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Pharmacological Research Jul 2023We evaluated the efficacy, safety, adherence, quality of life (QoL) and cost-effectiveness of long-acting growth hormone (LAGH) vs daily growth hormone (GH) preparations... (Meta-Analysis)
Meta-Analysis Review
Efficacy, safety, quality of life, adherence and cost-effectiveness of long-acting growth hormone replacement therapy compared to daily growth hormone in children with growth hormone deficiency: A systematic review and meta-analysis.
We evaluated the efficacy, safety, adherence, quality of life (QoL) and cost-effectiveness of long-acting growth hormone (LAGH) vs daily growth hormone (GH) preparations in the treatment of growth hormone deficiency (GHD) in children. Systematic searches were performed in PubMed, Embase and Web of Science up to July 2022 on randomized and non-randomized studies involving children with GHD receiving LAGH as compared to daily GH. Meta-analyses for efficacy and safety were performed comparing different LAGH/daily GH formulations. From the initial 1393 records, we included 16 studies for efficacy and safety, 8 studies for adherence and 2 studies for QoL. No studies reporting cost-effectiveness were found. Pooled mean differences of mean annualized height velocity (cm/year) showed no difference between LAGH and daily GH: Eutropin Plus® vs Eutropin® [- 0.14 (-0.43, 0.15)], Eutropin Plus® vs Genotropin® [- 0.74 (-1.83, 0.34)], Jintrolong® vs Jintropin AQ® [0.05 (-0.54, 0.65)], Somatrogon vs Genotropin® [- 1.40 (-2.91, 0.10)], TransCon vs Genotropin® [0.93 (0.26, 1.61)]. Also, other efficacy and safety outcomes, QoL and adherence were comparable for LAGH and daily GH. Our results showed that, although most of the included studies had some concerns for risk of bias, regarding efficacy and safety all the LAGH formulations were similar to daily GH. Future high quality studies are needed to confirm these data. Adherence and QoL should be addressed from real-world data studies for both the mid and long term and in a larger population. Cost-effectiveness studies are needed to measure the economic impact of LAGH from the healthcare payer's perspective.
Topics: Humans; Child; Human Growth Hormone; Growth Hormone; Quality of Life; Cost-Benefit Analysis; Dwarfism, Pituitary; Hormone Replacement Therapy
PubMed: 37236413
DOI: 10.1016/j.phrs.2023.106805 -
Advances in Therapy Sep 2023Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment... (Review)
Review
BACKGROUND
Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research.
METHODS
Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines.
RESULTS
Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments.
CONCLUSIONS
This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies.
Topics: Humans; Quality of Life; Achondroplasia; Human Growth Hormone; Cost-Benefit Analysis
PubMed: 37382866
DOI: 10.1007/s12325-023-02549-3 -
ESMO Open Aug 2023Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression on ≥1 human epidermal growth factor receptor 2 (HER2)-targeted therapies. However, interstitial lung disease (ILD) and cardiotoxicity are the most significant toxicities associated with T-DXd. Therefore, we conducted a systematic review and meta-analysis to assess the incidence and severity of these toxicities in mBC patients treated with T-DXd.
MATERIALS AND METHODS
We searched PubMed, Cochrane, and Scopus databases, and conferences websites for randomized clinical trials and nonrandomized studies of intervention including HER2-low or HER2-positive mBC patients who received at least one dose of T-DXd. Statistical analysis was carried out using R software.
RESULTS
We included 15 studies comprising 1970 patients with a mean follow-up of 13.3 months. Median age ranged from 53 to 59 years, 61.9% were non-Asian, and 67.4% had hormone receptor-positive mBC. In a pooled analysis, the incidence of ILD was 11.7% [222 patients; 95% confidence interval (CI) 9.1% to 15.0%]. Patients receiving T-DXd dose of 6.4 mg/kg developed a significantly higher rate of ILD (22.7%) compared to those receiving a dose of 5.4 mg/kg (9.3%) (P < 0.01). Most cases of ILD (80.2%; 174/217 patients) were mild (grade 1 or 2). Grade 3 or 4 ILD was reported in 29 patients (13.4%), and grade 5 in 14 patients (6.4%). The incidence of decreased left ventricular ejection fraction (LVEF) was 1.95% (95% CI 0.65% to 3.73%), and the QT interval (QTi) prolongation was 7.77% (95% CI 2.74% to 20.11%). Most patients were asymptomatic, but four had LV dysfunction and heart failure (0.26%).
CONCLUSIONS
In this meta-analysis of 1970 patients with mBC, treatment with T-DXd was associated with a 11.7% incidence of ILD, 7.7% incidence of prolonged QTi, and 1.9% incidence of reduced LVEF. Early detection and management of T-DXd-related toxicity by a multidisciplinary team may ultimately improve patient outcomes.
Topics: Humans; Middle Aged; Female; Breast Neoplasms; Cardiotoxicity; Incidence; Stroke Volume; Ventricular Function, Left; Lung Diseases, Interstitial
PubMed: 37481956
DOI: 10.1016/j.esmoop.2023.101613 -
Cancer Treatment Reviews Sep 2023The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor... (Meta-Analysis)
Meta-Analysis Review
The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings.
Topics: Humans; Female; Radiosurgery; Breast Neoplasms; Cyclin-Dependent Kinases; Cyclin-Dependent Kinase 4; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 6; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37336117
DOI: 10.1016/j.ctrv.2023.102586 -
The Journal of Clinical Endocrinology... Aug 2023Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by...
CONTEXT
Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish.
OBJECTIVE
The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders.
METHODS
We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers.
RESULTS
Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common.
CONCLUSION
Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.
Topics: Humans; Intellectual Disability; Hyperostosis, Cortical, Congenital; Phenotype; Electrolytes; Hypoparathyroidism
PubMed: 36916904
DOI: 10.1210/clinem/dgad147 -
ESMO Open Aug 2023Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis.
MATERIALS AND METHODS
A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777).
RESULTS
Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found.
CONCLUSIONS
Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Disease-Free Survival; Progression-Free Survival; Proportional Hazards Models
PubMed: 37413762
DOI: 10.1016/j.esmoop.2023.101592 -
Archives of Endocrinology and Metabolism Nov 2023FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation... (Meta-Analysis)
Meta-Analysis Review
FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.
Topics: Humans; Blood Glucose; Metabolic Diseases; Metabolic Syndrome; Obesity; Diabetes Mellitus
PubMed: 37948566
DOI: 10.20945/2359-4292-2022-0493 -
Communications Medicine Oct 2023Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR,...
BACKGROUND
Monogenic insulin resistance (IR) includes lipodystrophy and disorders of insulin signalling. We sought to assess the effects of interventions in monogenic IR, stratified by genetic aetiology.
METHODS
Systematic review using PubMed, MEDLINE and Embase (1 January 1987 to 23 June 2021). Studies reporting individual-level effects of pharmacologic and/or surgical interventions in monogenic IR were eligible. Individual data were extracted and duplicates were removed. Outcomes were analysed for each gene and intervention, and in aggregate for partial, generalised and all lipodystrophy.
RESULTS
10 non-randomised experimental studies, 8 case series, and 23 case reports meet inclusion criteria, all rated as having moderate or serious risk of bias. Metreleptin use is associated with the lowering of triglycerides and haemoglobin A1c (HbA1c) in all lipodystrophy (n = 111), partial (n = 71) and generalised lipodystrophy (n = 41), and in LMNA, PPARG, AGPAT2 or BSCL2 subgroups (n = 72,13,21 and 21 respectively). Body Mass Index (BMI) is lowered in partial and generalised lipodystrophy, and in LMNA or BSCL2, but not PPARG or AGPAT2 subgroups. Thiazolidinediones are associated with improved HbA1c and triglycerides in all lipodystrophy (n = 13), improved HbA1c in PPARG (n = 5), and improved triglycerides in LMNA (n = 7). In INSR-related IR, rhIGF-1, alone or with IGFBP3, is associated with improved HbA1c (n = 17). The small size or absence of other genotype-treatment combinations preclude firm conclusions.
CONCLUSIONS
The evidence guiding genotype-specific treatment of monogenic IR is of low to very low quality. Metreleptin and Thiazolidinediones appear to improve metabolic markers in lipodystrophy, and rhIGF-1 appears to lower HbA1c in INSR-related IR. For other interventions, there is insufficient evidence to assess efficacy and risks in aggregated lipodystrophy or genetic subgroups.
PubMed: 37794082
DOI: 10.1038/s43856-023-00368-9 -
Radiotherapy and Oncology : Journal of... Oct 2023The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-)... (Meta-Analysis)
Meta-Analysis
Safety and feasibility of CDK4/6 inhibitors treatment combined with radiotherapy in patients with HR-positive/HER2-negative breast cancer. A systematic review and meta-analysis.
BACKGROUND AND PURPOSE
The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy in hormone receptor-positive (HR+) human epidermal growth factor 2-negative (HER2-) breast cancer has led to practice-changing improvements in overall survival. However, there are conflicting data concerning the safety of CDK4/6i combination with radiotherapy, and no consensus guidelines exist to guide practice. We conducted a meta-analysis to assess the safety and feasibility of CDK4/6i treatment with radiotherapy.
MATERIALS AND METHODS
A comprehensive search was performed in PubMed/MEDLINE, Web of Science, and Scopus, for studies in advanced/metastatic breast cancer receiving CDK4/6i and radiotherapy with the provided safety data on the occurrence of toxicity. The main outcomes were safety (grade 3-5 adverse events), CDK 4/6i dose reduction, and the discontinuation rate due to toxicity.
RESULTS
Fifteen studies comprising 1133 patients with HR+/HER2- breast cancer patients were included. Among them, 617 pts received CDK4/6i and radiotherapy; the median follow-up was 17.0 months (IQR 9.2 - 18.0), and the median age was 58.8 years (IQR 55.5---62.5). The pooled prevalence of severe hematologic toxicity was 29.4% (95% CI 14.0% - 47.4%; I = 93%; τ = 0.084; p < 0.01 and severe non-hematologic toxicity was 2.8% (95% CI 1.1% - 4.8%; I = 0%; τ = 0.0; p = 0.67). The pooled prevalence of CDK4/6i dose reduction was 24.0% (95% CI 11.1% - 39.4%; I = 90%; τ = 0.052; p < 0.01) with no difference between CDK4/6i plus RT vs. CDK4/6i (odds ratio of 0.934; 95% CI 0.66 - 1.33; I = 0%; τ = 0.0; p = 0.56). The pooled prevalence of CDK4/6i discontinuation due to toxicity was 2.3% (95% CI 0.4% - 5.2%; I = 23%; τ = 0.002; p = 0.24).
CONCLUSION
The findings of this study suggest that radiotherapy in addition to CDK4/6i treatment in breast cancer patients is generally safe and well tolerated and remains a viable treatment option.
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Consensus; Cyclin-Dependent Kinase 4; Epidermal Growth Factor; Feasibility Studies; Protein Kinase Inhibitors; Radiotherapy
PubMed: 37536378
DOI: 10.1016/j.radonc.2023.109839 -
Biomolecules Sep 2023Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor... (Review)
Review
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.
Topics: Humans; Female; Breast Neoplasms; Progression-Free Survival; Cyclin-Dependent Kinase 4; Clinical Trials, Phase II as Topic
PubMed: 37759823
DOI: 10.3390/biom13091422