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BMC Medicine Nov 2023Sex difference exists in the prevalence of dementia and cognitive decline. The impacts of sex-specific reproductive risk factors across the lifespan on the risk of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Sex difference exists in the prevalence of dementia and cognitive decline. The impacts of sex-specific reproductive risk factors across the lifespan on the risk of dementia or cognitive decline are still unclear. Herein, we conducted this systemic review and meta-analysis to finely depict the longitudinal associations between sex-specific reproductive factors and dementia or cognitive decline.
METHODS
PubMed, EMBASE, and Cochrane Library were searched up to January 2023. Studies focused on the associations of female- and male-specific reproductive factors with dementia or cognitive decline were included. Multivariable-adjusted effects were pooled via the random effect models. Evidence credibility was scored by the GRADE system. The study protocol was pre-registered in PROSPERO and the registration number is CRD42021278732.
RESULTS
A total of 94 studies were identified for evidence synthesis, comprising 9,839,964 females and 3,436,520 males. Among the identified studies, 63 of them were included in the meta-analysis. According to the results, seven female-specific reproductive factors including late menarche (risk increase by 15%), nulliparous (11%), grand parity (32%), bilateral oophorectomy (8%), short reproductive period (14%), early menopause (22%), increased estradiol level (46%), and two male-specific reproductive factors, androgen deprivation therapy (18%), and serum sex hormone-binding globulin (22%) were associated with an elevated risk of dementia or cognitive decline.
CONCLUSIONS
These findings potentially reflect sex hormone-driven discrepancy in the occurrence of dementia and could help build sex-based precise strategies for preventing dementia.
Topics: Pregnancy; Female; Male; Humans; Dementia; Longevity; Androgen Antagonists; Prostatic Neoplasms; Cognitive Dysfunction; Risk Factors; Parity
PubMed: 37996855
DOI: 10.1186/s12916-023-03159-0 -
JACC. CardioOncology Oct 2023Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest...
BACKGROUND
Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists.
OBJECTIVES
This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists.
METHODS
Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: "myocardial infarction," "central nervous system hemorrhages and cerebrovascular conditions," and all-cause mortality. Bayesian meta-analysis models with random effects were fitted.
RESULTS
A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death.
CONCLUSIONS
Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.
PubMed: 37969642
DOI: 10.1016/j.jaccao.2023.05.011 -
European Urology Feb 2024Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies.
OBJECTIVE
To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients.
EVIDENCE ACQUISITION
We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators.
EVIDENCE SYNTHESIS
We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively.
CONCLUSIONS
MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain.
PATIENT SUMMARY
Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity.
Topics: Male; Humans; Prostatic Neoplasms; Prospective Studies; Androgen Antagonists; Progression-Free Survival; Hormones
PubMed: 37945451
DOI: 10.1016/j.eururo.2023.10.012 -
Current Oncology (Toronto, Ont.) Oct 2023Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate... (Meta-Analysis)
Meta-Analysis Review
Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752-0.974; = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566-0.692; = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637-0.877; = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide.
Topics: Humans; Male; Androgen Antagonists; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic
PubMed: 37887569
DOI: 10.3390/curroncol30100669 -
Psycho-oncology Nov 2023To evaluate the evidence base for patient, oncological, and treatment prognostic factors associated with multiple mental wellbeing outcomes in prostate cancer patients. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To evaluate the evidence base for patient, oncological, and treatment prognostic factors associated with multiple mental wellbeing outcomes in prostate cancer patients.
METHODS
We performed a literature search of MEDLINE, EMBASE, and CINAHL databases including studies evaluating patient, oncological, or treatment factors against one of five mental wellbeing outcomes; depression, anxiety, fear of cancer recurrence, masculinity, and body image perception. Data synthesis included a random effects meta-analysis for the prognostic effect of individual factors if sufficient homogenous data was available, with a structured narrative synthesis where this was not possible.
RESULTS
A final 62 articles were included. Older age was associated with a reducing odds of depression (OR 0.97, p = 0.04), with little evidence of effect for other outcomes. Additionally, baseline mental health status was related to depression and increasing time since diagnosis was associated with reducing fear of recurrence, albeith with low certainty of evidence. However, few other patient or oncological factors demonstrated any coherent relationship with any wellbeing outcome. Androgen deprivation therapy was associated with increased depression (HR 1.65, 95% CI 1.41-1.92, p < 0.01) and anxiety, however, little difference was seen between other treatment options. Overall, whilst numerous factors were identified, most were evaluated by single studies with few evaluating masculinity and body image outcomes.
CONCLUSION
We highlight the existing evidence for prognostic factors in mental wellbeing outcomes in prostate cancer, allowing us to consider high-risk groups of patients for preventative and treatment measures. However, the current evidence is heterogenous with further work required exploring less conclusive factors and outcomes.
Topics: Male; Humans; Prostatic Neoplasms; Depression; Prognosis; Androgen Antagonists; Neoplasm Recurrence, Local; Quality of Life
PubMed: 37789603
DOI: 10.1002/pon.6225 -
Cureus Aug 2023Oral spironolactone has been proposed as a potential treatment for hair loss due to its antiandrogenic properties. However, the efficacy and safety of spironolactone for... (Review)
Review
Oral spironolactone has been proposed as a potential treatment for hair loss due to its antiandrogenic properties. However, the efficacy and safety of spironolactone for treating hair loss are not well-established. The objective of this study was to conduct a systematic review of the current literature on the use of oral spironolactone in female pattern hair loss. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies that assessed the efficacy and safety of oral spironolactone for treating hair loss. We searched for eligible papers in PubMed, Web of Science (ISI), Embase, and Scopus. All analyses were done using R software version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). The overall rate of improved hair loss was 56.60%, with a higher rate of improvement (65.80%) observed in the combined therapy group compared to the monotherapy group (43.21%). However, there was significant heterogeneity in the efficacy outcomes, and hair loss did not improve or showed a modest improvement in 37.80% of all patients. The rates of adverse events reported in at least two studies were scalp pruritus or increased scurf (18.92%), menstrual disorders (11.85%), facial hypertrichosis (6.93%), and drug discontinuation (2.79%). The overall adverse events rate was 3.69%, but there was significant heterogeneity in the rates of different adverse events. In conclusion, the present study suggests that spironolactone is an effective and safe treatment option for hair loss. However, further research is needed to fully understand the heterogeneity of treatment response and adverse events and identify factors that may predict treatment response.
PubMed: 37719557
DOI: 10.7759/cureus.43559 -
Frontiers in Endocrinology 2023Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer,... (Meta-Analysis)
Meta-Analysis
AIMS
Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer, combined with spironolactone, an antiandrogen medication, may exert complementary effects on PCOS. We therefore performed a meta-analysis of trials in which metformin combined with spironolactone was applied to treat PCOS to evaluate the efficacy and safety of the combination therapy.
METHODS
We retrieved the PubMed, Embase, Scopus, Cochrane Library, CNKI, CBM, Wangfang, and VIP databases for literatures published from their inception to December 16, 2022 on the effects of metformin combined with spironolactone in the treatment of PCOS. Inclusion criteria according to P.I.C.O.S criteria were: PCOS patients, metformin combined with spironolactone interventions, metformin alone control group, and randomized controlled trials with the following outcome data: body mass index (BMI), hirsutism score, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and side effects including nausea, vomiting, diarrhea and drug withdrawal.
RESULTS
Our results revealed that metformin combined with spironolactone significantly reduced BMI and TT, but that it exerted no significant effects on hirsutism score, or on FSH or LH concentrations. Combined treatment also resulted in a significant diminution in FBG and insulin resistance using the HOMA-IR when the interventional time was greater than 6 months. In addition, the combination did not have a higher occurrence of adverse reactions than metformin alone.
CONCLUSION
Compared with metformin alone, metformin combined with spironolactone therapy may be more effective in reducing BMI and serum androgen levels, but the combination showed no significant effect on the hirsutism score or gonadotropin hormone levels, and was not associated with an elevation in side-effects. Moreover, when the treatment course was greater than 6 months, combination therapy reduced FBG and improved insulin resistance more effectively than metformin alone. However, more research is needed to determine the most effective course of treatment.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022355515.
Topics: Female; Humans; Hirsutism; Insulin Resistance; Polycystic Ovary Syndrome; Spironolactone; Drug-Related Side Effects and Adverse Reactions; Follicle Stimulating Hormone, Human; Luteinizing Hormone
PubMed: 37635987
DOI: 10.3389/fendo.2023.1223768 -
Cancers Jul 2023Measuring serum testosterone determination during medical castration is recommended by prostate cancer (PCa) guidelines to assess its efficacy and define castration... (Review)
Review
Measuring serum testosterone determination during medical castration is recommended by prostate cancer (PCa) guidelines to assess its efficacy and define castration resistance. It has been suggested that other biochemical compounds, such as free testosterone or luteinising hormone (LH), could also assess castration efficacy. We aimed to analyse the current evidence for serum biochemical compounds that could be appropriate candidates for evaluating medical castration efficacy. A systematic review was conducted after two investigators independently searched the literature in the PubMed, Cochrane Library, and EMBASE databases published between January 1980 and February 2023. Their searches used the medical subject headings 'prostatic neoplasms', 'testosterone and androgen antagonists', 'gonadotropin-releasing hormone/analogues and derivatives', 'free testosterone', and 'luteinising hormone'. Studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria, and their eligibility was based on the Participants, Intervention, Comparator, and Outcome strategy. The search was limited to original articles published in English. Among the 6599 initially identified titles, 15 original studies analysing the clinical impact of serum testosterone levels in PCa patients undergoing androgen deprivation therapy (ADT) were selected for evidence acquisition. The risk of bias in individual studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. All selected studies used immunoassays to measure serum testosterone, although only methods based on liquid or gas chromatography and mass spectrometry are recommended to measure low testosterone concentrations. The reported series were not uniform in clinical stage, ADT types, and the time or number of serum testosterone measurements. Only some studies found low serum testosterone levels (<20 or <32 ng/dL) associated with greater survival free of biochemical progression and castration resistance. We conclude that little current evidence justifies the measurement of serum testosterone during ADT using no appropriate methods. No reported longitudinal studies have examined the clinical impact of serum testosterone measured using liquid chromatography with tandem mass spectrometry (LC-MSMS), free testosterone, or LH in PCa patients undergoing medical castration. We conclude that well-designed longitudinal studies examining the clinical impact of serum testosterone measured with LC-MSMS, serum-free testosterone, and LH on biochemical progression and castration resistance in PCa patients undergoing neo-adjuvant castration in radiation therapy or continuous castration are needed.
PubMed: 37444589
DOI: 10.3390/cancers15133479 -
The Lancet. Oncology Jul 2023Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about... (Meta-Analysis)
Meta-Analysis
Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.
BACKGROUND
Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours.
METHODS
The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591.
FINDINGS
We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (p=0·0019), higher volume of metastases (p=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival).
INTERPRETATION
The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes.
FUNDING
UK Medical Research Council and Prostate Cancer UK.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms; Androgen Antagonists; Disease-Free Survival; Hormones; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic
PubMed: 37414011
DOI: 10.1016/S1470-2045(23)00230-9 -
European Urology Oncology Feb 2024Since 2015 there have been major advances in the management of primary metastatic hormone-sensitive prostate cancer (mHSPC) following the publication of key clinical... (Review)
Review
Does Research from Clinical Trials in Metastatic Hormone-sensitive Prostate Cancer Treatment Translate into Access to Treatments for Patients in the "Real World"? A Systematic Review.
CONTEXT
Since 2015 there have been major advances in the management of primary metastatic hormone-sensitive prostate cancer (mHSPC) following the publication of key clinical trials that demonstrated significant clinical benefits with docetaxel chemotherapy or novel hormone therapy (NHT) in addition to androgen deprivation therapy (ADT). Despite these advances, there is evidence to show that these treatments are not being utilised for mHSPC in clinical practice.
OBJECTIVE
To determine the utilisation of docetaxel and NHT in mHSPC in routine practice and the determinants of variation in their use.
EVIDENCE ACQUISITION
MEDLINE and Embase were searched systematically for studies on utilisation of treatments for primary mHSPC that were based on regional or national data sets and published after January 2005. Study results were summarised using a narrative synthesis.
EVIDENCE SYNTHESIS
Thirteen papers were included in the analysis, six full-text articles and seven abstracts, on studies that included a total of 166 876 patients. The utilisation rate of treatment intensification with either docetaxel or NHT (enzalutamide, apalutamide, or abiraterone) in addition to ADT ranged from 9.3% to 38.1% across the studies. Younger, White patients with fewer comorbidities and living in more urban settings were more likely to be prescribed treatment intensification. Patients treated in private academic institutions by oncologists were more likely to receive docetaxel or NHT. Socioeconomic status did not impact receipt of systemic therapy. NHT utilisation rates appear to have increased over time.
CONCLUSIONS
These results highlight the need to change the approach to the treatment of primary mHSPC in the real world by harnessing the practice-changing results from recent trials in this setting to optimise upfront systemic therapy for this patient population.
PATIENT SUMMARY
We reviewed the use of treatments for primary metastatic hormone-sensitive prostate cancer that showed a benefit in key clinical trials. We found that these treatments are underused, particularly among certain patient groups.
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Treatment Outcome; Hormones; Health Services Accessibility
PubMed: 37380578
DOI: 10.1016/j.euo.2023.05.002