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BMC Cancer May 2024Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN)...
BACKGROUND
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are currently recommended by the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) guidelines as the first-line (1 L) treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced/metastatic breast cancer (HR+/HER2- LABC/mBC). Although there are many treatment options, there is no clear standard of care for patients following 1 L CDK4/6i. Understanding the real-world effectiveness of subsequent therapies may help to identify an unmet need in this patient population. This systematic literature review qualitatively synthesized effectiveness and safety outcomes for treatments received in the real-world setting after 1 L CDK4/6i therapy in patients with HR+/ HER2- LABC/mBC.
METHODS
MEDLINE®, Embase, and Cochrane were searched using the Ovid® platform for real-world evidence studies published between 2015 and 2022. Grey literature was searched to identify relevant conference abstracts published from 2019 to 2022. The review was conducted in accordance with PRISMA guidelines (PROSPERO registration: CRD42023383914). Data were qualitatively synthesized and weighted average median real-world progression-free survival (rwPFS) was calculated for NCCN/ESMO-recommended post-1 L CDK4/6i treatment regimens.
RESULTS
Twenty records (9 full-text articles and 11 conference abstracts) encompassing 18 unique studies met the eligibility criteria and reported outcomes for second-line (2 L) treatments after 1 L CDK4/6i; no studies reported disaggregated outcomes in the third-line setting or beyond. Sixteen studies included NCCN/ESMO guideline-recommended treatments with the majority evaluating endocrine-based therapy; five studies on single-agent ET, six studies on mammalian target of rapamycin inhibitors (mTORi) ± ET, and three studies with a mix of ET and/or mTORi. Chemotherapy outcomes were reported in 11 studies. The most assessed outcome was median rwPFS; the weighted average median rwPFS was calculated as 3.9 months (3.3-6.0 months) for single-agent ET, 3.6 months (2.5-4.9 months) for mTORi ± ET, 3.7 months for a mix of ET and/or mTORi (3.0-4.0 months), and 6.1 months (3.7-9.7 months) for chemotherapy. Very few studies reported other effectiveness outcomes and only two studies reported safety outcomes. Most studies had heterogeneity in patient- and disease-related characteristics.
CONCLUSIONS
The real-world effectiveness of current 2 L treatments post-1 L CDK4/6i are suboptimal, highlighting an unmet need for this patient population.
Topics: Humans; Cyclin-Dependent Kinase 4; Breast Neoplasms; Receptor, ErbB-2; Cyclin-Dependent Kinase 6; Female; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Receptors, Estrogen; Receptors, Progesterone; Progression-Free Survival
PubMed: 38783218
DOI: 10.1186/s12885-024-12269-8 -
BMC Medicine Oct 2022Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence.
METHODS
We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples.
RESULTS
We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here.
CONCLUSIONS
Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.
Topics: Elafin; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins; Immunologic Factors; Interferons; Interleukin 1 Receptor Antagonist Protein; Interleukin-16; Interleukin-1alpha; Interleukin-6; Interleukins; Lactoferrin; Menstrual Cycle; Muramidase; Progesterone; beta-Defensins
PubMed: 36195867
DOI: 10.1186/s12916-022-02532-9 -
Frontiers in Endocrinology 2021Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that can block the luteinizing hormone (LH) surge through progesterone instead of... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that can block the luteinizing hormone (LH) surge through progesterone instead of traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist, and in order to achieve multi-follicle recruitment. This paper aims to investigate the effectiveness of PPOS and its suitability for infertile patients with different ovarian reserve functions.
METHODS
We searched published randomized controlled trials (RCTs) about PPOS on Cochrane Library, PubMed, Embase, and Web of Science. The search period spanned from January 1, 2015 to November 16, 2020. The data were extracted, and the meta-analysis was performed on ovarian stimulation as well as embryological and clinical outcomes. The outcomes were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis was performed for different ovarian reserve patients.
RESULTS
The clinical pregnancy rates and live birth or ongoing pregnancy rates with the PPOS protocol were not different from those with the control group. In the diminished ovarian reserve (DOR) subgroup, the PPOS protocol had a lower rate of premature LH surge [RR = 0.03, 95% CI = 0.01 to 0.13, < 0.001]. The PPOS protocol had a lower rate of ovarian hyperstimulation syndrome (OHSS) [RR = 0.52, 95% CI = 0.36 to 0.76, < 0.001, = 0.00%]. The secondary outcomes showed that the number of oocytes retrieved, MII oocytes, and viable embryos was higher than that of the control protocol in DOR patients [(MD = 0.33, 95% CI = 0.30 to 0.36, < 0.001), (MD = 0.30, 95% CI = 0.27 to 0.33, < 0.001), (MD = 0.21, 95% CI = 0.18 to 0.24, < 0.001)] and normal ovarian reserve (NOR) patients [(MD = 1.41, 95% CI = 0.03 to 2.78, < 0.001), (MD = 1.19, 95% CI = 0.04 to 2.35, < 0.001), (MD = 1.01, 95% CI = 0.21 to 1.81, = 0.01)].
CONCLUSION
The findings suggest that PPOS is an effective ovarian stimulation protocol and is beneficial for patients with different ovarian reserve functions, which needs to be validated in more RCTs with larger samples.
Topics: Female; Humans; Pregnancy; Fertilization in Vitro; Infertility, Female; Live Birth; Ovarian Reserve; Ovulation Induction; Pregnancy Rate; Progestins; Randomized Controlled Trials as Topic
PubMed: 34531825
DOI: 10.3389/fendo.2021.702558 -
Journal of Gynecology Obstetrics and... Sep 2021To systematically evaluate the effect of progestin-primed ovarian stimulation (PPOS) in in vitro fertilization (IVF)/oocyte intracytoplasmic sperm injection-embryo... (Meta-Analysis)
Meta-Analysis
PURPOSE
To systematically evaluate the effect of progestin-primed ovarian stimulation (PPOS) in in vitro fertilization (IVF)/oocyte intracytoplasmic sperm injection-embryo transfer (ICSI-ET) in patients with poor ovarian response and to find an optimal ovulation induction protocol for such patients.
METHOD
A literature search of PubMed, Medline, EBSCO, Cochrane Library, Vip.com, CNKI, and the Wanfang database was conducted to find case-control studies of PPOS with medroxyprogesterone acetate and other traditional stimulation regimens for ovulation induction in patients with poor ovarian response. The period of time searched was from the database establishment to August 2020. Patients in the experimental group underwent PPOS and those in the control group underwent another program (e.g., the gonadotropin-releasing hormone antagonist protocol). RevMan 5.3 software was used for meta-analysis.
RESULTS
A total of sixteen case-control studies (one of them is randomized controlled trial), with 4422 induction cycles, were included. All the included patients met the 2011 Bologna diagnostic criteria for poor ovarian response. The numbers of mature eggs, available embryos, optimal embryos, and the rate of cumulative pregnancies in the PPOS group were all better than those in the control group (P<0.05). There was a lower Serum luteinizing hormone on the day of human chorionic gonadotropin (HCG) injection and a lower rate of cycle cancellation in the PPOS group (P<0.05). No other differences between PPOS and other treatments were statistically significant.
CONCLUSION
PPOS can reduce the need for cycle cancellation, improve the follicles and embryos, and improve the pregnancy rate and thus, can present an effective choice for IVF/ICSI-ET in patients with poor ovarian response.
Topics: Adult; Case-Control Studies; Contraceptive Agents, Hormonal; Female; Humans; Medroxyprogesterone Acetate; Ovary; Ovulation Induction; Treatment Outcome
PubMed: 33387677
DOI: 10.1016/j.jogoh.2020.102049 -
The Cochrane Database of Systematic... Oct 2020A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration.
OBJECTIVES
To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR).
SEARCH METHODS
The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects.
MAIN RESULTS
Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes.
AUTHORS' CONCLUSIONS
There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.
Topics: Abortion, Spontaneous; Bias; Clomiphene; Cryopreservation; Drug Administration Schedule; Embryo Implantation; Embryo Transfer; Embryo, Mammalian; Endometrium; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Letrozole; Live Birth; Oocyte Donation; Pregnancy; Pregnancy Rate; Progesterone; Progestins; Randomized Controlled Trials as Topic
PubMed: 33112418
DOI: 10.1002/14651858.CD006359.pub3 -
Revista Da Associacao Medica Brasileira... Sep 2019Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among...
Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among other things, cyclic AMP. Notwithstanding all the literature data, there is still no sound knowledge or a clear understanding of the hormone's action on the physiology of ovarian follicular cells. OBJECTIVE To review and evaluate studies about melatonin action on the ovarian granulosa/theca interna cells from the literature. METHODS The systematic review was carried out according to the PRISMA recommendations. The MEDLINE and Cochrane primary databases were consulted with the use of specific terms. There was no limitation on language or publication year. RESULTS Seven papers about melatonin action on granulosa cells were selected. The following can be attributed to the hormone's effects: a) progesterone increase in culture medium; b) increased estrogen production; c) antagonistic action on estrogen; d) improvement in cell quality resulting in improved embryo and higher pregnancy rates; e) improved cell proliferation via MAPK; f) reduction of free radicals. Nevertheless, there are contrarian papers reporting a reduction in progesterone production. Melatonin interferes in sex steroid production, boosting progesterone output. Such action may help improve oocyte quality.
Topics: Cells, Cultured; Female; Granulosa Cells; Humans; Melatonin; Oocytes; Ovarian Follicle; Pregnancy; Progesterone; Theca Cells
PubMed: 31531613
DOI: 10.1590/1806-9282.65.8.1122