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Tremor and Other Hyperkinetic Movements... 2023Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1... (Review)
Review
BACKGROUND
Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunction, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in and . EA3-8 are reported in rare families. Advances in genetic testing have broadened the and phenotypes, and detected EA as an unusual presentation of several other genetic disorders. Additionally, there are various secondary causes of EA and mimicking disorders. Together, these can pose diagnostic challenges for neurologists.
METHODS
A systematic literature review was performed in October 2022 for 'episodic ataxia' and 'paroxysmal ataxia', restricted to publications in the last 10 years to focus on recent clinical advances. Clinical, genetic, and treatment characteristics were summarized.
RESULTS
EA1 and EA2 phenotypes have further broadened. In particular, EA2 may be accompanied by other paroxysmal disorders of childhood with chronic neuropsychiatric features. New treatments for EA2 include dalfampridine and fampridine, in addition to 4-aminopyridine and acetazolamide. There are recent proposals for EA9-10. EA may also be caused by gene mutations associated with chronic ataxias (), epilepsy syndromes (), GLUT-1, mitochondrial disorders (), metabolic disorders (Maple syrup urine disease, Hartnup disease, type I citrullinemia, thiamine and biotin metabolism defects), and others. Secondary causes of EA are more commonly encountered than primary EA (vascular, inflammatory, toxic-metabolic). EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, and functional symptoms. Primary and secondary EA are frequently treatable which should prompt a search for the cause.
DISCUSSION
EA may be overlooked or misdiagnosed for a variety of reasons, including phenotype-genotype variability and clinical overlap between primary and secondary causes. EA is highly treatable, so it is important to consider in the differential diagnosis of paroxysmal disorders. Classical EA1 and EA2 phenotypes prompt single gene test and treatment pathways. For atypical phenotypes, next generation genetic testing can aid diagnosis and guide treatment. Updated classification systems for EA are discussed which may assist diagnosis and management.
Topics: Humans; Ataxia; Cerebellar Ataxia; Acetazolamide; Mutation
PubMed: 37008993
DOI: 10.5334/tohm.747 -
ESMO Open Dec 2022Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments'... (Review)
Review
BACKGROUND
Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available.
METHODS
We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib.
RESULTS
A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients.
CONCLUSIONS
Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.
Topics: Female; Humans; Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Quality of Life; Cyclin-Dependent Kinase 6; Protein Kinase Inhibitors
PubMed: 36399953
DOI: 10.1016/j.esmoop.2022.100629 -
Expert Review of Anticancer Therapy Mar 2021: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.: Here, we analyze... (Comparative Study)
Comparative Study Meta-Analysis
: CDK4/6 inhibitor approval for hormone-responsive breast tumors has significantly changed therapeutic algorithms, with three drugs currently approved.: Here, we analyze the toxicity profiles of palbociclib, ribociclib, and abemaciclib through a systematic review and meta-analysis. Palbociclib and ribociclib showed high rates of hematological toxicity, primarily neutropenia, and were associated with a low rate of severe infections. Abemaciclib was associated with a high rate of gastrointestinal toxicities, primarily diarrhea, of grade 1-2 in most cases. Ribociclib was associated with a high rate of hepatic, and respiratory toxicity and with QTc prolongation. The toxicity rate of ribociclib was higher in metastatic patients than non-metastatic patients, with approximately 33% more grade 3-4 toxicities and 21% more grade 3-4 neutropenic events. A 5% higher risk of diarrhea was observed in postmenopausal patients. Pre-treated patients did not show a higher toxicity rate for palbociclib/ribociclib than previously untreated patients, while a 26% higher risk of any grade neutropenia and 6% higher risk of grade 3-4 diarrhea were observed with abemaciclib.: Considering the similar efficacies and indications of palbociclib, ribociclib, and abemaciclib, the evaluation of their toxicity profiles may facilitate treatment choice.
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Piperazines; Protein Kinase Inhibitors; Purines; Pyridines
PubMed: 33233970
DOI: 10.1080/14737140.2021.1852934 -
Cancer Apr 2023This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC). (Meta-Analysis)
Meta-Analysis
Efficacy and safety of first-line treatments for patients with advanced anaplastic lymphoma kinase mutated, non-small cell cancer: A systematic review and network meta-analysis.
BACKGROUND
This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non-small cell lung cancer (NSCLC).
METHODS
A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed.
RESULTS
The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20-0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12-0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4-5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0-2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%).
CONCLUSIONS
For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit.
PLAIN LANGUAGE SUMMARY
Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non-small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Crizotinib; Anaplastic Lymphoma Kinase; Network Meta-Analysis; Bayes Theorem; Lactams, Macrocyclic; Protein Kinase Inhibitors
PubMed: 36748799
DOI: 10.1002/cncr.34664 -
Lung Cancer (Amsterdam, Netherlands) Oct 2023Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of... (Meta-Analysis)
Meta-Analysis Review
Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis.
OBJECTIVE
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making.
MATERIALS AND METHODS
We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework.
RESULTS
Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs.
CONCLUSIONS
The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.
Topics: Humans; Anaplastic Lymphoma Kinase; Protein-Tyrosine Kinases; Carcinoma, Non-Small-Cell Lung; Tyrosine Kinase Inhibitors; Crizotinib; Network Meta-Analysis; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 37597303
DOI: 10.1016/j.lungcan.2023.107319 -
Journal of Chemotherapy (Florence,... Apr 2022Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and... (Meta-Analysis)
Meta-Analysis
Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor-naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis.
Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, = 0.03) and alectinib (Hazard ratio: 0.65, = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free survival than brigatinib (Hazard ratio: 0.57, = 0.03) and alectinib (Hazard ratio: 0.59, = 0.03) for ALK inhibitor-naive patients. Among lorlatinib, alectinib, brigatinib, and crizotinib, lorlatinib had the highest probability to reach the best overall confirmed response rates (probability of 48%) and intracranial confirmed response rates (probability of 44%). No significant difference was found among them in overall survival and adverse events analysis. In terms of progression free survival, our results indicated that lorlatinib was the best treatment choice for patients with ALK inhibitor-naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. The future head-to-head trials assessing the relative efficacy of lorlatinib, alectinib and brigatinib were warranted.
Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lactams; Lung Neoplasms; Network Meta-Analysis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 34139965
DOI: 10.1080/1120009X.2021.1937782 -
The Lancet. Oncology Oct 2019Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with... (Comparative Study)
Comparative Study Meta-Analysis
Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis.
BACKGROUND
Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches.
METHODS
We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR.
FINDINGS
We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25-0·70), ribociclib plus letrozole (0·43; 0·24-0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23-0·76), palbociclib plus fulvestrant (0·37; 0·23-0·59), ribociclib plus fulvestrant (0·48; 0·31-0·74), abemaciclib plus fulvestrant (0·44; 0·28-0·70), everolimus plus exemestane (0·42; 0·28-0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22-0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8·95; 95% CrI 1·03-76·92).
INTERPRETATION
In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer.
FUNDING
None.
Topics: Aminopyridines; Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bevacizumab; Breast Neoplasms; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Female; Fulvestrant; Humans; Letrozole; Network Meta-Analysis; Paclitaxel; Piperazines; Postmenopause; Progression-Free Survival; Purines; Pyridines; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 31494037
DOI: 10.1016/S1470-2045(19)30420-6 -
The Cochrane Database of Systematic... Dec 2020Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.
OBJECTIVES
To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.
SELECTION CRITERIA
Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.
MAIN RESULTS
We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence).
AUTHORS' CONCLUSIONS
There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.
Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Bias; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Phenylbutyrates; Pyrazoles; Pyridines; Quality of Life; Quinolines; Quinolones; Randomized Controlled Trials as Topic
PubMed: 33331662
DOI: 10.1002/14651858.CD010966.pub3 -
The Annals of Pharmacotherapy Aug 2023This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis. (Review)
Review
OBJECTIVE
This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis.
DATA SOURCES
A systematic review of the literature was performed using the terms OR OR in MEDLINE (PubMed) and EMBASE databases between January 2012 and October 2022. Bibliographies and the ClinicalTrials.gov website were also searched to identify further studies.
STUDY SELECTION AND DATA EXTRACTION
Studies written in English and relevant to pharmacology, clinical trials, and safety were considered for inclusion.
DATA SYNTHESIS
In two 8-week phase III clinical trials, disease severity as assessed by a score of "clear" or "almost clear" and a 2-point improvement on Investigator Global Assessment (IGA) was 42.4% and 37.5% at week 8 in DERMIS-1 and DERMIS-2, respectively, compared to 6.1% and 6.9% in the control groups. In the 52-week phase III trial, treatment success rates for plaque psoriasis and intertriginous psoriasis were similar to the 8-week data with 45% of patients in the treatment group were evaluated as an IGA of "clear" or "almost clear" at week 52.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS
Roflumilast is a new US Food and Drug Administration (FDA)-approved topical phosphodiesterase inhibitor that shows promise for the treatment of mild-severe plaque psoriasis. It is an effective and safe topical nonsteroidal alternative to currently available topical corticosteroids, but there are currently no comparative studies with other psoriasis treatments.
CONCLUSION
Roflumilast is effective and safe for the treatment of plaque psoriasis and intertriginous psoriasis. Future trials should compare its efficacy and tolerability with that of the older, clinically established topical corticosteroids. Prohibitive factors may include limited patient adherence to topical treatments and cost.
Topics: Humans; Adrenal Cortex Hormones; Aminopyridines; Dermatologic Agents; Immunoglobulin A; Psoriasis; Severity of Illness Index; Treatment Outcome; Clinical Trials as Topic
PubMed: 36420929
DOI: 10.1177/10600280221137750 -
Lung Cancer (Amsterdam, Netherlands) Nov 2021Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC.
MATERIALS AND METHODS
We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models.
RESULTS
The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11-85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79-1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57-1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44-2.44).
CONCLUSION
Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.
Topics: Anaplastic Lymphoma Kinase; Bradycardia; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Protein Kinase Inhibitors
PubMed: 34492553
DOI: 10.1016/j.lungcan.2021.08.014