometrial cancer. • To define the lowest effective dose(s) of progestogen used in combination with estrogen therapy for protecting the endometrium. We searched for trials in the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL (containing output from two trial registers and CINAHL), MEDLINE, Embase, and PsycINFO to 22 July 2024. We also checked references and contacted study authors to identify additional studies. Interventions of interest were unopposed estrogen, continuous combined estrogen and progestogen, and sequential combined estrogen and progestogen, administered for at least one year. These interventions could be compared head to head or with placebo. Trials had to report rates of endometrial hyperplasia or endometrial cancer (histologic diagnosis). Our critical outcomes were endometrial hyperplasia and endometrial cancer at one year and after one year. Our important outcomes were adherence to therapy, requirement for additional interventions, and withdrawal due to adverse events. We used the original Cochrane risk of bias tool (RoB 1). Where meta-analysis was possible, we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for each outcome. This update included 72 studies (involving 40,652 women) conducted worldwide. There were 42 multicenter trials. There were too few studies with events to draw conclusions about endometrial cancer. The results for endometrial hyperplasia are presented below. Unopposed estrogen versus placebo Unopposed estrogen probably increases the risk of endometrial hyperplasia at one year compared with placebo (22-43 events/1000 women versus 5 events/1000 women; OR 5.86, 95% CI 4.09 to 8.40; I² = 0%; 6 RCTs, 2493 women; moderate-certainty-evidence). Unopposed estrogen probably increases the risk of endometrial hyperplasia after one year (40-68 events/1000 women versus 6 events/1000 women; OR 8.97, 95% CI 6.78 to 11.87; I² = 49%; 9 RCTs, 2539 women; moderate-certainty-evidence). Continuous combined estrogen plus progestogen versus placebo Continuous combined therapy may have little to no effect on the risk of endometrial hyperplasia at one year compared with placebo (0-16 events/1000 women versus 5 events/1000 women; OR 0.51, 95% CI 0.08 to 3.38; I² = 48%; 4 RCTs, 3893 women; low-certainty-evidence). We are unsure about the effect of continuous combined therapy after one year (OR 0.25, 95% CI 0.04 to 1.40; I² = 47%; 4 RCTs, 789 women; very low-certainty evidence). Sequential combined estrogen plus progestogen versus placebo Sequential combined therapy may increase the risk of endometrial hyperplasia at one year compared with placebo (6-27 events/1000 women versus 2 events/1000 women; OR 5.53, 95% CI 2.60 to 11.76; I² = 0%; 4 RCTs, 1030 women; low-certainty-evidence). Sequential combined therapy may result in little to no difference in the risk of endometrial hyperplasia after one year (16-97 events/1000 women versus 20 events/1000 women; OR 2.30, 95% CI 0.76 to 6.99; I² = 0%; 3 RCTs, 534 women; low-certainty-evidence). Unopposed estrogen versus continuous combined estrogen plus progestogen Unopposed estrogen probably increases the risk of endometrial hyperplasia at one year compared with continuous combined therapy (46-75 events/1000 women versus 3 events /1000 women; OR 21.90, 95% CI 16.76 to 28.62; I² = 53%; 11 RCTs, 7856 women; moderate-certainty-evidence). Unopposed estrogen probably increases the risk of endometrial hyperplasia after one year compared with continuous combined therapy (33-73 events/1000 women versus 3 events/1000 women; OR 16.78, 95% CI 11.01 to 25.55; I² = 69%; 3 RCTs, 1191 women; moderate-certainty-evidence). Unopposed estrogen versus sequential combined estrogen plus progestogen Unopposed estrogen may increase the risk of endometrial hyperplasia at one year compared with sequential combined therapy (156-301 events/1000 women versus 16 events/1000 women; OR 17.19, 95% CI 11.27 to 26.22; I² = 70%; 5 RCTs, 2354 women; low-certainty-evidence). Unopposed estrogen may increase the risk of endometrial hyperplasia after one year compared with sequential combined treatment (379-612 events/1000 women versus 49 events/1000 women; OR 19.21, 95% CI 11.95 to 30.90; I² = 15%; 2 RCTs, 417 women; low-certainty-evidence). Continuous combined estrogen plus progestogen versus sequential combined estrogen plus progestogen All analyses had insufficient events to draw conclusions. Continuous combined estrogen plus progestogen - dose comparisons We are unsure about the effect of moderate-dose estrogen plus low-dose progestogen compared with moderate-dose estrogen plus moderate-dose progestogen on the risk of endometrial hyperplasia at one year (OR 1.18, 95% CI 0.24 to 5.84; I² = 36%; 2 RCTs, 2363 women; very low-certainty-evidence). The remaining dose comparisons had insufficient events to draw conclusions. Sequential combined estrogen plus progestogen - dose comparisons Moderate-dose estrogen plus low-dose progestogen may result in little to no difference in the risk of endometrial hyperplasia at one year compared with moderate-dose estrogen plus moderate-dose progestogen (3-32 events/1000 women versus 6 events/1000 women; OR 1.66, 95% CI 0.49 to 5.65; I² = 0%; 4 RCTs, 1072 women; low-certainty-evidence). The remaining dose comparisons had insufficient events to draw conclusions. Unopposed estrogen probably increases the risk of endometrial hyperplasia versus placebo and continuous combined therapy at one year and later. Sequential combined therapy may increase the risk of endometrial hyperplasia at one year versus placebo. The evidence is less certain for continuous versus sequential combined regimens and dose comparisons of continuous and sequential combined regimens. The trials had few events, and long-term follow-up was challenging. For endometrial cancer, events were rare and trials were underpowered to draw meaningful conclusions. This review had no dedicated funding. Original review (1999) DOI: 10.1002/14651858.CD000402 Review update (2004) DOI: 10.1002/14651858.CD000402.pub2 Review update (2009) DOI: 10.1002/14651858.CD000402.pub3 Review update (2012) DOI: 10.1002/14651858.CD000402.pub4.

Neoadjuvant chemotherapy before surgery versus surgery followed by chemotherapy for initial treatment in advanced epithelial ovarian cancer

Epithelial ovarian cancer (EOC) presents at an advanced stage in the majority of women. These women require a combination of surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery. To assess the advantages and disadvantages of treating women with advanced EOC with chemotherapy before cytoreductive surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows cytoreductive surgery (primary cytoreductive surgery (PCRS)). We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 21 March 2024. We also checked the reference lists of relevant papers for further studies. We contacted the principal investigators of relevant trials for further information. Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery. We extracted data on overall (OS) and progression-free survival (PFS), adverse events, surgically related mortality and morbidity, and quality of life outcomes. We used the Cochrane RoB 1 tool to assess risk of bias in RCTs. We conducted meta-analyses using random-effects models (due to heterogeneity between studies) to calculate hazard ratios (HR), risk ratios (RR), mean differences (MD), and 95% confidence intervals (CI) for all outcomes. We assessed the certainty of evidence according to the GRADE approach. We identified a further 1022 titles and abstracts through our searches in this update (958 unique records after further de-duplication), adding to the 2227 titles and abstracts identified in previous versions of this review. A total of five RCTs of varying quality and size met the inclusion criteria. We identified no new completed studies in this update, but we did include additional data from existing studies. The studies assessed a total of 1774 women with stage III/IV ovarian cancer randomised to NACT followed by interval cytoreductive surgery (ICRS) or PCRS followed by chemotherapy. We included data from four studies in the meta-analyses (1692 participants). Survival We found little or no difference between groups in OS (HR 0.96, 95% CI 0.86 to 1.08; P = 0.49; I The available high- to moderate-certainty evidence shows there is likely little or no difference in primary survival outcomes between PCRS and NACT for those with advanced EOC who are suitable for either treatment option. NACT reduces the risk of postoperative mortality and likely reduces the risk of serious adverse events, especially those around the time of surgery, and the need for stoma formation. These data should inform women and clinicians (involving specialist gynaecological multidisciplinary teams) and allow treatment to be tailored to the individual patient, taking into account surgical resectability, age, histology, stage, and performance status. Data from an unpublished study and ongoing studies are awaited. This Cochrane review update had no dedicated funding. Protocol (2005): DOI: 10.1002/14651858.CD005343 Original review (2007): DOI: 10.1002/14651858.CD005343.pub2 Review update (2012): DOI: 10.1002/14651858.CD005343.pub3 Review update (2019): DOI: 10.1002/14651858.CD005343.pub4 Review update (2021): DOI: 10.1002/14651858.CD005343.pub5 Review updated (2021a): DOI: 10.1002/14651858.CD005343.pub6.

Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer

Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of  surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treatment that works by preventing cancer cells from repairing DNA damage, especially in those with breast cancer susceptibility gene (BRCA) variants. PARPi offer a different mechanism of anticancer treatment from conventional chemotherapy. To determine the benefits and risks of poly (ADP-ribose) polymerase) inhibitors (PARPi) for the treatment of epithelial ovarian cancer (EOC). We identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (Central 2020, Issue 10), Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to October 2020), Embase (1990 to October 2020), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials, the National Research Register (NRR), FDA database and pharmaceutical industry biomedical literature. We included trials that randomised women with EOC to PARPi with no treatment, or PARPi versus conventional chemotherapy, or PARPi together with conventional chemotherapy versus conventional chemotherapy alone. We used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data. Outcomes included overall survival (OS), objective response rate (ORR), quality of life (QoL) and rate of adverse events. We included 15 studies (6109 participants); four (3070 participants) with newly-diagnosed, advanced EOC and 11 (3039 participants) with recurrent EOC. The studies varied in types of comparisons and evaluated PARPi. Eight studies were judged as at low risk of bias in most of the domains. Quality of life data were generally poorly reported. Below we present six key comparisons.  The majority of participants had BRCA mutations, either in their tumour (sBRCAmut) and/or germline (gBRCAmut), or homologous recombination deficiencies (HRD) in their tumours. Newly diagnosed EOC Overall, four studies evaluated the effect of PARPi in newly-diagnosed, advanced EOC. Two compared PARPi with chemotherapy and chemotherapy alone. OS data were not reported. The combination of PARPi with chemotherapy may have little to no difference in progression-free survival (PFS) (two studies, 1564 participants; hazard ratio (HR) 0.82, 95% confidence interval (CI 0).49 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months' 63% with PARPi versus 69% for placebo).  PARPi with chemotherapy likely increases any severe adverse event (SevAE) (grade 3 or higher) slightly (45%) compared with chemotherapy alone (51%) (two studies, 1549 participants, risk ratio (RR) 1.13, 95% CI 1.07 to 1.20; high-certainty evidence). PARPi combined with chemotherapy compared with chemotherapy alone likely results in little to no difference in the QoL (one study; 744 participants, MD 1.56 95% CI -0.42 to 3.54; moderate-certainty evidence).  Two studies compared PARPi monotherapy with placebo as maintenance after first-line chemotherapy in newly diagnosed EOC. PARPi probably results in little to no difference in OS (two studies, 1124 participants; HR 0.81, 95%CI 0.59 to 1.13; moderate-certainty evidence) (alive at 12 months 68% with PARPi versus 62% for placebo). However, PARPi may increase PFS (two studies, 1124 participants; HR 0.42, 95% CI 0.19 to 0.92; low-certainty evidence) (no evidence of disease progression at 12 months' 55% with PARPi versus 24% for placebo). There may be an increase in the risk of experiencing any SevAE (grade 3 or higher) with PARPi (54%) compared with placebo (19%)(two studies, 1118 participants, RR 2.87, 95% CI 1.65 to 4.99; very low-certainty evidence), but the evidence is very uncertain. There is probably a slight reduction in QoL with PARPi, although this may not be clinically significant (one study, 362 participants; MD -3.00, 95%CI -4.48 to -1.52; moderate-certainty evidence).  Recurrent, platinum-sensitive EOC Overall, 10 studies evaluated the effect of PARPi in recurrent platinum-sensitive EOC. Three studies compared PARPi monotherapy with chemotherapy alone. PARPi may result in little to no difference in OS (two studies, 331 participants; HR 0.95, 95%CI 0.62 to 1.47; low-certainty evidence) (percentage alive at 36 months 18% with PARPi versus 17% for placebo). Evidence is very uncertain about the effect of PARPi on PFS (three studies, 739 participants; HR 0.88, 95%CI 0.56 to 1.38; very low-certainty evidence)(no evidence of disease progression at 12 months 26% with PARPi versus 22% for placebo). There may be little to no difference in rates of any SevAE (grade 3 or higher) with PARPi (50%) than chemotherapy alone (47%) (one study, 254 participants; RR 1.06, 95%CI 0.80 to 1.39; low-certainty evidence). Four studies compared PARPi monotherapy as maintenance with placebo. PARPi may result in little to no difference in OS (two studies, 560 participants; HR 0.88, 95%CI 0.65 to 1.20; moderate-certainty evidence)(percentage alive at 36 months 21% with PARPi versus 17% for placebo). However, evidence suggests that PARPi as maintenance therapy results in a large PFS (four studies, 1677 participants; HR 0.34, 95% CI 0.28 to 0.42; high-certainty evidence)(no evidence of disease progression at 12 months 37% with PARPi versus 5.5% for placebo). PARPi maintenance therapy may result in a large increase in any SevAE (51%) (grade 3 or higher) than placebo (19%)(four studies, 1665 participants, RR 2.62, 95%CI 1.85 to 3.72; low-certainty evidence). PARPi compared with chemotherapy may result in little or no change in QoL (one study, 229 participants, MD 1.20, 95%CI -1.75 to 4.16; low-certainty evidence). Recurrent, platinum-resistant EOC Two studies compared PARPi with chemotherapy. The certainty of evidence in both studies was graded as very low. Overall, there was minimal information on the QoL and adverse events. PARPi maintenance treatment after chemotherapy may improve PFS in women with newly-diagnosed and recurrent platinum-sensitive EOC; there may be little to no effect on OS, although OS data are immature. Overall, this is likely at the expense of an increase in SevAE. It is  disappointing that data on quality of life outcomes  are relatively sparse. More research is needed to determine whether PARPi have a role to play in platinum-resistant disease.

Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer

Cervical cancer ranks as the fourth leading cause of death from cancer in women. Historically, women with metastatic or recurrent cervical cancer have had limited treatment options. New anti-angiogenesis therapies, such as vascular endothelial growth factor (VEGF) targeting agents, offer an alternative strategy to conventional chemotherapy; they act by inhibiting the growth of new blood vessels, thereby restricting tumour growth by blocking the blood supply. To assess the benefits and harms of VEGF targeting agents in the management of persistent, recurrent, or metastatic cervical cancer. We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, online registers of clinical trials, and abstracts of scientific meetings up until 27 May 2020. We examined randomised controlled trials (RCTs) that evaluated the use of VEGF targeting agents alone or in combination with conventional chemotherapy or other VEGF targeting agents. Three review authors independently screened the results of search strategies, extracted data, assessed risk of bias, and analysed data according to the standard methods expected by Cochrane. The certainty of evidence was assessed via the GRADE approach. A total of 1634 records were identified. From these, we identified four studies with a total of 808 participants for inclusion. We also identified two studies that were awaiting classification and nine ongoing studies. Bevacizumab plus chemotherapy versus chemotherapy Treatment with bevacizumab plus chemotherapy may result in lower risk of death compared to chemotherapy alone (hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.62 to 0.95; 1 study, 452 participants; low-certainty evidence). However, there are probably more specific adverse events when compared to chemotherapy alone, including gastrointestinal perforations or fistulae (risk ratio (RR) 18.00, 95% CI 2.42 to 133.67; 1 study, 440 participants; moderate-certainty evidence); serious thromboembolic events (RR 4.5, 95% CI 1.55 to 13.08; 1 study, 440 participants; moderate-certainty evidence); and hypertension (RR 13.75, 95% CI 5.07 to 37.29; 1 study, 440 participants; moderate-certainty evidence). There may also be a higher incidence of serious haemorrhage (RR 5.00, 95% CI 1.11 to 22.56; 1 study, 440 participants; low-certainty evidence). In addition, the incidence of serious adverse events is probably higher (RR 1.44, 95% CI 1.16 to 1.79; 1 study, 439 participants; moderate-certainty evidence). The incremental cost-effectiveness ratio was USD 295,164 per quality-adjusted life-year (1 study, 452 participants; low-certainty evidence). Cediranib plus chemotherapy versus chemotherapy Treatment with cediranib plus chemotherapy may or may not result in similar risk of death when compared to chemotherapy alone (HR 0.94, 95% CI 0.53 to 1.65; 1 study, 69 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 3.27, 95% CI 0.14 to 77.57; 1 study, 67 participants; very low-certainty evidence); serious haemorrhage (RR 5.45, 95% CI 0.27 to 109.49; 1 study, 67 participants; very low-certainty evidence); serious thromboembolic events (RR 3.41, 95% CI 0.14 to 80.59; 1 study, 60 participants; very low-certainty evidence); and serious hypertension (RR 0.36, 95% CI 0.02 to 8.62; 1 study, 67 participants; very low-certainty evidence). In addition, there may or may not be a similar incidence of serious adverse events compared to chemotherapy alone (RR 1.15, 95% CI 0.75 to 1.78; 1 study, 67 participants; low-certainty evidence). Apatinib plus chemotherapy or chemotherapy/brachytherapy versus chemotherapy or chemotherapy/brachytherapy Treatment with apatinib plus chemotherapy or chemotherapy/brachytherapy may or may not result in similar risk of death compared to chemotherapy alone or chemotherapy/brachytherapy alone (HR 0.90, 95% CI 0.51 to 1.60; 1 study, 52 participants; low-certainty evidence). However, hypertension events may occur at a higher incidence as compared to chemotherapy alone or chemotherapy/brachytherapy alone (RR 5.14, 95% CI 1.28 to 20.73; 1 study, 52 participants; low-certainty evidence). Pazopanib plus lapatinib versus lapatinib Treatment with pazopanib plus lapatinib may result in higher risk of death compared to lapatinib alone (HR 2.71, 95% CI 1.16 to 6.31; 1 study, 117 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 2.00, 95% CI 0.19 to 21.59; 1 study, 152 participants; very low-certainty evidence); haemorrhage (RR 2.00, 95% CI 0.72 to 5.58; 1 study, 152 participants; very low-certainty evidence); and thromboembolic events (RR 3.00, 95% CI 0.12 to 72.50; 1 study, 152 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 12.00, 95% CI 2.94 to 49.01; 1 study, 152 participants; moderate-certainty evidence). There may or may not be a similar incidence of serious adverse events as compared to lapatinib alone (RR 1.45, 95% CI 0.94 to 2.26; 1 study, 152 participants; low-certainty evidence). Pazopanib versus lapatinib Treatment with pazopanib may or may not result in similar risk of death as compared to lapatinib (HR 0.96, 95% CI 0.67 to 1.38; 1 study, 152 participants; low-certainty evidence). We found very uncertain results for the incidences of specific adverse events, including gastrointestinal perforations or fistulae (RR 1.03, 95% CI 0.07 to 16.12; 1 study, 150 participants; very low-certainty evidence); haemorrhage (RR 1.03, 95% CI 0.31 to 3.40; 1 study, 150 participants; very low-certainty evidence); and thromboembolic events (RR 3.08, 95% CI 0.13 to 74.42; 1 study, 150 participants; very low-certainty evidence). In addition, the incidence of hypertension events is probably higher (RR 11.81, 95% CI 2.89 to 48.33; 1 study, 150 participants; moderate-certainty evidence). The risk of serious adverse events may or may not be similar as compared to lapatinib (RR 1.31, 95% CI 0.83 to 2.07; 1 study, 150 participants; low-certainty evidence). We found low-certainty evidence in favour of the use of bevacizumab plus chemotherapy. However, bevacizumab probably increases specific adverse events (gastrointestinal perforations or fistulae, thromboembolic events, hypertension) and serious adverse events. We found low-certainty evidence that does not support the use of cediranib plus chemotherapy, apatinib plus chemotherapy, apatinib plus chemotherapy/brachytherapy, or pazopanib monotherapy. We found low-certainty evidence suggesting that pazopanib plus lapatinib worsens outcomes. The VEGF inhibitors apatinib and pazopanib may increase the probability of hypertension events.

Interventions for fertility preservation in women with cancer undergoing chemotherapy

Predictive value of homologous recombination deficiency status for survival outcomes in primary tubo-ovarian high-grade serous carcinoma

This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors.

Cytoreductive surgery plus chemotherapy versus chemotherapy alone for recurrent epithelial ovarian cancer

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of secondary CRS and chemotherapy in comparison to chemotherapy alone for women with platinum-sensitive recurrent epithelial ovarian cancer.

Fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer

Endometrial cancer is the sixth most common cancer in women worldwide, and the fourth most common in high-income countries, where its incidence is increasing. Atypical endometrial hyperplasia (AEH) is an overgrowth of the womb lining and can be a precursor of endometrial cancer. Between 14% and 25% of cases of endometrial cancer are diagnosed in premenopausal women. Due to delays in childbearing age and increasing obesity rates, a growing number of women wish to explore fertility-sparing management of endometrial cancer or AEH. To compare the effectiveness and safety of fertility-sparing treatments, including pharmacological interventions (e.g. oral progestin, levonorgestrel intrauterine system (IUS), metformin) and bariatric or hysteroscopic surgery, for AEH and presumed stage IA grade 1 endometrioid endometrial cancer. We searched the following electronic databases to 3 February 2025: CENTRAL; Ovid MEDLINE; and Ovid Embase. We also searched five trials registers and conference proceedings and abstracts. We included randomised controlled trials (RCTs) that compared fertility-sparing therapy for presumed stage IA grade 1 endometrioid endometrial cancer or AEH with oral progestin compared to levonorgestrel IUS or metformin or other pharmacological interventions, or bariatric or hysteroscopic surgery (any comparison); or any of these interventions with the usual treatment (surgery). Other comparative non-randomised studies were also eligible for inclusion (quasi-randomised trials, non-randomised studies (NRS), and prospective and retrospective cohort studies). Two review authors independently extracted data and assessed the methodological quality of the studies. We used standard Cochrane methodological procedures. Where possible, we pooled data from RCTs in a meta-analysis. Otherwise, we provided a narrative description of the results. Primary outcomes are overall survival and live birth rate. Secondary outcomes are progression-free survival, complete pathological response rate (CR), severe adverse events, psychological symptoms, quality of life, pregnancy rate, and surgery for persistent/progressive disease. We assessed the certainty of the evidence using GRADE. We assessed the risk of bias only in RCTs, using the Cochrane risk of bias tool, RoB 1. We included 12 studies with 904 participants; six RCTs and six NRSs. Four studies included women with AEH, two, women with endometrial cancer, and six, both AEH and endometrial cancer. We judged the studies at high risk of overall bias. We pooled two RCTs into one meta-analysis and described the remaining comparisons narratively. None of the included studies provided evidence for overall survival, progression-free survival or quality of life for any comparison. Metformin plus progestin compared with progestin Metformin plus progestin may have little to no effect on live birth rate (risk ratio (RR) 1.80, 95% confidence interval (CI) 0.88 to 3.68); 2 RCTs, 72 women; low-certainty evidence) but may slightly increase CR (RR 1.85, 95% CI 1.07 to 3.19; P = 0.03; 2 RCTs; 141 women; low-certainty evidence). No fatal adverse events were observed. Weight gain was the most frequent adverse event in one RCT, with 5/74 (6.8%) cases of grade 3-4 weight gain in the progestin group versus 2/76 (2.6%) in the metformin plus progestin group (RR 0.39, 95% CI 0.08 to 1.95; 1 RCT; 150 women; low-certainty evidence). Metformin plus progestin may make little to no difference in the need for surgery for persistent/progressive disease (RR 0.96, 95% CI 0.24 to 3.78; 2 RCTs; 166 women; low-certainty evidence). Levonorgestrel IUS compared to oral progestin Only one RCT evaluated live birth rate, showing little to no difference between levonorgestrel IUS and oral progestin (RR 1.80, 95% CI 0.74 to 4.39; 1 RCT, 34 women; low-certainty evidence). Data from two RCTs showed no evidence of a difference in CR in women with AEH (data not pooled): RR 1.78 (95% CI 0.98 to 3.25; 89 women), and RR 1.24 (95% CI 0.86 to 1.78; 19 women), both low-certainty evidence. One RCT found that levonorgestrel IUS may decrease severe adverse events (weight gain) slightly (RR 0.19; 95% CI 0.04 to 0.84; 1 RCT, 118 women; low-certainty evidence). Evidence on surgery for persistent/progressive disease information was incomplete. Oral progestin plus levonorgestrel IUS compared to oral progestin One RCT in endometrial cancer evaluated live birth rate, finding no difference between oral progestin plus levonorgestrel IUS and oral progestin alone (RR 1.40, 95% 0.46 to 4.24; 1 RCT, 33 women; low-certainty evidence). Similarly, no differences were found in women with AEH (RR 1.38, 95% CI 0.50 to 3.82;1 RCT, 47 women; low-certainty evidence). Data from two RTCs showed no difference in CR in women with endometrial cancer (RR 1.30, 95% CI 0.47 to 3.59; 1 RCT, 54 women) or with AEH (RR 1.45, 95% CI 0.77 to 2.76; 1 RCT, 86 women low-certainty). The only grade 3 adverse event was weight gain, with no difference between the groups for endometrial cancer (RR 1.11, 95% CI 0.17 to 7.34; 1 RCT, 59 women; low-certainty evidence) and AEH (RR 0.97, 95% CI 0.43 to 2.20; 1 RCT, 112 women; low-certainty evidence). Surgery for persistent/progressive disease was also similar in the two treatment arms, both for women with endometrial cancer (RR 2.07, 95% CI 0.20 to 21.60; 1 RCT, 59 women; low-certainty evidence) and with AEH (RR 1.00, 95% CI 0.06 to 15.48; 1 RCT, 86 women; low-certainty evidence). In light of the low certainty of the evidence, it is unclear which intervention and which route of administration or dose of progestins could be of benefit compared to others for fertility-sparing management of endometrial cancer or AEH. The addition of metformin to progestins may increase complete response slightly. Levonorgestrel IUS may result in no difference in efficacy in complete response, compared to oral progestins, whilst it may reduce adverse events slightly. Therefore, levonorgestrel IUS may improve quality of life and compliance with treatment.

Sentinel node biopsy for diagnosis of lymph node involvement in endometrial cancer

Pelvic lymphadenectomy provides prognostic information for those diagnosed with endometrial (womb) cancer and provides information that may influence decisions regarding adjuvant treatment. However, studies have not shown a therapeutic benefit, and lymphadenectomy causes significant morbidity. The technique of sentinel lymph node biopsy (SLNB), allows the first draining node from a cancer to be identified and examined histologically for involvement with cancer cells. SLNB is commonly used in other cancers, including breast and vulval cancer. Different tracers, including colloid labelled with radioactive technetium-99, blue dyes, e.g. patent or methylene blue, and near infra-red fluorescent dyes, e.g. indocyanine green (ICG), have been used singly or in combination for detection of sentinel lymph nodes (SLN). To assess the diagnostic accuracy of sentinel lymph node biopsy (SLNB) in the identification of pelvic lymph node involvement in women with endometrial cancer, presumed to be at an early stage prior to surgery, including consideration of the detection rate. We searched MEDLINE (1946 to July 2019), Embase (1974 to July 2019) and the relevant Cochrane trial registers. We included studies that evaluated the diagnostic accuracy of tracers for SLN assessment (involving the identification of a SLN plus histological examination) against a reference standard of histological examination of removed pelvic +/- para-aortic lymph nodes following systematic pelvic +/- para-aortic lymphadenectomy (PLND/PPALND) in women with endometrial cancer, where there were sufficient data for the construction of two-by-two tables. Two review authors (a combination of HN, JM, NW, RG, and WH) independently screened titles and abstracts for relevance, classified studies for inclusion/exclusion and extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We calculated the detection rate as the arithmetic mean of the total number of SLNs detected out of the total number of women included in the included studies with the woman as the unit of analysis, used univariate meta-analytical methods to estimate pooled sensitivity estimates, and summarised the results using GRADE. The search revealed 6259 unique records after removal of duplicates. After screening 232 studies in full text, we found 73 potentially includable records (for 52 studies), although we were only able to extract 2x2 table data for 33 studies, including 2237 women (46 records) for inclusion in the review, despite writing to trial authors for additional information. We found 11 studies that analysed results for blue dye alone, four studies for technetium-99m alone, 12 studies that used a combination of blue dye and technetium-99m, nine studies that used indocyanine green (ICG) and near infra-red immunofluorescence, and one study that used a combination of ICG and technetium-99m. Overall, the methodological reporting in most of the studies was poor, which resulted in a very large proportion of 'unclear risk of bias' ratings. Overall, the mean SLN detection rate was 86.9% (95% CI 82.9% to 90.8%; 2237 women; 33 studies; moderate-certainty evidence). In studies that reported bilateral detection the mean rate was 65.4% (95% CI 57.8% to 73.0%) . When considered according to which tracer was used, the SLN detection rate ranged from 77.8% (95% CI 70.0% to 85.6%) for blue dye alone (559 women; 11 studies; low-certainty evidence) to 100% for ICG and technetium-99m (32 women; 1 study; very low-certainty evidence). The rates of positive lymph nodes ranged from 5.2% to 34.4% with a mean of 20.1% (95% CI 17.7% to 22.3%). The pooled sensitivity of SLNB was 91.8% (95% CI 86.5% to 95.1%; total 2237 women, of whom 409 had SLN involvement; moderate-certainty evidence). The sensitivity for of SLNB for the different tracers were: blue dye alone 95.2% (95% CI 77.2% to 99.2%; 559 women; 11 studies; low-certainty evidence); Technetium-99m alone 90.5% (95% CI 67.7% to 97.7%; 257 women; 4 studies; low-certainty evidence); technetium-99m and blue dye 91.9% (95% CI 74.4% to 97.8%; 548 women; 12 studies; low-certainty evidence); ICG alone 92.5% (95% CI 81.8% to 97.1%; 953 women; 9 studies; moderate-certainty evidence); ICG and blue dye 90.5% (95% CI 63.2.6% to 98.1%; 215 women; 2 studies; low-certainty evidence); and ICG and technetium-99m 100% (95% CI 63% to 100%; 32 women; 1 study; very low-certainty evidence). Meta-regression analyses found that the sensitivities did not differ between the different tracers used, between studies with a majority of women with FIGO stage 1A versus 1B or above; between studies assessing the pelvic lymph node basin alone versus the pelvic and para-aortic lymph node basin; or between studies that used subserosal alone versus subserosal and cervical injection. It should be noted that a false-positive result cannot occur, as the histological examination of the SLN is unchanged by the results from any additional nodes removed at systematic lymphadenectomy. The diagnostic test accuracy for SLNB using either ICG alone or a combination of a dye (blue or ICG) and technetium-99m is probably good, with high sensitivity, where a SLN could be detected. Detection rates with ICG or a combination of dye (ICG or blue) and technetium-99m may be higher. The value of a SLNB approach in a treatment pathway, over adjuvant treatment decisions based on uterine factors and molecular profiling, requires examination in a high-quality intervention study.

Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis

Cervical cancer is the fourth most common cause of cancer-related death amongst females worldwide. Persistent infection with high-risk human papillomavirus (HPV) is the key factor in cervical cancer development. HPV vaccines aim to prevent cancer by generating antibodies against HPV infection. To evaluate the safety and efficacy of HPV vaccines, in females and males, to prevent cervical cancer and other HPV-related diseases, in standard (pairwise) and network meta-analysis (NMA) of randomised controlled trials. On 10 January 2022, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase. We searched Epistemonikos, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, the Health Technology Assessment database and vaccine manufacturer websites, and we checked reference lists from other relevant systematic reviews. We applied for Clinical Study Reports (CSRs) from the European Medicines Agency. An update search of electronic databases was done on 18 September 2024. We included randomised controlled trials (RCTs) regardless of language or publication status, assessing HPV vaccines pre-qualified by the World Health Organization (WHO) (Cervarix, Gardasil, Gardasil-9 and Cecolin). We used methods recommended by Cochrane. We primarily used CSRs to collect data, and we included outcome data irrespective of participants' baseline HPV infection or serostatus. We assessed risk of bias using the Cochrane tool (RoB 2). All outcomes were dichotomous, and we estimated risk ratios (RR) with 95% confidence intervals (CI). We used pairwise analysis for all outcomes. Where data were available, we carried out NMA for critical outcomes for networks in females and males in three age groups, ranking the vaccines using surface under the cumulative ranking curve (SUCRA) and mean ranks. We assessed the certainty of evidence using the GRADE approach. We included 60 individual studies with 157,414 participants ranging in follow-up from seven months to 11 years. Few participants were under 15. There were no studies for males under 15 years and males over 25 years. We obtained CSRs for 33 of the included studies. We assessed the risk of bias as low to 'some concerns' for the critical outcomes. Cancer and pre-cancer outcomes The studies were not of sufficient duration for cancers to develop. Four studies reported on cancer. No cancers were detected. Critical pre-cancer outcomes were reported in 15- to 25-year-old populations by 11 studies and in > 25-year-old females by three studies with up to seven years follow-up. None were reported in the under 15 years age group. In 15- to 25-year-old females, there was a reduction in CIN2+ irrespective of HPV type after six years (RR 0.70, 95% CI 0.56 to 0.88) (moderate-certainty) and a larger reduction in CIN2+ from vaccine-matched HPV types after six years (RR 0.40, 95% CI 0.30 to 0.54) (moderate-certainty). In females over 25 years old, there was little to no difference between Cervarix and Gardasil compared with control (moderate-certainty). There was no evidence on CIN2+ irrespective of HPV type from studies assessing Cecolin, or from studies assessing different dose schedules. In 15- to 25-year-old females, there was a slight reduction in vaccine-matched HPV-type high-grade vulval (VIN) or vaginal (VaIN) intraepithelial neoplasia following vaccination with Gardasil or Gardasil-9 (moderate-certainty). The NMA found a slight reduction of 1 case per 1000 following Gardasil (RR 0.21, 95% CI 0.1 to 0.45) and 0 cases per 1000 following Gardasil-9 (RR 0.16, 95% CI 0.05 to 0.51). Little to no difference was found in the NMA for Cervarix compared with control (RR 0.28, 95% CI 0.06 to 1.37), or for Cervarix, Gardasil and Gardasil-9 compared to each other. There was a reduction in high-grade anal intraepithelial neoplasia (AIN) irrespective of HPV type in the Gardasil group in one study in men who have sex with men (RR 0.75, 95% CI 0.53 to 1.07) (low-certainty). For both high-grade penile intraepithelial neoplasia (PeIN) irrespective of HPV type and vaccine-matched HPV-type high-grade PeIN, little to no difference per 1000 participants was reported in the Gardasil group in one study with 3880 participants at 36 months follow-up (RR 1.00, 95% CI 0.20 to 4.93) (low-certainty). Serious adverse events In a pairwise analysis of serious adverse events in 39 studies across all vaccine types with 97,272 participants, there was little to no difference in the HPV vaccine groups compared with the control group at up to 72 months follow-up (RR 0.99, 95% CI 0.94 to 1.04) (high-certainty). Treatment rates for HPV-related pre-invasive disease In pairwise analysis of five studies with 38,606 participants, there were 12 fewer people that needed to seek treatment per 1000 participants (95% CI 5 to 17 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 84 months follow-up (RR 0.76, 95% CI 0.65 to 0.89) (moderate-certainty). Anogenital warts In pairwise analysis of three studies with 21,271 participants, there were 25 fewer cases of anogenital warts irrespective of HPV type per 1000 participants (95% CI 22 to 28 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 48 months follow-up (RR 0.38, 95% CI 0.32 to 0.46) (high-certainty). In the NMA for females 15 to 25 years old, Gardasil-9 was most likely to reduce the risk of developing anogenital warts. The evidence in this network meta-analysis of HPV vaccines is based on extensive searches and analyses. There is evidence from randomised controlled trials that HPV vaccination reduces the risk of pre-cancerous outcomes such as CIN2+ and anogenital warts. No data were available for cervical cancer or other cancer outcomes, and no data on pre-cancer outcomes were available for vaccination under age 15 years. There were no safety concerns noted in the studies.

Simple hysterectomy with pelvic lymphadenectomy versus radical hysterectomy with pelvic lymphadenectomy for women with stage IA2-IB1 cervical cancer

Radical hysterectomy is a standard operation for women with early-stage cervical cancer, involving removal of the womb, cervix (neck of the womb), surrounding tissues (parametrial tissue), and part of the vagina. Given a relatively low risk of parametrial involvement in a selected group of women with early-stage cervical cancer, simple hysterectomy (removing only the uterus and cervix) with pelvic lymphadenectomy (surgical removal of the lymph glands found in the pelvis) might be an alternative option to reduce risk of complications. To determine the benefits and harms of simple hysterectomy with pelvic lymphadenectomy versus radical hysterectomy with pelvic lymphadenectomy for women with stage IA2-IB1 cervical cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection, PubMed, and two trial registry databases, along with reference checking and citation searching. The last search date was 19 March 2025. We included randomised clinical trials comparing simple hysterectomy with pelvic lymphadenectomy versus radical hysterectomy with pelvic lymphadenectomy for women with cervical cancer FIGO 2019 stage IA2-IB1. Critical outcomes were all-cause mortality, overall survival (OS), cancer-related mortality, and disease-free survival (DFS). Important outcomes included cancer recurrence, adverse events, sexual dysfunction, cost-effectiveness, and quality of life (QoL). Two review authors independently assessed the risk of bias of each included study using the Cochrane Risk of bias 2 (RoB 2) tool. We conducted meta-analyses using random-effects models to calculate hazard ratios (HRs), risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs) for all outcomes. We used GRADE to assess the certainty of evidence. We included two trials involving 740 participants. One small trial was conducted in Brazil (40 participants). The larger trial, involving 700 participants, included centres in Western Europe, South Korea, and Canada. In this larger trial, 75.0% of participants were white. We classified one report as awaiting classification, and did not identify any ongoing studies. Critical outcomes Low-certainty evidence revealed that simple hysterectomy may result in little or no difference in all-cause mortality (RR 1.12, 95% CI 0.44 to 2.89; I Simple hysterectomy may be a viable option for carefully selected women with early-stage cervical cancer, as it may result in little to no differences in survival and cancer recurrence rates compared to radical hysterectomy. Additionally, there were likely fewer perioperative adverse events and there may be better short-term QoL and sexual function in women undergoing simple hysterectomy. The included studies did not directly compare the effect of the route of surgery (open versus minimal access). This review has a limited representation of non-white women and women from low-resource settings. No specific funding was received for this review. Cochrane protocol (2016) DOI: 10.1002/14651858.CD012335. PROSPERO 2016 CRD42016047631. Available from: crd.york.ac.uk/PROSPERO/view/CRD42016047631.

Human papillomavirus (HPV) vaccination in women with conisation

Cervical cancer is the fourth most common cancer affecting women worldwide, caused by persistent infection with oncogenic human papillomavirus (HPV) types. While HPV infections usually resolve spontaneously, persistent infections with high-risk HPV types can progress to premalignant glandular or - mostly - squamous intraepithelial lesions, usually classified in cervical intraepithelial neoplasia (CIN). Women with CIN 2 and CIN 3 (i.e. high-grade CIN) typically undergo cervical conisation to remove precancerous cervical lesions. While conisation is effective, there is a risk of recurrence and progression to invasive cervical cancer. Additionally, women who have undergone conisation are at higher risk of HPV-associated anogenital precancerous lesions and cancers in other locations. HPV vaccination is an important measure to prevent HPV-related cancer. It is unclear to what extent HPV vaccination offers protection to women with conisation. Of note, the term 'with conisation' is interchangeably used for all time points of HPV vaccination relative to the conisation procedure for the purpose of this review. To investigate the benefits and harms of HPV vaccination (given shortly before, at, or after conisation) in comparison to no HPV vaccination in women with conisation. We searched CENTRAL, MEDLINE, Embase, and Clarivate Web of Science (May 2023). We also searched ClinicalTrials.gov to identify ongoing studies. We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSI) if they compared an HPV vaccine (nonavalent, quadrivalent, or bivalent) with no HPV vaccine, placebo, or other vaccines not directed against HPV in women of any age with conisation for treating precancerous lesions following HPV infection. Critical outcomes: CIN 2+ (irrespective of HPV type and related to HPV 16/18), CIN 3+ (irrespective of HPV type and related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type and related to HPV 16/18), persistent HPV infection (irrespective of HPV type and related to HPV 16/18) and incident HPV infection (irrespective of HPV type and related to HPV 16/18). We evaluated RCTs using the Cochrane RoB 2 tool and NRSI using the 'Risk of Bias in Non-randomised Studies of Interventions' tool (ROBINS-I). Two review authors independently screened, extracted data, and assessed risk of bias. We used random-effects meta-analyses for our primary analyses. We rated the certainty of evidence using the GRADE approach. The search identified 13 studies (2 RCTs, 11 NRSI), with 21,453 women with conisation. Studies were conducted in Europe (10), China (1), South Korea (1), and Iran (1), and published between 2013 and 2023. The length of follow-up after conisation was up to 36 months in RCTs and up to greater than 60 months in NRSI. Eight studies included women older than 25 years. The remaining studies included women across different age groups (range 17 to greater than 50 years). In 10 studies, the treatment for cervical lesions included loop electrosurgical excision procedures or large loop excision of the transformation zone as the conisation procedure. The spectrum of precancerous lesions (in terms of baseline characteristics) varied widely between women. Seven studies used the quadrivalent HPV vaccine, one used the nonavalent HPV vaccine, four used various HPV vaccine types, and one did not specify the HPV vaccine type. All studies compared the HPV vaccine with no intervention. Critical outcomes HPV vaccination compared to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ (evidence from RCTs: risk ratio (RR) 0.40, 95% confidence interval (CI) 0.26 to 0.63; 2 RCTs, 420 women; evidence from NRSI: hazard ratio (HR) 0.49, 95% CI 0.27 to 0.89; 5 NRSI, 19,059 women; odds ratio (OR) 0.23, 95% CI 0.05 to 0.97; 3 NRSI, 928 women; RR 0.24, 95% CI 0.13 to 0.46; 3 NRSI, 1027 women; low-certainty evidence). There were similar results for CIN 2+ (related to HPV 16/18) (evidence from NRSI: RR 0.38, 95% CI 0.21 to 0.68; 7 NRSI, 2970 women; low-certainty evidence). Effects on CIN 3+ varied between studies. One study suggested similar effects to CIN 2+ favouring HPV vaccination (evidence from NRSI: OR 0.20, 95% CI 0.10 to 0.60; 1 NRSI, 285 women; low-certainty evidence), while the remaining evidence was very uncertain (evidence from NRSI: RR 0.53, 95% CI 0.15 to 1.90; 2 NRSI, 17,472 women; very low-certainty evidence). The evidence on CIN 2+ (related to HPV 16/18) based on RCT evidence was very uncertain. The evidence on CIN 3+ (related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type), and persistent HPV infections (irrespective of HPV type and related to HPV 16/18) was very uncertain. Adverse events One RCT reported minor local reactions (redness and rash: 127/138 (92%) women; headache: 11/138 (8%) women) and severe allergies (2/158 (1%) women). HPV vaccination given around the time of conisation in comparison to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ and CIN 2+ (related to HPV 16/18; evidence based on NRSI). Effects on CIN 3+ (irrespective of HPV type) varied, with one NRSI suggesting similar effects to CIN 2+, while the remaining evidence was very uncertain. The evidence on other outcomes was predominantly very uncertain or inconclusive. Overall, the existing evidence for HPV vaccination in women with conisation is largely based on NRSI with serious or critical risk of bias and low- to very low-certainty evidence. Evidence from RCTs is limited (i.e. only two RCTs are available). Additional RCTs with a placebo intervention in the control group to evaluate the efficacy and safety of HPV vaccination (particularly with the nonavalent vaccine) as an adjuvant to conisation would provide more robust evidence. Future RCTs should also aim to assess how effects of vaccination around the time of conisation vary according to whether a previous HPV vaccine for primary prevention was received, timing of HPV vaccination related to conisation, and different age groups. EU4Health Programme. PROSPERO (CRD42023428998).

Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer

Cancer of ovarian, fallopian tube and peritoneal origin, referred to collectively as ovarian cancer, is the eighth most common cancer in women and is often diagnosed at an advanced stage. Women with relapsed epithelial ovarian cancer (EOC) are less well and have a limited life expectancy, therefore maintaining quality of life with effective symptom control is an important aim of treatment. However, the unwanted effects of chemotherapy agents may be severe, and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride, is one of several treatment modalities that may be considered for treatment of relapsed EOCs. This is an update of the original Cochrane Review which was published in Issue 7, 2013. To evaluate the efficacy and safety of PLD, with or without other anti-cancer drugs, in women with relapsed high grade epithelial ovarian cancer (EOC). We searched CENTRAL, MEDLINE (via Ovid) and Embase (via Ovid) from 1990 to January 2022. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. We included randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. Two review authors independently extracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses. This is an update of a previous review with 12 additional studies, so this updated review includes a total of 26 RCTs with 8277 participants that evaluated the effects of PLD alone or in combination with other drugs in recurrent EOC: seven in platinum-sensitive disease (2872 participants); 11 in platinum-resistant disease (3246 participants); and eight that recruited individuals regardless of platinum sensitivity status (2079 participants). The certainty of the evidence was assessed for the three most clinically relevant comparisons out of eight comparisons identified in the included RCTs. Recurrent platinum-sensitive EOC PLD with conventional chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.83 to 1.04; 5 studies, 2006 participants; moderate-certainty evidence) but likely increases progression-free survival (PFS) (HR 0.81, 95% CI 0.74 to 0.89; 5 studies, 2006 participants; moderate-certainty evidence). The combination may slightly improve quality of life at three months post-randomisation, measured using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (mean difference 4.80, 95% CI 0.92 to 8.68; 1 study, 608 participants; low-certainty evidence), but this may not represent a clinically meaningful difference. PLD in combination with another chemotherapy agent compared to alternative combination chemotherapy likely results in little to no difference in the rate of overall severe adverse events (grade ≥ 3) (risk ratio (RR) 1.11, 95% CI 0.95 to 1.30; 2 studies, 834 participants; moderate-certainty evidence). PLD with chemotherapy likely increases anaemia (grade ≥ 3) (RR 1.37, 95% CI 1.02 to 1.85; 5 studies, 1961 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD with conventional chemotherapy on hand-foot syndrome (HFS)(grade ≥ 3) (RR 4.01, 95% CI 1.00 to 16.01; 2 studies, 1028 participants; very low-certainty evidence) and neurological events (grade ≥ 3) (RR 0.38, 95% CI 0.20 to 0.74; 4 studies, 1900 participants; very low-certainty evidence). Recurrent platinum-resistant EOC PLD alone compared to another conventional chemotherapy likely results in little to no difference in OS (HR 0.96, 95% CI 0.77 to 1.19; 6 studies, 1995 participants; moderate-certainty evidence). The evidence is very uncertain about the effect of PLD on PFS (HR 0.94, 95% CI 0.85 to 1.04; 4 studies, 1803 participants; very low-certainty evidence), overall severe adverse events (grade ≥ 3) (RR ranged from 0.61 to 0.97; 2 studies, 964 participants; very low-certainty evidence), anaemia (grade ≥ 3) (RR ranged from 0.19 to 0.82; 5 studies, 1968 participants; very low-certainty evidence), HFS (grade ≥ 3) (RR ranged from 15.19 to 109.15; 6 studies, 2184 participants; very low-certainty evidence), and the rate of neurological events (grade ≥ 3)(RR ranged from 0.08 to 3.09; 3 studies, 1222 participants; very low-certainty evidence). PLD with conventional chemotherapy compared to PLD alone likely results in little to no difference in OS (HR 0.92, 95% CI 0.70 to 1.21; 1 study, 242 participants; moderate-certainty evidence) and it may result in little to no difference in PFS (HR 0.94, 95% CI 0.73 to 1.22; 2 studies, 353 participants; low-certainty evidence). The combination likely increases overall severe adverse events (grade ≥ 3) (RR 2.48, 95% CI 1.98 to 3.09; 1 study, 663 participants; moderate-certainty evidence) and anaemia (grade ≥ 3) (RR 2.38, 95% CI 1.46 to 3.87; 2 studies, 785 participants; moderate-certainty evidence), but likely results in a large reduction in HFS (grade ≥ 3) (RR 0.24, 95% CI 0.14 to 0.40; 2 studies, 785 participants; moderate-certainty evidence). It may result in little to no difference in neurological events (grade ≥ 3) (RR 1.40, 95% CI 0.85 to 2.31; 1 study, 663 participants; low-certainty evidence). In platinum-sensitive relapsed EOC, including PLD in a combination chemotherapy regimen probably makes little to no difference in OS compared to other combinations, but likely improves PFS. Choice of chemotherapy will therefore be guided by symptoms from previous chemotherapy and other patient considerations. Single-agent PLD remains a useful agent for platinum-resistant relapsed EOC and choice of agent at relapse will depend on patient factors, e.g. degree of bone marrow suppression or neurotoxicity from previous treatments. Adding another agent to PLD likely increases overall grade ≥ 3 adverse events with little to no improvement in survival outcomes. The limited evidence relating to PLD in combination with other agents in platinum-resistant relapsed EOC does not indicate a benefit, but there is some evidence of increased side effects.

Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer

This is an update of the Cochrane Review published in Issue 4, 2015. Cervical cancer is one of the most frequent cause of death from gynaecological cancers worldwide. Many new cervical cancer cases in low-income countries present at an advanced stage. Standard care in Europe and the US for locally advanced cervical cancer (LACC) is chemoradiotherapy. In low-income countries, with limited access to radiotherapy, LACC may be treated with chemotherapy and hysterectomy. It is not certain if this improves survival. It is important to assess the value of hysterectomy with radiotherapy or chemotherapy, or both, as an alternative. To determine whether hysterectomy, in addition to standard treatment with radiotherapy or chemotherapy, or both, in women with LACC (Stage IB We searched CENTRAL, MEDLINE via Ovid, Embase via Ovid, LILACS, trial registries and the grey literature up to 3 February 2022. We searched for randomised controlled trials (RCTs) that compared treatments involving hysterectomy versus radiotherapy or chemotherapy, or both, in women with LACC International Federation of Gynecology and Obstetrics (FIGO) Stages IB We used standard methodological procedures expected by Cochrane. We independently assessed study eligibility, extracted data and assessed the risk of bias. Where possible, we synthesised overall (OS) and progression-free (PFS) or disease-free (DFS) survival in a meta-analysis using a random-effects model. Adverse events (AEs) were incompletely reported and we described the results of single trials in narrative form. We used the GRADE approach to assess the certainty of the evidence. From the searches we identified 968 studies. After deduplication, title and abstract screening, and full-text assessment, we included 11 RCTs (2683 women) of varying methodological quality. This update identified four new RCTs and three ongoing RCTs. The included studies compared: hysterectomy (simple or radical) with radiotherapy or chemoradiotherapy or neoadjuvant chemotherapy (NACT) versus radiotherapy alone or chemoradiotherapy (CCRT) alone or CCRT and brachytherapy. There is also one ongoing study comparing three groups: hysterectomy with CCRT versus hysterectomy with NACT versus CCRT. There were two comparison groups for which we were able to do a meta-analysis. Hysterectomy (radical) with neoadjuvant chemotherapy versus chemoradiotherapy alone Two RCTs with similar design characteristics (620 and 633 participants) found no difference in five-year OS between NACT with hysterectomy versus CCRT. Meta-analysis assessing 1253 participants found no evidence of a difference in risk of death (OS) between women who received NACT plus hysterectomy and those who received CCRT alone (HR 0.94, 95% CI 0.76 to 1.16; moderate-certainty evidence). In both studies, the five-year DFS in the NACT plus surgery group was worse (57%) compared with the CCRT group (65.6%), mostly for Stage IIB. Results of single trials reported no apparent difference in long-term severe complications, grade 3 acute toxicity and severe late toxicity between groups (very low-quality evidence). Hysterectomy (simple or radical) with neoadjuvant chemotherapy versus radiotherapy alone Meta-analysis of three trials of NACT with hysterectomy versus radiotherapy alone, assessing 571 participants, found that women who received NACT plus hysterectomy had less risk of death (OS) than those who received radiotherapy alone (HR 0.71, 95% CI 0.55 to 0.93; I From the available RCTs, we found insufficient evidence that hysterectomy with radiotherapy, with or without chemotherapy, improves the survival of women with LACC who are treated with radiotherapy or CCRT alone. The overall certainty of the evidence was variable across the different outcomes and was universally downgraded due to concerns about risk of bias. The certainty of the evidence for NACT and radical hysterectomy versus radiotherapy alone for survival outcomes was moderate. The same occurred for the comparison involving NACT and hysterectomy compared with CCRT alone. Evidence from other comparisons was generally sparse and of low or very low-certainty. This was mainly based on poor reporting and sparseness of data where results were based on single trials. More trials assessing medical management with and without hysterectomy may test the robustness of the findings of this review as further research is likely to have an important impact on our confidence in the estimate of effect.

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer

Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti-cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression-free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly-diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum-sensitive EOC; 19 in platinum-resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly-diagnosed EOC Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate-certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low-certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) -6.4, 95% CI -8.86 to -3.94; 1 study, 890 participants; high-certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low-certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF-R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate-certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate-certainty evidence). The combination likely reduces QoL slightly (MD -1.86, 95% CI -3.46 to -0.26; 1 study, 1340 participants; moderate-certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate-certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low-certainty evidence).  Recurrent EOC (platinum-sensitive) Moderate-certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI -2.11 to 3.71; 1 study, 486 participants; low-certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high-certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low-certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate-certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI -0.96 to 13.16; 1 study, 146 participants; low-certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum-resistant) Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high-certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate-certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low-certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate-certainty evidence), with low-certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from -0.19 at 6 weeks to -3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high-certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low-certainty evidence). Bevacizumab likely improves both OS and PFS in platinum-resistant relapsed EOC. In platinum-sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum-resistant relapsed EOC are similar. The effects on OS or PFS in newly-diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti-angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti-angiogenesis treatments should be carefully considered.

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery

Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence).

Menopausal status, ultrasound and biomarker tests in combination for the diagnosis of ovarian cancer in symptomatic women

Ovarian cancer (OC) has the highest case fatality rate of all gynaecological cancers. Diagnostic delays are caused by non-specific symptoms. Existing systematic reviews have not comprehensively covered tests in current practice, not estimated accuracy separately in pre- and postmenopausal women, or used inappropriate meta-analytic methods. To establish the accuracy of combinations of menopausal status, ultrasound scan (USS) and biomarkers for the diagnosis of ovarian cancer in pre- and postmenopausal women and compare the accuracy of different test combinations. We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), five other databases and three trial registries from 1991 to 2015 and MEDLINE (Ovid) and Embase (Ovid) form June 2015 to June 2019. We also searched conference proceedings from the European Society of Gynaecological Oncology, International Gynecologic Cancer Society, American Society of Clinical Oncology and Society of Gynecologic Oncology, ZETOC and Conference Proceedings Citation Index (Web of Knowledge). We searched reference lists of included studies and published systematic reviews. We included cross-sectional diagnostic test accuracy studies evaluating single tests or comparing two or more tests, randomised trials comparing two or more tests, and studies validating multivariable models for the diagnosis of OC investigating test combinations, compared with a reference standard of histological confirmation or clinical follow-up in women with a pelvic mass (detected clinically or through USS) suspicious for OC. Two review authors independently extracted data and assessed quality using QUADAS-2. We used the bivariate hierarchical model to indirectly compare tests at commonly reported thresholds in pre- and postmenopausal women separately. We indirectly compared tests across all thresholds and estimated sensitivity at fixed specificities of 80% and 90% by fitting hierarchical summary receiver operating characteristic (HSROC) models in pre- and postmenopausal women separately. We included 59 studies (32,059 women, 9545 cases of OC). Two tests evaluated the accuracy of a combination of menopausal status and USS findings (IOTA Logistic Regression Model 2 (LR2) and the Assessment of Different NEoplasias in the adneXa model (ADNEX)); one test evaluated the accuracy of a combination of menopausal status, USS findings and serum biomarker CA125 (Risk of Malignancy Index (RMI)); and one test evaluated the accuracy of a combination of menopausal status and two serum biomarkers (CA125 and HE4) (Risk of Ovarian Malignancy Algorithm (ROMA)). Most studies were at high or unclear risk of bias in participant, reference standard, and flow and timing domains. All studies were in hospital settings. Prevalence was 16% (RMI, ROMA), 22% (LR2) and 27% (ADNEX) in premenopausal women and 38% (RMI), 45% (ROMA), 52% (LR2) and 55% (ADNEX) in postmenopausal women. The prevalence of OC in the studies was considerably higher than would be expected in symptomatic women presenting in community-based settings, or in women referred from the community to hospital with a suspicion of OC. Studies were at high or unclear applicability because presenting features were not reported, or USS was performed by experienced ultrasonographers for RMI, LR2 and ADNEX. The higher sensitivity and lower specificity observed in postmenopausal compared to premenopausal women across all index tests and at all thresholds may reflect highly selected patient cohorts in the included studies. In premenopausal women, ROMA at a threshold of 13.1 (± 2), LR2 at a threshold to achieve a post-test probability of OC of 10% and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 77.4%, 95% CI 72.7% to 81.5%; LR2: 83.3%, 95% CI 74.7% to 89.5%; ADNEX: 95.5%, 95% CI 91.0% to 97.8%) compared to RMI (57.2%, 95% CI 50.3% to 63.8%). The specificity of ROMA and ADNEX were lower in premenopausal women (ROMA: 84.3%, 95% CI 81.2% to 87.0%; ADNEX: 77.8%, 95% CI 67.4% to 85.5%) compared to RMI 92.5% (95% CI 90.3% to 94.2%). The specificity of LR2 was comparable to RMI (90.4%, 95% CI 84.6% to 94.1%). In postmenopausal women, ROMA at a threshold of 27.7 (± 2), LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) demonstrated a higher sensitivity (ROMA: 90.3%, 95% CI 87.5% to 92.6%; LR2: 94.8%, 95% CI 92.3% to 96.6%; ADNEX: 97.6%, 95% CI 95.6% to 98.7%) compared to RMI (78.4%, 95% CI 74.6% to 81.7%). Specificity of ROMA at a threshold of 27.7 (± 2) (81.5, 95% CI 76.5% to 85.5%) was comparable to RMI (85.4%, 95% CI 82.0% to 88.2%), whereas for LR2 (post-test probability 10%) and ADNEX (post-test probability 10%) specificity was lower (LR2: 60.6%, 95% CI 50.5% to 69.9%; ADNEX: 55.0%, 95% CI 42.8% to 66.6%). In specialist healthcare settings in both premenopausal and postmenopausal women, RMI has poor sensitivity. In premenopausal women, ROMA, LR2 and ADNEX offer better sensitivity (fewer missed cancers), but for ROMA and ADNEX this is off-set by a decrease in specificity and increase in false positives. In postmenopausal women, ROMA demonstrates a higher sensitivity and comparable specificity to RMI. ADNEX has the highest sensitivity in postmenopausal women, but reduced specificity. The prevalence of OC in included studies is representative of a highly selected referred population, rather than a population in whom referral is being considered. The comparative accuracy of tests observed here may not be transferable to non-specialist settings. Ultimately health systems need to balance accuracy and resource implications to identify the most suitable test.

Taxane monotherapy regimens for the treatment of recurrent epithelial ovarian cancer

Ovarian cancer is the seventh most frequent cancer diagnosis worldwide, and the eighth leading cause of cancer mortality. Epithelial ovarian cancer is the most common kind, accounting for 90% of cases. First-line therapy for women with epithelial ovarian cancer consists of a combination of cytoreductive surgery and platinum and taxane-based chemotherapy. However, more than 50% of women with epithelial ovarian cancer will experience a relapse and require further chemotherapy and at some point develop resistance to platinum-based drugs. Currently, guidance on the use of most chemotherapy drugs, including taxanes, is unclear for women whose epithelial ovarian cancer has recurred. Paclitaxel, topotecan, pegylated liposomal doxorubicin hydrochloride, trabectedin and gemcitabine are all licensed for use in the UK at the discretion of clinicians, following discussion with the women as to potential adverse effects. Taxanes can be given in once-weekly regimens (at a lower dose) or three-weekly regimens (at a higher dose), which may have differences in the severity of side effects and effectiveness. As relapsed disease suggests incurable disease, it is all the more important to consider side effects and the impact of treatment schedules, as well as quality of life, and not only the life-prolonging effects of treatment. To assess the efficacy and toxicity of different taxane monotherapy regimens for women with recurrent epithelial ovarian, tubal or primary peritoneal cancer. We searched CENTRAL, MEDLINE and Embase, up to 22 March 2022. Other related databases and trial registries were searched as well as grey literature and no additional studies were identified. A total of 1500 records were identified. We included randomised controlled trials of taxane monotherapy for adult women diagnosed with recurrent epithelial ovarian, tubal or primary peritoneal cancer, previously treated with platinum-based chemotherapy. We included trials comparing two or more taxane monotherapy regimens. Participants could be experiencing their first recurrence of disease or any line of recurrence. Two review authors screened, independently assessed studies, and extracted data from the included studies. The clinical outcomes we examined were overall survival, response rate, progression-free survival, neurotoxicity, neutropenia, alopecia, and quality of life. We performed statistical analyses using fixed-effect and random-effects models following standard Cochrane methodology. We rated the certainty of evidence according to the GRADE approach. Our literature search yielded 1500 records of 1466 studies; no additional studies were identified by searching grey literature or handsearching. We uploaded the search results into Covidence. After the exclusion of 92 duplicates, we screened titles and abstracts of 1374 records. Of these, we identified 24 studies for full-text screening. We included four parallel-group randomised controlled trials (RCTs). All trials were multicentred and conducted in a hospital setting. The studies included 981 eligible participants with recurrent epithelial ovarian cancer, tubal or primary peritoneal cancer with a median age ranging between 56 to 62 years of age. All participants had a WHO (World Health Organization) performance status of between 0 to 2. The proportion of participants with serous histology ranged between 56% to 85%. Participants included women who had platinum-sensitive (71%) and platinum-resistant (29%) relapse. Some participants were taxane pre-treated (5.6%), whilst the majority were taxane-naive (94.4%). No studies were classified as having a high risk of bias for any of the domains in the Cochrane risk of bias tool. We found that there may be little or no difference in overall survival (OS) between weekly paclitaxel and three-weekly paclitaxel, but the evidence is very uncertain (risk ratio (RR) of 0.94, 95% confidence interval (CI) 0.66 to 1.33, two studies, 263 participants, very low-certainty evidence). Similarly, there may be little or no difference in response rate (RR of 1.07, 95% CI 0.78 to 1.48, two studies, 263 participants, very low-certainty evidence) and progression-free survival (PFS) (RR of 0.83, 95% CI 0.46 to 1.52, two studies, 263 participants, very low-certainty evidence) between weekly and three-weekly paclitaxel, but the evidence is very uncertain. We found differences in the chemotherapy-associated adverse events between the weekly and three-weekly paclitaxel regimens. The weekly paclitaxel regimen may result in a reduction in neutropenia (RR 0.51, 95% 0.27 to 0.95, two studies, 260 participants, low-certainty evidence) and alopecia (RR 0.58, 95% CI 0.46 to 0.73, one study, 205 participants, low-certainty evidence). There may be little or no difference in neurotoxicity, but the evidence was very low-certainty and we cannot exclude an effect (RR 0.53, 95% CI 0.19 to 1.45, two studies, 260 participants). When examining the effect of paclitaxel dosage in the three-weekly regimen, the 250 mg/m Fewer people may experience neutropenia when given weekly rather than three-weekly paclitaxel (low-certainty evidence), although it may make little or no difference to the risk of developing neurotoxicity (very low-certainty evidence). This is based on the participants receiving lower doses of drug more often. However, our confidence in this result is low and the true effect may be substantially different from the estimate of the effect. Weekly paclitaxel probably reduces the risk of alopecia, although the rates in both arms were high (46% versus 79%) (low-certainty evidence). A change to weekly from three-weekly chemotherapy could be considered to reduce the likelihood of toxicity, as it may have little or no negative impact on response rate (very low-certainty evidence), PFS (very low-certainty evidence) or OS (very low-certainty evidence). Three-weekly paclitaxel, given at a dose of 175 mg/m

Pelvic floor muscle therapy for sexual dysfunction in gynaecological cancer survivors

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of pelvic floor muscle therapy for sexual dysfunction in gynaecological cancer survivors.

Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with epithelial ovarian cancer

Epithelial ovarian cancer is the sixth most common cancer worldwide: 295,414 new cases were diagnosed in 2018, with 184,799 deaths. The lack of an effective screening strategy has led to the majority of women being diagnosed at an advanced stage. For these women, intravenous carboplatin combined with paclitaxel for six cycles is widely accepted as the standard first-line treatment for epithelial ovarian cancer, in combination with debulking surgery. However, there is conflicting evidence regarding the optimal dosing schedule of paclitaxel when combined with carboplatin in this setting. To compare the efficacy and tolerability of intravenous weekly paclitaxel with that of tri-weekly paclitaxel, in combination with intravenous carboplatin, as first-line treatment for epithelial ovarian cancer (defined as epithelial ovarian, primary peritoneal and fallopian tube cancer). We searched CENTRAL, MEDLINE, and Embase databases for relevant studies up to 15 November 2021, using keywords and MeSH terms. We additionally handsearched conference libraries, online clinical trial databases and screened through lists of retrieved references. We Included randomised controlled trials (RCTs) comparing weekly paclitaxel in combination with carboplatin versus tri-weekly paclitaxel in combination with carboplatin, for treatment of newly-diagnosed epithelial ovarian cancer. We used the hazard ratio (HR) to estimate the primary efficacy outcomes progression-free (PFS) and overall survival (OS). We used the risk ratio (RR) to estimate the primary toxicity outcome of severe neutropenia and secondary outcomes of quality of life (QoL) and treatment-related adverse events. Two review authors independently selected studies, extracted data, and assessed risk of bias, using standard Cochrane methodological procedures. We included individual participant data (IPD) from one of the included studies, ICON-8, provided by the study team. We analysed data using a random-effects model in Review Manager 5.4 software. Additionally, we reconstructed IPD for PFS and OS data from published Kaplan-Meier curves from all studies and subsequently pooled these to analyse the two primary efficacy outcomes. From 2469 records, we identified four eligible RCTs with data for 3699 participants. All eligible studies were included in the main meta-analysis and reported on PFS and OS. There was likely a slight improvement in PFS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.89, 95% confidence interval (CI) 0.81 to 0.98; 4 studies, 3699 participants; moderate-certainty evidence). We found little to no improvement in OS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.92, 95% CI 0.79 to 1.06; 4 studies, 3699 participants; high-certainty evidence). There was likely little to no difference in high-grade (grade 3 or 4) neutropenia when paclitaxel was dosed weekly compared to tri-weekly (RR 1.11, 95% CI 0.86 to 1.43; 4 studies, 3639 participants; moderate-certainty evidence). However, weekly paclitaxel increased high-grade (grade 3 or 4) anaemia when compared to tri-weekly dosing (RR 1.57, 95% CI 1.12 to 2.20; 4 studies, 3639 participants; high-certainty evidence). There may be little to no difference in high-grade neuropathy when paclitaxel was dosed weekly compared to tri-weekly (RR 1.12, 95% CI 0.64 to 1.94; 4 studies, 3639 participants; low-certainty evidence). The overall risk of detection bias and performance bias was low for OS, but was unclear for other outcomes, as treatments were not blinded. The risk of bias in other domains was low or unclear. We note that OS data were immature for three of the included studies (GOG-0262, ICON-8 and MITO-7). Weekly paclitaxel combined with carboplatin for first-line treatment of epithelial ovarian cancer likely improves PFS slightly (moderate-certainty evidence) but not OS (high-certainty evidence), compared to tri-weekly paclitaxel combined with carboplatin. However, this was associated with increased risk for high-grade anaemia, treatment discontinuation, dose delays and dose omissions (high- to low-certainty evidence). Our findings may not apply to women receiving bevacizumab in first-line therapy, those receiving treatment in the neo-adjuvant setting, or those with rare subtypes of clear cell or mucinous ovarian cancer.

Caesarean myomectomy in pregnant women with uterine fibroids

Postpartum haemorrhage, defined as a blood loss of 500 mL or more within 24 hours of birth, is the leading global cause of maternal morbidity and mortality. Uterine fibroids are non-cancerous growths that develop in or around the uterus, and affect an increasing number of women. Caesarean myomectomy is the surgical removal of fibroids during a caesarean section. Traditionally, obstetricians have avoided this procedure given the risk of uncontrollable haemorrhage. There is also the risk of longer operating time and more days in the hospital. However, there could be potential benefits in removing uterine fibroids for improved fertility, and caesarean section may provide an effective and efficient opportunity to perform this procedure. Given the link between removal of uterine fibroids and postpartum haemorrhage, it is prudent to evaluate current literature and assess the benefits and harms of caesarean myomectomy in pregnant women with uterine fibroids. To assess the benefits and harms of caesarean myomectomy in pregnant women with uterine fibroids undergoing caesarean section. We searched CENTRAL, MEDLINE, Embase, Global Index Medicus, ICTRP portal, and ClinicalTrials.gov; performed supplementary searches of references and citations; and contacted study authors on 2 February 2024. We included published randomised and quasi-randomised controlled trials, and observational controlled studies that assessed the impact of myomectomy on maternal health outcomes in pregnant women with fibroids undergoing caesarean birth. We excluded qualitative studies, case reports or series, conference abstracts, opinion papers, letters, and book chapters. There were no restrictions on ethnicity, race, socioeconomic status, education level, or place of residence. Critical outcomes were requirement for blood transfusion, risk of haemorrhage, change in haemoglobin, length of hospitalisation, length of operation, major surgery at time of procedure, fertility outcome, and postpartum fever. We assessed risk of bias for non-randomised controlled studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. We conducted a meta-analysis for each outcome when more than one study provided data. If it was not possible to analyse data via meta-analysis, we synthesised results narratively using Synthesis Without Meta-analysis (SWiM) guidance. We used GRADE to assess certainty of evidence for each critical and important outcome. We included 23 non-randomised studies with 7504 women. Most studies were conducted in high-income or upper-middle-income countries. Five studies enrolled women with singleton pregnancies and one study was restricted to women with a twin pregnancy. Most studies did not report whether the caesarean section was elective or emergent. Thirteen studies diagnosed fibroids prior to operation. Blood transfusion The evidence is very uncertain about whether caesarean myomectomy affects the risk of requiring blood transfusion compared to caesarean section alone (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.01 to 1.79; I The available evidence for all critical outcomes is very low certainty. As such, it is not possible to draw conclusions about the effects of caesarean myomectomy on the risk of requiring blood transfusion, risk of haemorrhage, length of hospitalisation, length of operation, risk of major surgery at time of procedure, and risk of postpartum fever. Data retrieved on mean change in haemoglobin were too heterogenous to be pooled. There were no data on fertility outcomes. This Cochrane review had no dedicated funding. The review was registered with PROSPERO (CRD42024554215) and available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024554215.

Lymphadenectomy or sentinel node biopsy for the management of endometrial cancer

Endometrial cancer, which affects the lining of the uterus, is the most common form of uterine cancer (96%), and the sixth most common cancer in females worldwide, accounting for 4.5% of all cancers in females. In 2022, there were 420,242 cases of uterine cancer and 97,704 deaths from the disease worldwide. Most women have early-stage endometrial cancer at diagnosis. Traditionally, surgical staging included removal of all lymph nodes (lymphadenectomy) in the pelvis (pelvic lymphadenectomy) with or without para-aortic areas (pelvic/para-aortic lymphadenectomy), to determine the need for further treatment. However, rates of lymph node involvement are relatively low and may be predicted by uterine histopathology and molecular markers. Lymphadenectomy carries a significant risk of long-term morbidity from lymphoedema and previous studies comparing pelvic lymphadenectomy with no lymphadenectomy found no survival benefit. Detecting the first draining lymph node(s) from each side of the uterus, called sentinel lymph node biopsy, can replace lymphadenectomy in terms of accuracy of detecting nodes, but no studies have shown whether sentinel lymph node biopsy is beneficial to women, despite its wide use. To evaluate the benefits and harms of lymphadenectomy and sentinel lymph node biopsy for the management of endometrial cancer comparing different head-to-head comparisons in a network meta-analysis allowing ranking of treatment strategies. We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and the WHO ICTRP for studies up to 22 March 2024. We included randomised controlled trials (RCTs) of women with early-stage endometrial cancer, comparing combinations of no lymphadenectomy, pelvic lymphadenectomy, pelvic/para-aortic lymphadenectomy and sentinel lymph node biopsy. We excluded non-randomised studies and studies assessing diagnostic test accuracy of lymph node sampling. Overall survival; progression-free survival; morbidity and mortality related to surgery; early and late adverse events, including lymphoedema and lymphocyst formation; and quality of life. We used RoB 2 to assess risk of bias. We conducted meta-analyses using random-effects models to calculate hazard ratios (HR) for time-to-event data and risk ratios (RR) and mean difference (MD) for other outcomes, with 95% confidence intervals (CI). We used GRADE to summarise the certainty of evidence. We intended to compare treatments in a network meta-analysis. We included five RCTs (one remains ongoing) with 2074 women. Studies were conducted in the UK, South Africa, Poland, New Zealand, Chile, Italy, Egypt and Brazil, and published between 2008 and 2023. Another 10 studies are ongoing. Three studies (1955 participants) compared no lymphadenectomy with pelvic lymphadenectomy, one study (50 participants) compared no lymphadenectomy with pelvic/para-aortic lymphadenectomy, and one study (69 participants - ongoing) compared sentinel lymph node biopsy with pelvic/para-aortic lymphadenectomy. No lymphadenectomy versus pelvic lymphadenectomy No lymphadenectomy probably results in little to no difference in overall survival (HR 0.85, 95% CI 0.66 to 1.10; 2 studies, 1922 participants; moderate-certainty evidence) and improves progression-free survival (HR 0.78, 95% CI 0.63 to 0.96; 2 studies, 1922 participants; high-certainty evidence) compared to pelvic lymphadenectomy. No lymphadenectomy may reduce early adverse effects from direct surgical morbidity slightly (RR 0.68, 95% CI 0.27 to 1.71; 3 studies, 1955 participants; low-certainty evidence) and probably reduces early adverse effects due to surgically related systemic morbidity (RR 0.28, 95% CI 0.09 to 0.93; 3 studies, 1955 participants; moderate-certainty evidence). No lymphadenectomy probably results in a large reduction in lymphoedema (RR 0.12, 95% CI 0.05 to 0.26; 3 studies, 1955 participants; moderate-certainty evidence) and likely reduces lymphocyst formation (RR 0.20, 95% CI 0.04 to 0.91; 1 study, 1403 participants; moderate-certainty evidence). There were no quality of life data. Sentinel lymph node biopsy versus pelvic/para-aortic lymphadenectomy One study shared unpublished data and the evidence is very uncertain about the effect of sentinel lymph node biopsy on overall survival, progression-free survival, early adverse events, lymphocyst formation and quality of life at 12 months. Sentinel lymph node biopsy compared with pelvic/para-aortic lymphadenectomy probably reduces the development of lymphoedema (RR 0.30, 95% CI 0.09 to 0.97; 1 study, 69 participants; moderate-certainty evidence). No lymphadenectomy versus pelvic/para-aortic lymphadenectomy One study closed after the recruitment of 50 participants due to slow uptake, and we were unable to extract data for use in the meta-analysis. Because of this, we were unable to form a linked network for meta-analysis. Other comparisons Studies of other comparisons are ongoing or results are yet to be published. Data suggest 'less is probably more' in terms of surgical staging for women with presumed endometrial cancer, as no lymphadenectomy is favoured over pelvic lymphadenectomy in terms of important outcomes, with overall moderate certainty. Preliminary results for sentinel lymph node biopsy versus pelvic/para-aortic lymphadenectomy have a similar direction of effect, but the evidence is very uncertain. Data from several studies are ongoing. However, given the weight of evidence that supports no lymphadenectomy over lymphadenectomy, our ability to make adjuvant treatment decisions based on uterine factors, and the advent of molecular profiling, it is disappointing that only one study compared no lymphadenectomy with sentinel lymph node biopsy, potentially putting many women at continued risk of short- and significant long-term consequences of extensive lymphadenectomy. This Cochrane review had no dedicated funding. This review is based on an updated protocol including network meta-analysis methods and new RoB 2 assessment of a previously published review. Updated protocol 2023 available via https://doi.org/10.1002/14651858.CD015786.

Ultrasound and blind endometrial sampling for detection of endometrial cancer in women with postmenopausal bleeding

This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the diagnostic accuracy of endometrial sampling with histology in the diagnosis of endometrial cancer in women with postmenopausal bleeding and thickened endometrium on ultrasound. Diagnosis will be verified by the reference standards, hysteroscopy with histology, obtained by targeted (such as grasp biopsy of the endometrium or resection of focal pathology) or global sampling (with dilation and curettage), and histology of hysterectomy specimens. Secondary objectives To determine the diagnostic accuracy of different sampling devices and methods in the detection of endometrial cancer To assess the diagnostic accuracy of endometrial sampling devices and methods to detect endometrial hyperplasia To determine accuracy in diagnosing endometrial cancer and endometrial hyperplasia at different endometrial thicknesses of 3 mm, 4 mm and 5 mm To investigate sources of heterogeneity.

Interventions for weight reduction in obesity to improve survival in women with endometrial cancer

This is an updated version of the original Cochrane Review published in Issue 2, 2018. Diagnoses of endometrial cancer are increasing secondary to the rising prevalence of obesity. Obesity plays an important role in promoting the development of endometrial cancer, by inducing a state of unopposed oestrogen excess, insulin resistance and inflammation. It also affects treatment, increasing the risk of surgical complications and the complexity of radiotherapy planning, and may additionally impact on subsequent survival. Weight-loss interventions have been associated with improvements in breast and colorectal cancer-specific survival, as well as a reduction in the risk of cardiovascular disease, which is a frequent cause of death in endometrial cancer survivors. To evaluate the benefits and harm of weight-loss interventions, in addition to standard management, on overall survival and the frequency of adverse events in women with endometrial cancer who are overweight or obese compared with any other intervention, usual care, or placebo. We used standard, extensive Cochrane search methods. The latest search date was from January 2018 to June 2022 (original review searched from inception to January 2018). We included randomised controlled trials (RCTs) of interventions to facilitate weight loss in women with endometrial cancer who are overweight or obese undergoing treatment for, or previously treated for, endometrial cancer compared with any other intervention, usual care, or placebo.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. overall survival and 2. frequency of adverse events. Our secondary outcomes were 3. recurrence-free survival, 4. cancer-specific survival, 5. weight loss, 6. cardiovascular and metabolic event frequency and 7. quality of Life. We used GRADE to assess certainty of evidence. We contacted study authors to obtain missing data, including details of any adverse events. We identified nine new RCTs and combined these with the three RCTs identified in the original review. Seven studies are ongoing.  The 12 RCTs randomised 610 women with endometrial cancer who were overweight or obese. All studies compared combined behavioural and lifestyle interventions designed to facilitate weight loss through dietary modification and increased physical activity with usual care. Included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow-up (withdrawal rate up to 28% and missing data up to 65%, largely due to the effects of the COVID-19 pandemic). Importantly, the short duration of follow-up limits the directness of the evidence in evaluating the impact of these interventions on any of the survival and other longer-term outcomes.  Combined behaviour and lifestyle interventions were not associated with improved overall survival compared with usual care at 24 months (risk ratio (RR) mortality, 0.23, 95% confidence interval (CI) 0.01 to 4.55, P = 0.34; 1 RCT, 37 participants; very low-certainty evidence). There was no evidence that such interventions were associated with improvements in cancer-specific survival or cardiovascular event frequency as the studies reported no cancer-related deaths, myocardial infarctions or strokes, and there was only one episode of congestive heart failure at six months (RR 3.47, 95% CI 0.15 to 82.21; P = 0.44, 5 RCTs, 211 participants; low-certainty evidence). Only one RCT reported recurrence-free survival; however, there were no events. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six or 12 months compared with usual care (at six months: mean difference (MD) -1.39 kg, 95% CI -4.04 to 1.26; P = 0.30, I

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen

Adjuvant tamoxifen reduces the risk of breast cancer recurrence in women with oestrogen receptor-positive breast cancer. Tamoxifen also increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer. The levonorgestrel-releasing intrauterine system (LNG-IUS) causes profound endometrial suppression. This systematic review considered the evidence that the LNG-IUS prevents the development of endometrial pathology in women taking tamoxifen as adjuvant endocrine therapy for breast cancer. To determine the effectiveness and safety of the levonorgestrel intrauterine system (LNG-IUS) in pre- and postmenopausal women taking adjuvant tamoxifen following breast cancer for the outcomes of endometrial and uterine pathology including abnormal vaginal bleeding or spotting, and secondary breast cancer events. We searched the following databases on 29 June 2020; The Cochrane Gynaecology and Fertility Group specialised register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO and Cumulative Index to Nursing and Allied Health Literature. We searched the Cochrane Breast Cancer Group specialised register on 4 March 2020. We also searched two trials registers, checked references for relevant trials and contacted study authors and experts in the field to identify additional studies. We included randomised controlled trials (RCTs) of women with breast cancer on adjuvant tamoxifen that compared the effectiveness of the LNG-IUS with endometrial surveillance versus endometrial surveillance alone on the incidence of endometrial pathology. We used standard methodological procedures recommended by Cochrane. The primary outcome measure was endometrial pathology (including polyps, endometrial hyperplasia, or endometrial cancer), diagnosed at hysteroscopy or endometrial biopsy. Secondary outcome measures included fibroids, abnormal vaginal bleeding or spotting, breast cancer recurrence, and breast cancer-related deaths. We rated the overall certainty of evidence using GRADE methods. We included four RCTs (543 women analysed) in this review. We judged the certainty of the evidence to be moderate for all of the outcomes, due to imprecision (i.e. limited sample sizes and low event rates). In the included studies, the active treatment arm was the 20 μg/day LNG-IUS plus endometrial surveillance; the control arm was endometrial surveillance alone. In tamoxifen users, the LNG-IUS probably reduces the incidence of endometrial polyps compared to the control group over both a 12-month period (Peto odds ratio (OR) 0.22, 95% confidence interval (CI) 0.08 to 0.64, I² = 0%; 2 RCTs, n = 212; moderate-certainty evidence) and over a long-term follow-up period (24 to 60 months) (Peto OR 0.22, 95% CI 0.13 to 0.39; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). For long-term follow-up, this suggests that if the incidence of endometrial polyps following endometrial surveillance alone is assumed to be 23.5%, the incidence following LNG-IUS with endometrial surveillance would be between 3.8% and 10.7%.  The LNG-IUS probably slightly reduces the incidence of endometrial hyperplasia compared with controls over a long-term follow-up period (24 to 60 months) (Peto OR 0.13, 95% CI 0.03 to 0.67; I² = 0%; 4 RCTs, n = 417; moderate-certainty evidence). This suggests that if the chance of endometrial hyperplasia following endometrial surveillance alone is assumed to be 2.8%, the chance following LNG-IUS with endometrial surveillance would be between 0.1% and 1.9%. However, it should be noted that there were only six cases of endometrial hyperplasia. There was insufficient evidence to reach a conclusion regarding the incidence of endometrial cancer in tamoxifen users, as no studies reported cases of endometrial cancer. At 12 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting compared to the control group (Peto OR 7.26, 95% CI 3.37 to 15.66; I² = 0%; 3 RCTs, n = 376; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 1.7%, the chance following LNG-IUS with endometrial surveillance would be between 5.6% and 21.5%. By 24 months of follow-up, abnormal vaginal bleeding or spotting occurs less frequently than at 12 months of follow-up, but is still more common in the LNG-IUS group than the control group (Peto OR 2.72, 95% CI 1.04 to 7.10; I² = 0%; 2 RCTs, n = 233; moderate-certainty evidence). This suggests that if the chance of abnormal vaginal bleeding or spotting following endometrial surveillance alone is assumed to be 4.2%, the chance following LNG-IUS with endometrial surveillance would be between 4.4% and 23.9%. By 60 months of follow-up, there were no cases of abnormal vaginal bleeding or spotting in either group. The numbers of events for the following outcomes were low: fibroids (n = 13), breast cancer recurrence (n = 18), and breast cancer-related deaths (n = 16). As a result, there is probably little or no difference in these outcomes between the LNG-IUS treatment group and the control group.  AUTHORS' CONCLUSIONS: The LNG-IUS probably slightly reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS probably increases abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. Data were lacking on whether the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available RCTs that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events.