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BJU International Apr 2022To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel.
METHODS
Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible.
RESULTS
Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS.
CONCLUSIONS
All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Docetaxel; Hormones; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms
PubMed: 34171173
DOI: 10.1111/bju.15507 -
European Urology Dec 2022Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide,... (Meta-Analysis)
Meta-Analysis Review
Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with Androgen Deprivation Therapy for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Meta-analysis.
CONTEXT
Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
OBJECTIVE
To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.
EVIDENCE ACQUISITION
Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.
EVIDENCE SYNTHESIS
Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.
CONCLUSIONS
We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.
PATIENT SUMMARY
Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.
Topics: Humans; Male; Docetaxel; Androgen Antagonists; Androgens; Receptors, Androgen; Antineoplastic Combined Chemotherapy Protocols; Prostatic Neoplasms
PubMed: 35995644
DOI: 10.1016/j.eururo.2022.08.002 -
JAMA Oncology May 2023The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.
OBJECTIVE
To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.
DATA SOURCES
For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available.
STUDY SELECTION
Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.
MAIN OUTCOMES AND MEASURES
Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.
RESULTS
This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT.
CONCLUSIONS AND RELEVANCE
The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.
Topics: Aged; Humans; Male; Middle Aged; Androgen Antagonists; Androgens; Castration; Network Meta-Analysis; Prostatic Neoplasms; Quality of Life
PubMed: 36862387
DOI: 10.1001/jamaoncol.2022.7762 -
European Urology Jul 2019Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC).
OBJECTIVE
To systematically review trials of prostate radiotherapy.
DESIGN, SETTING, AND PARTICIPANTS
Using a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators.
INTERVENTION
We included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Hazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis.
RESULTS AND LIMITATIONS
We identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81-1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84-1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67-0.82, p=0.94×10) and FFS (HR=0.76, 95% CI 0.69-0.84, p=0.64×10), equivalent to ∼10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden-a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR=1.47, 95% CI 1.11-1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases.
CONCLUSIONS
Prostate radiotherapy should be considered for men with mHSPC with a low metastatic burden.
PATIENT SUMMARY
Prostate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.
Topics: Bone Neoplasms; Disease-Free Survival; Gonadotropin-Releasing Hormone; Humans; Male; Orchiectomy; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate; Tumor Burden
PubMed: 30826218
DOI: 10.1016/j.eururo.2019.02.003 -
British Journal of Sports Medicine Aug 2021We systemically reviewed the literature to assess how long-term testosterone suppressing gender-affirming hormone therapy influenced lean body mass (LBM), muscular area,...
How does hormone transition in transgender women change body composition, muscle strength and haemoglobin? Systematic review with a focus on the implications for sport participation.
OBJECTIVES
We systemically reviewed the literature to assess how long-term testosterone suppressing gender-affirming hormone therapy influenced lean body mass (LBM), muscular area, muscular strength and haemoglobin (Hgb)/haematocrit (HCT).
DESIGN
Systematic review.
DATA SOURCES
Four databases (BioMed Central, PubMed, Scopus and Web of Science) were searched in April 2020 for papers from 1999 to 2020.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Eligible studies were those that measured at least one of the variables of interest, included transwomen and were written in English.
RESULTS
Twenty-four studies were identified and reviewed. Transwomen experienced significant decreases in all parameters measured, with different time courses noted. After 4 months of hormone therapy, transwomen have Hgb/HCT levels equivalent to those of cisgender women. After 12 months of hormone therapy, significant decreases in measures of strength, LBM and muscle area are observed. The effects of longer duration therapy (36 months) in eliciting further decrements in these measures are unclear due to paucity of data. Notwithstanding, values for strength, LBM and muscle area in transwomen remain above those of cisgender women, even after 36 months of hormone therapy.
CONCLUSION
In transwomen, hormone therapy rapidly reduces Hgb to levels seen in cisgender women. In contrast, hormone therapy decreases strength, LBM and muscle area, yet values remain above that observed in cisgender women, even after 36 months. These findings suggest that strength may be well preserved in transwomen during the first 3 years of hormone therapy.
Topics: Adipose Tissue; Androgen Antagonists; Athletic Performance; Body Composition; Cyproterone Acetate; Estradiol; Female; Hematocrit; Hemoglobin A; Humans; Male; Muscle Strength; Muscle, Skeletal; Sports; Testosterone; Time Factors; Transgender Persons; Transsexualism
PubMed: 33648944
DOI: 10.1136/bjsports-2020-103106 -
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 -
JAMA Oncology Jul 2023The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.
OBJECTIVE
To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.
DATA SOURCES
PubMed, EMBASE, and Scopus (inception to September 12, 2022).
STUDY SELECTION
Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue, weakness), or falls were evaluated.
DATA EXTRACTION AND SYNTHESIS
Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality and Transparency of Health Research reporting guidelines. Tabular counts for all-grade toxic effects were determined to test the hypothesis formulated before data collection.
MAIN OUTCOMES AND MEASURES
Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics.
RESULTS
The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).
CONCLUSIONS AND RELEVANCE
The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Cognition; Fatigue; Prospective Studies; Prostatic Neoplasms; Quality of Life; Retrospective Studies
PubMed: 37227736
DOI: 10.1001/jamaoncol.2023.0998 -
JAMA Oncology Mar 2021Multiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Multiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.
OBJECTIVE
To compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC.
DATA SOURCES
Bibliographic databases (MEDLINE, Embase, and Cochrane Central), regulatory documents (US Food and Drug Administration and European Medicines Agency), and trial registries (ClinicalTrials.gov and European Union clinical trials register) were searched from inception through November 5, 2019.
STUDY SELECTION, DATA EXTRACTION, AND SYNTHESIS
Eligible studies were randomized clinical trials evaluating the addition of docetaxel, abiraterone acetate, apalutamide, or enzalutamide to androgen-deprivation therapy (ADT) for treatment of mCSPC. Two investigators independently performed screening. Discrepancies were resolved through consensus. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by bayesian network meta-analysis and survival models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.
MAIN OUTCOMES AND MEASURES
Overall survival, radiographic progression-free survival, and serious adverse events (SAEs).
RESULTS
Seven trials with 7287 patients comparing 6 treatments (abiraterone acetate, apalutamide, docetaxel, enzalutamide, standard nonsteroidal antiandrogen, and placebo/no treatment) were identified. Ordered from the most to the least effective determined by results of clinical trials, treatments associated with improved overall survival when added to ADT included abiraterone acetate (hazard ratio [HR], 0.61; 95% credible interval [CI], 0.54-0.70), apalutamide (HR, 0.67; 95% CI, 0.51-0.89), and docetaxel (HR, 0.79; 95% CI, 0.71-0.89); treatments associated with improved radiographic progression-free survival when added to ADT included enzalutamide (HR, 0.39; 95% CI, 0.30-0.50), apalutamide (HR, 0.48; 95% CI, 0.39-0.60), abiraterone acetate (HR, 0.51; 95% CI, 0.45-0.58), and docetaxel (HR, 0.67; 95% CI 0.60-0.74). Docetaxel was associated with substantially increased SAEs (odds ratio, 23.72; 95% CI, 13.37-45.15), abiraterone acetate with slightly increased SAEs (odds ratio, 1.42; 95% CI, 1.10-1.83), and other treatments with no significant increase in SAEs. Risk of bias was noted for 4 trials with open-label design, 3 trials with missing data, and 2 trials with potential unprespecified analyses.
CONCLUSIONS AND RELEVANCE
In this network meta-analysis, as add-on treatments to ADT, abiraterone acetate and apalutamide may provide the largest overall survival benefits with relatively low SAE risks. Although enzalutamide may improve radiographic progression-free survival to the greatest extent, longer follow-up is needed to examine the overall survival benefits associated with enzalutamide.
Topics: Androgen Antagonists; Bayes Theorem; Castration; Humans; Male; Network Meta-Analysis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 33443584
DOI: 10.1001/jamaoncol.2020.6973 -
The Cochrane Database of Systematic... Jul 2019Polycystic ovarian syndrome (PCOS) is characterised by the clinical signs of oligo-amenorrhoea, infertility and hirsutism. Conventional treatment of PCOS includes a...
BACKGROUND
Polycystic ovarian syndrome (PCOS) is characterised by the clinical signs of oligo-amenorrhoea, infertility and hirsutism. Conventional treatment of PCOS includes a range of oral pharmacological agents, lifestyle changes and surgical modalities. Beta-endorphin is present in the follicular fluid of both normal and polycystic ovaries. It was demonstrated that the beta-endorphin levels in ovarian follicular fluid of otherwise healthy women who were undergoing ovulation were much higher than the levels measured in plasma. Given that acupuncture impacts on beta-endorphin production, which may affect gonadotropin-releasing hormone (GnRH) secretion, it is postulated that acupuncture may have a role in ovulation induction via increased beta-endorphin production effecting GnRH secretion. This is an update of our previous review published in 2016.
OBJECTIVES
To assess the effectiveness and safety of acupuncture treatment for oligo/anovulatory women with polycystic ovarian syndrome (PCOS) for both fertility and symptom control.
SEARCH METHODS
We identified relevant studies from databases including the Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CNKI, CBM and VIP. We also searched trial registries and reference lists from relevant papers. CENTRAL, MEDLINE, Embase, PsycINFO, CNKI and VIP searches are current to May 2018. CBM database search is to November 2015.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that studied the efficacy of acupuncture treatment for oligo/anovulatory women with PCOS. We excluded quasi- or pseudo-RCTs.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the studies, extracted data and assessed risk of bias. We calculated risk ratios (RR), mean difference (MD), standardised mean difference (SMD) and 95% confidence intervals (CIs). Primary outcomes were live birth rate, multiple pregnancy rate and ovulation rate, and secondary outcomes were clinical pregnancy rate, restored regular menstruation period, miscarriage rate and adverse events. We assessed the quality of the evidence using GRADE methods.
MAIN RESULTS
We included eight RCTs with 1546 women. Five RCTs were included in our previous review and three new RCTs were added in this update of the review. They compared true acupuncture versus sham acupuncture (three RCTs), true acupuncture versus relaxation (one RCT), true acupuncture versus clomiphene (one RCT), low-frequency electroacupuncture versus physical exercise or no intervention (one RCT) and true acupuncture versus Diane-35 (two RCTs). Studies that compared true acupuncture versus Diane-35 did not measure fertility outcomes as they were focused on symptom control.Seven of the studies were at high risk of bias in at least one domain.For true acupuncture versus sham acupuncture, we could not exclude clinically relevant differences in live birth (RR 0.97, 95% CI 0.76 to 1.24; 1 RCT, 926 women; low-quality evidence); multiple pregnancy rate (RR 0.89, 95% CI 0.33 to 2.45; 1 RCT, 926 women; low-quality evidence); ovulation rate (SMD 0.02, 95% CI -0.15 to 0.19, I = 0%; 2 RCTs, 1010 women; low-quality evidence); clinical pregnancy rate (RR 1.03, 95% CI 0.82 to 1.29; I = 0%; 3 RCTs, 1117 women; low-quality evidence) and miscarriage rate (RR 1.10, 95% CI 0.77 to 1.56; 1 RCT, 926 women; low-quality evidence).Number of intermenstrual days may have improved in participants receiving true acupuncture compared to sham acupuncture (MD -312.09 days, 95% CI -344.59 to -279.59; 1 RCT, 141 women; low-quality evidence).True acupuncture probably worsens adverse events compared to sham acupuncture (RR 1.16, 95% CI 1.02 to 1.31; I = 0%; 3 RCTs, 1230 women; moderate-quality evidence).No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes.We were uncertain whether acupuncture improved ovulation rate (measured by ultrasound three months post treatment) compared to relaxation (MD 0.35, 95% CI 0.14 to 0.56; 1 RCT, 28 women; very low-quality evidence) or Diane-35 (RR 1.45, 95% CI 0.87 to 2.42; 1 RCT, 58 women; very low-quality evidence).Overall evidence ranged from very low quality to moderate quality. The main limitations were failure to report important clinical outcomes and very serious imprecision.
AUTHORS' CONCLUSIONS
For true acupuncture versus sham acupuncture we cannot exclude clinically relevant differences in live birth rate, multiple pregnancy rate, ovulation rate, clinical pregnancy rate or miscarriage. Number of intermenstrual days may improve in participants receiving true acupuncture compared to sham acupuncture. True acupuncture probably worsens adverse events compared to sham acupuncture.No studies reported data on live birth rate and multiple pregnancy rate for the other comparisons: physical exercise or no intervention, relaxation and clomiphene. Studies including Diane-35 did not measure fertility outcomes as the women in these trials did not seek fertility.We are uncertain whether acupuncture improves ovulation rate (measured by ultrasound three months post treatment) compared to relaxation or Diane-35. The other comparisons did not report on this outcome.Adverse events were recorded in the acupuncture group for the comparisons physical exercise or no intervention, clomiphene and Diane-35. These included dizziness, nausea and subcutaneous haematoma. Evidence was very low quality with very wide CIs and very low event rates.There are only a limited number of RCTs in this area, limiting our ability to determine effectiveness of acupuncture for PCOS.
Topics: Abortion, Spontaneous; Acupuncture Therapy; Cyproterone Acetate; Drug Combinations; Ethinyl Estradiol; Female; Humans; Infertility, Female; Menstruation; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic
PubMed: 31264709
DOI: 10.1002/14651858.CD007689.pub4 -
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