Daily Archives: September 17, 2024
RCT: Twice-Yearly Depemokimab Reduced Exacerbations in Severe Eosinophilic Asthma
17 Sep, 2024 | 22:39h | UTCBackground: Severe asthma with an eosinophilic phenotype often leads to frequent exacerbations despite treatment with medium- or high-dose inhaled glucocorticoids and additional controllers. Interleukin-5 is pivotal in eosinophil growth and survival, contributing to airway inflammation. Existing biologic therapies targeting interleukin-5 require frequent dosing intervals. Depemokimab is an ultra-long-acting anti–interleukin-5 biologic with enhanced binding affinity, potentially allowing effective dosing every six months.
Objective: To evaluate the efficacy and safety of twice-yearly depemokimab in reducing exacerbations in patients with severe eosinophilic asthma.
Methods: Two multicenter, randomized, double-blind, placebo-controlled phase 3A trials (SWIFT-1 and SWIFT-2) were conducted. Patients aged ≥12 years with severe asthma and an eosinophilic phenotype (blood eosinophil count ≥300 cells/μL in the previous 12 months or ≥150 cells/μL at screening) and at least two exacerbations in the prior year despite medium- or high-dose inhaled glucocorticoids plus another controller were enrolled. Participants were randomized 2:1 to receive depemokimab 100 mg or placebo subcutaneously at weeks 0 and 26, alongside standard care. The primary endpoint was the annualized rate of exacerbations over 52 weeks. Secondary endpoints included changes from baseline in the St. George’s Respiratory Questionnaire (SGRQ) score, prebronchodilator FEV₁, and asthma symptom scores at 52 weeks.
Results: A total of 792 patients were randomized, with 762 included in the full analysis set (502 depemokimab, 260 placebo). In SWIFT-1, depemokimab significantly reduced the annualized exacerbation rate compared to placebo (0.46 vs 1.11; rate ratio 0.42; 95% CI, 0.30–0.59; P < .001). Similar results were observed in SWIFT-2 (0.56 vs 1.08; rate ratio 0.52; 95% CI, 0.36–0.73; P < .001). No significant between-group differences were found in change from baseline in SGRQ scores. The incidence of adverse events was similar between groups in both trials.
Conclusions: Twice-yearly administration of depemokimab significantly reduced the annualized rate of exacerbations in patients with severe eosinophilic asthma.
Implications for Practice: Depemokimab administered every six months may offer an effective treatment option for reducing exacerbations in severe eosinophilic asthma, potentially enhancing patient adherence and reducing treatment burden associated with more frequent dosing schedules.
Study Strengths and Limitations: Strengths include large, multicenter, randomized, placebo-controlled design and replicate trials confirming efficacy. Limitations involve the lack of significant improvement in quality-of-life measures, low exacerbation rates in the placebo group, potential impact of the COVID-19 pandemic on trial conduct and outcomes, and limited data on certain subpopulations.
Future Research: Further studies are needed to assess long-term safety and efficacy, effects on quality-of-life measures, and the role of depemokimab in broader asthma populations, including those with varying eosinophil counts and biomarker profiles.
Systematic Review: Antidepressants Offer Limited Pain Relief with Potential Harms in Older Adults
17 Sep, 2024 | 11:34h | UTCBackground: Chronic pain is prevalent among older adults and significantly affects their quality of life. Antidepressants are commonly prescribed for pain management in this population across various countries. While several systematic reviews have evaluated the efficacy and safety of antidepressants for pain in adults, none have specifically focused on individuals aged 65 years and older. The efficacy and safety profile of antidepressants for pain relief in older adults remains unclear.
Objective: To assess the efficacy and safety of antidepressant medications compared to all alternatives for the management of non-cancer pain in older adults aged 65 years and above.
Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. Thirteen databases were searched from inception to February 1, 2024, to identify relevant studies. Trials included compared any antidepressant medication to any alternative (e.g., placebo, other medications, or non-drug therapies) for the treatment of non-cancer pain in older adults. Data extracted included study and participant characteristics, primary efficacy outcomes (pain scores converted to a 0–100 scale), and harms. Estimates for efficacy were pooled using a random-effects model and reported as mean differences with 95% confidence intervals (CIs). The quality of included trials was assessed using the Cochrane risk of bias tool.
Results: Fifteen studies encompassing 1,369 participants met the inclusion criteria. The most frequently studied antidepressants were duloxetine and amitriptyline (six studies each). Pain related to knee osteoarthritis was the most commonly studied condition (six studies). For knee osteoarthritis:
- Immediate Term (0–2 weeks): Antidepressants did not provide a statistically significant reduction in pain compared to alternatives (mean difference [MD], –5.6; 95% CI, –11.5 to 0.3).
- Intermediate Term (≥6 weeks and <12 months): Duloxetine provided a statistically significant, albeit very small, reduction in pain (MD, –9.1; 95% CI, –11.8 to –6.4).
Nearly half of the studies (7 out of 15) reported increased withdrawal of participants in the antidepressant treatment group compared to the comparator group due to adverse events.
Conclusions: For most chronic painful conditions in older adults, the benefits and harms of antidepressant medications are unclear. The available evidence predominantly comes from trials with small sample sizes (less than 100 participants), disclosed industry ties, and trials classified as having unclear or high risk of bias.
Implications for Practice:
- Minimal Benefit: Antidepressants, particularly duloxetine, may offer a very small benefit for pain relief in older adults with knee osteoarthritis over the intermediate term.
- Risk of Harms: The potential harms, including increased adverse events leading to higher withdrawal rates, may outweigh these minimal benefits.
- Clinical Decision-Making: Clinicians should carefully weigh the benefits against the risks when considering prescribing antidepressants for pain in older adults.
- Alternative Strategies: Non-pharmacological interventions and alternative pain management strategies should be prioritized in this population.
Study Strengths and Limitations: Strengths include the comprehensive search strategy across multiple databases and the focus on older adults, a population often underrepresented in clinical trials. Limitations involve the generally low quality of the included trials, small sample sizes, high risk of bias, and inconsistent reporting of pain outcomes and adverse events among studies.
Future Research: Further large-scale, high-quality randomized controlled trials are needed to investigate the efficacy and safety of antidepressants for pain management in older adults. Future studies should also compare antidepressants to non-pharmacological interventions and explore long-term outcomes and optimal dosing regimens in this population.
Meta-Analysis: Moderate Hypofractionation Improves Safety and Cosmesis Over Conventional Fractionation in Breast Cancer Radiotherapy
17 Sep, 2024 | 11:14h | UTCBackground:
Breast cancer remains the most prevalent malignancy among women worldwide, with postoperative radiation therapy playing a crucial role in reducing locoregional recurrence and improving survival outcomes. Conventional fractionation (CF), involving a total dose of approximately 50 Gy delivered over five to six weeks in daily fractions of 1.8–2 Gy, has been the historical standard. In recent years, hypofractionated regimens—including moderate hypofractionation (MHF) and ultra-hypofractionation (UHF)—have emerged as alternatives that offer shorter treatment durations. Despite evidence supporting hypofractionation, its adoption varies due to concerns about potential side effects, cosmetic outcomes, and the limited long-term data on UHF.
Objective:
To provide a comprehensive assessment of various radiation dose fractionation schemes—CF, MHF, and UHF—in breast cancer, focusing on side effects, cosmesis, quality of life, recurrence risks, and survival outcomes.
Methods:
A systematic review and meta-analysis were conducted by searching Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 October 2023. Randomized controlled trials comparing CF (daily fractions of 1.8–2 Gy over 5–6 weeks), MHF (fractions of 2.65–3.3 Gy over 3–5 weeks), and UHF (five fractions) were included. Two independent investigators screened studies, extracted data, and assessed risk of bias using the Cochrane Collaboration’s tool and the GRADE approach. Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. A network meta-analysis integrated all available evidence.
Results:
From 1,754 studies, 35 trials encompassing 20,237 patients were included. Compared with CF, MHF significantly reduced the risk of grade ≥2 acute radiation dermatitis:
- All patients: RR, 0.59; 95% CI, 0.51–0.69; P<0.001.
- Breast-Conserving Therapy: RR, 0.54; 95% CI, 0.49–0.61; P<0.001.
- Post-Mastectomy: RR, 0.68; 95% CI, 0.49–0.93; P=0.02.
MHF also showed lower incidences of:
- Hyperpigmentation: RR, 0.77; 95% CI, 0.62–0.95; P=0.02.
- Grade ≥2 Breast Shrinkage: RR, 0.92; 95% CI, 0.85–0.99; P=0.03.
MHF was associated with improved cosmesis and quality of life compared to CF. Survival and recurrence outcomes were similar across UHF, MHF, and CF regimens. While UHF demonstrated comparable safety and efficacy profiles, data were less conclusive due to fewer trials and shorter follow-up periods.
Conclusions:
Moderate hypofractionation improves safety profiles, cosmetic outcomes, and quality of life compared with conventional fractionation while maintaining equivalent oncological efficacy. Ultra-hypofractionation shows promise with similar short-term safety and effectiveness but requires further research for definitive conclusions.
Implications for Practice:
- Preferred Regimen: MHF should be considered the preferred radiation therapy regimen for breast cancer patients due to reduced side effects, improved cosmesis, shorter treatment duration, and maintained oncological outcomes.
- Ultra-Hypofractionation Potential: UHF offers advantages of further reduced treatment times and patient convenience but requires additional long-term data before widespread adoption.
- Resource Utilization: Adoption of hypofractionated regimens can improve healthcare resource utilization and enhance patient quality of life.
Study Strengths and Limitations:
Strengths include a comprehensive assessment of both clinical and patient-centered outcomes across a large number of randomized controlled trials, providing a multidimensional perspective crucial for informed clinical decision-making.
Limitations involve potential risk of bias due to lack of blinding in some studies, variability in outcome reporting across trials, and limited long-term data on UHF regimens.
Future Research:
Further studies are needed to solidify the evidence base for UHF, particularly regarding long-term safety and efficacy. Research should focus on optimizing fractionation regimens tailored to patient-specific factors, such as breast size and smoking status, to enhance outcomes.
Reference:
RCT: Cabozantinib Improves Progression-Free Survival in Advanced Neuroendocrine Tumors
17 Sep, 2024 | 11:03h | UTCBackground: Advanced neuroendocrine tumors (NETs) present limited treatment options, with many patients experiencing disease progression despite existing therapies. Angiogenesis is pivotal in NET pathogenesis. Cabozantinib, an oral tyrosine kinase inhibitor targeting VEGF receptors, MET, AXL, and RET, has demonstrated clinical activity in phase 2 studies involving NETs. The efficacy of cabozantinib in patients with progressive, advanced extrapancreatic or pancreatic NETs after prior treatments remains uncertain.
Objective: To assess the efficacy and safety of cabozantinib compared with placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs.
Methods: A multicenter, double-blind, randomized, placebo-controlled phase 3 trial (CABINET) was conducted at 62 sites in the United States from October 2018 to August 2023. Eligible patients were adults aged ≥18 years with histologically confirmed, locally advanced or metastatic well- or moderately differentiated extrapancreatic or pancreatic NETs (WHO grades 1–3) and documented disease progression within 12 months prior to enrollment. Patients were randomized 2:1 to receive cabozantinib (60 mg orally once daily) or placebo. Randomization was stratified by concurrent somatostatin analogue use and primary tumor site. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review according to RECIST 1.1 criteria. Key secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.
Results: A total of 203 patients with extrapancreatic NETs and 95 patients with pancreatic NETs were randomized.
- Extrapancreatic NET Cohort:
- Median PFS was 8.4 months with cabozantinib vs. 3.9 months with placebo (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.25–0.59; P<0.001).
- Partial responses were observed in 5% of patients receiving cabozantinib vs. 0% with placebo.
- Pancreatic NET Cohort:
- Median PFS was 13.8 months with cabozantinib vs. 4.4 months with placebo (stratified HR, 0.23; 95% CI, 0.12–0.42; P<0.001).
- Partial responses were observed in 19% of patients receiving cabozantinib vs. 0% with placebo.
Grade ≥3 treatment-related adverse events occurred in 62–65% of patients receiving cabozantinib and 23–27% receiving placebo. Common grade ≥3 adverse events included hypertension (21–22%), fatigue (11–13%), diarrhea (11%), and thromboembolic events (11%).
Conclusions: Cabozantinib significantly improved progression-free survival compared to placebo in patients with previously treated, progressive advanced extrapancreatic or pancreatic NETs. The safety profile was consistent with known adverse events associated with cabozantinib.
Implications for Practice:
- New Treatment Option: Cabozantinib offers a new therapeutic avenue for patients with advanced NETs who have progressed after prior therapies.
- Broad Applicability: The findings support the use of cabozantinib in both extrapancreatic and pancreatic NETs.
- Adverse Event Management: Clinicians should closely monitor and manage treatment-related adverse events to optimize patient outcomes.
Study Strengths and Limitations: Strengths include a large sample size, randomized controlled design, and inclusion of patients who had progressed after standard therapies, enhancing the applicability of the findings to clinical practice. Limitations involve early trial termination based on interim analysis, which may overestimate the treatment effect, the use of placebo rather than an active comparator, and the high rate of dose modifications due to adverse events.
Future Research: Further studies should explore the optimal sequencing of cabozantinib with other therapies in NETs and investigate combination treatments. Long-term studies assessing overall survival benefits and quality of life are warranted.