scholarly journals PDCT-15. EFFICACY AND SAFETY OF BEVACIZUMAB IN TREATING RECURRENT PEDIATRIC LOW-GRADE GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF PATIENT OUTCOMES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi186
Author(s):  
Victor Lu ◽  
John Welby ◽  
David Daniels

Abstract BACKGROUND Although rare, the propensity for pediatric low-grade glioma (pLGG) to recur despite upfront intervention presents a management conundrum for clinicians. One novel salvage option is anti-angiogenic bevacizumab, however, its safety and efficacy in this specific demographic is poorly defined. Correspondingly, our aim was to pool systematically-identified metadata in the literature to substantiate the clinical relevance of bevacizumab in treating recurrent pLGG. METHODS Searches of 7 electronic databases from inception to June 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions. RESULTS Six pertinent studies described the outcomes of 110 recurrent pLGG patients managed with bevacizumab. While on-treatment, the rate of clinical response was 58% (95% CI, 43–72%), and the rate of radiographic response was 80% (95% CI, 58–96%). Additionally, the rate of serious adverse events (Grade 3 and above) was 11% (95% CI, 5–18%), with proteinuria the most common of those events. By the time patients were off-treatment, the rate of progression was estimated to be 51% (95% CI, 28–74%). Certainty of these results ranged from very low to low. CONCLUSIONS The use of bevacizumab as therapy for recurrent pLGG appears to confer appreciable clinical and radiographic response with relatively low serious adverse events risk while on-treatment. However, the long-term off-treatment benefits of this therapy have yet to be consolidated. Traditional clinical heterogeneity concerns preclude the formalization of any recommendations until larger, more standardized investigations can be performed.

2020 ◽  
Vol 7 (4) ◽  
pp. 359-368
Author(s):  
Victor M Lu ◽  
John P Welby ◽  
Cody L Nesvick ◽  
David J Daniels

Abstract Background Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression. Methods A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions. Results Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%). Conclusions Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.


2021 ◽  
Author(s):  
Hai-Bo Yao ◽  
Jie-Ru Peng ◽  
Xue-Mei Zheng ◽  
Zhuo Yang ◽  
Huang Yan ◽  
...  

Abstract Background: Remdesivir, a nucleoside analogue antiviral drug developed for Ebola, is approved by the US Food and Drug Administration for the treatment of COVID-19. However, the findings of randomised controlled trials (RCTs) and observational studies vary regarding the effectiveness of remdesivir. We aimed to comprehensively review the available evidence identify the effectiveness and safety of remdesivir in patients with COVID-19.Methods: Seven databases (PubMed, Web of Science, Embase, Wanfang database, SinoMed, Chinese National Knowledge Infrastructure and Chinese Science Journal Database) were searched for literatures published until November 2020.Following the PRISMA flow diagram, we included RCTs and prospective observational studies that reported the effectiveness and safety of remdesivir in patients with COVID-19. With extracting study details, as well as patient characteristics and outcomes, data were meta-analyzed by using Review Manager software version 5.4.1. Meta-analyses were conducted with fixed-effect model or random-effect model to calculate risk ratio (RR).Results: Four studies involving 2,279 patients were included in this meta-analysis. Compared with placebo, 10-day remdesivir was associated with significant increased clinical improvement on days 14 and 28 with RR 1.19 (95%CI 1.09-1.30) and RR 1.09 (95%CI 1.03-1.16). The clinical improvement of 5-day remdesivir was better than 10-day remdesivir on days 7 with RR 1.20 (95%CI 1.02-1.41), but the efficacy advantage of 5-day remdesivir disappeared on days 14 (RR 1.08; 95%CI 0.90-1.29). Remdesivir was associated with lower serious adverse events rates and grade 3 or 4 adverse events rates as compared with placebo with RR 0.75(95%CI 0.63-0.89) and RR 0.89(95%CI 0.80-0.99). Compared with 10-day remdesivir, 5-day remdesivir for patients with COVID-19 decreased the risk of serious adverse events rates and grade 3 or 4 adverse events rates with RR 0.65(95%CI 0.47-0.88) and RR 0.74 (95%CI 0.58-0.95). Conclusions: Our meta-analysis suggested that remdesivir would increase clinical improvement conditions and decrease serious adverse events on patients with COVID-19. 5-day remdesivir had the similar clinical effectiveness and mortality with 10-day remdesivir, and had lower serious adverse events rate. Comprehensive considering the cost and benefit, 5-day remdesivir may be a better therapeutic option if available medical resources are limited.


2021 ◽  
Vol 12 ◽  
pp. 204209862110425
Author(s):  
Chenchula Santenna ◽  
Kota Vidyasagar ◽  
Krishna Chaitanya Amarneni ◽  
Sai Nikhila Ghanta ◽  
Balakrishnan Sadasivam ◽  
...  

Introduction: Remdesivir, an experimental antiviral drug has shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both in vitro and in vivo. The present systematic review and meta-analysis were performed to quantify the safety and tolerability of remdesivir, based on safety outcome findings from randomized controlled trials, observational studies and case reports of remdesivir in coronavirus disease 2019 (COVID-19) patients. Methods: We have performed a systematic search in the PubMed, Google Scholar and Cochrane Library using specific keywords such as ‘COVID-19’ OR ‘SARS CoV-2’ AND ‘Remdesivir’. The study endpoints include total adverse events (AEs), serious adverse events (SAEs), grade 3 and grade 4 AEs, mortality and drug tolerability. Statistical analysis was carried out by using Revman 5.4 software. Results: Total 15 studies were included for systematic review, but only 5 randomized clinical trials (RCTs) ( n = 13,622) were included for meta-analysis. Visual inspection of the forest plots for remdesivir 10-day versus placebo and remdesivir 10-day versus 5-day groups revealed that there is a significant difference in SAEs [10-day remdesivir versus control (odds ratio [OR] = 0.55, 0.40–0.74) p = 0.0001; I2 = 0%; 10-day remdesivir versus 5-day remdesivir (OR = 0.56, 0.38–0.84) p = 0.005; I2 = 13%]. In grade 4 AEs, there is a significant difference in 10-day remdesivir versus control (OR = 0.32, 0.19–0.54) p = 0.0001; I2 = 0%, but not in comparison to 5-day remdesivir (OR = 0.95, 0.59–1.54) p = 0.85; I2 = 0%. But there is no significant difference in grade 3 AEs [remdesivir 10 day versus control (OR = 0.81, 0.59–1.11) p = 0.19; I2 = 0%; 10-day remdesivir versus 5-day remdesivir (OR = 1.24, 0.86–1.80) p = 0.25; I2 = 0%], in total AEs [remdesivir 10 day versus control (OR = 1.07, 0.66–1.75) p = 0.77; I2 = 79%; remdesivir 10 day versus 5 day (OR = 1.08, 0.70–1.68) p = 0.73; I2 = 54%)], in mortality [10-day remdesivir versus control (OR = 0.93, 0.80–1.08) p = 0.32; I2 = 0%; 10-day remdesivir versus 5-day remdesivir (OR = 1.39, 0.73–2.62) p = 0.32; I2 = 0%)] and tolerability [remdesivir 10 day versus control (OR = 1.05, 0.51–2.18) p = 0.89; I2 = 65%, 10-day remdesivir versus 5-day remdesivir (OR = 0.86, 0.18–4.01) p = 0.85; I2 = 78%]. Discussion & Conclusion: Ten-day remdesivir was a safe antiviral agent but not tolerable over control in the hospitalized COVID-19 patients with a need of administration cautiousness for grade 3 AEs. There was no added benefit of 10- or 5-day remdesivir in reducing mortality over placebo. To avoid SAEs, we suggest for prior monitoring of liver function tests (LFT), renal function tests (RFT), complete blood count (CBC) and serum electrolytes for those with preexisting hepatic and renal impairments and patients receiving concomitant hepatotoxic or nephrotoxic drugs. Furthermore, a number of RCTs of remdesivir in COVID-19 patients are suggested. Plain Language Summary Ten-day remdesivir is a safe antiviral drug with common adverse events in comparison to placebo. The rate of serious adverse events and grade 3 adverse events were significantly lower in 10-day remdesivir in comparison to placebo/5-day remdesivir. There was no significant difference in the rate of tolerability and mortality reduction in 10-day remdesivir over placebo/5-day remdesivir. There were no new safety signals reported in vulnerable populations, paediatric, pregnant and lactating women.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15151-e15151
Author(s):  
Laith Al-Showbaki ◽  
Michelle Nadler ◽  
Alexandra Desnoyers ◽  
Fahad Almugbel ◽  
David W. Cescon ◽  
...  

e15151 Background: Multiple ICIs have been approved, and in some diseases there is a choice of more than one ICI. The comparative safety, efficacy, and tolerability are not known. Here we report on a network meta-analysis comparing different ICIs targeting PD1 or PDL1. Methods: Randomized trials (RCTs) supporting the registration of a single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis including only disease sites in which more than one ICI has been approved. Multiple pair-wise comparisons were then performed. When more than 2 comparisons were available for a pair of ICIs these were pooled into a single estimate. Analyses were performed in Microsoft Excel and RevMan 5.3. Results: Of 16 RCTs included, 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. There was a total of 10673 patients in the analysis. Compared to pembrolizumab, efficacy was similar for nivolumab (HR 1.06, 95% CI 0.97-1.16) and for atezolizumab (HR 1.05, 95% CI 0.93-1.20). However, avelumab appeared inferior (HR 1.29, 95% CI 1.07-1.57). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR 1.12, 95% CI 0.56-2.27) and atezolizumab (OR 1.05, 95% CI 0.55-2.04). However, compared to nivolumab, atezolizumab was associated with more SAEs (OR 2.14, 95% CI 1.47-3.12). Avelumab had the lowest odds of grade 3-4 adverse events compared to pembrolizumab (OR 0.42, 95% CI 0.24-0.74), nivolumab (OR 0.38, 95% CI 0.24-0.62) and atezolizumab (OR 0.21, 95% CI 0.14-0.33). Atezolizumab was associated with more grade 3-4 adverse events than nivolumab (OR 1.84, 95% CI 1.37-2.47). The odds of treatment discontinuation without progression were similar between nivolumab and atezolizumab (OR 1.20, 95% CI 0.73-2.00), but higher with pembrolizumab compared to nivolumab (OR 1.35, 95% CI 0.83-2.17) and atezolizumab (OR 2.56, 95% CI 1.29-5.00). Pembrolizumab was associated with higher OR of immune related adverse events (IRAEs) compared to nivolumab (OR 2.12, 95% CI 1.49-3.03) and atezolizumab (OR 1.63, 95% CI 1.09-2.43), while the OR of IRAEs was almost similar between nivolumab and atezolizumab. Conclusions: Pembrolizumab, nivolumab, and atezolizumab have similar efficacy. Avelumab appears efficacious. Safety and tolerability seem better with avelumab, but worse with atezolizumab and pembrolizumab.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
I-Hsin Huang ◽  
Po-Chien Wu ◽  
Ya-Han Lee ◽  
Yi-No Kang

Abstract Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.


2019 ◽  
Vol 14 (1) ◽  
pp. 31-36
Author(s):  
Raafat Abdel-Malek ◽  
Kyrillus S. Shohdy ◽  
Noha Abbas ◽  
Mohamed Ismail ◽  
Emad Hamada ◽  
...  

Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.


2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Sophie Juul ◽  
Faiza Siddiqui ◽  
Marija Barbateskovic ◽  
Caroline Kamp Jørgensen ◽  
Michael Pascal Hengartner ◽  
...  

Abstract Background Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. Methods/design A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, ‘active placebo’, or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events. Discussion As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder. Systematic review registration PROSPERO CRD42020220279


2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii367-iii367
Author(s):  
Nongnuch Sirachainan ◽  
Attaporn Boongerd ◽  
Samart Pakakasama ◽  
Usanarat Anurathapan ◽  
Ake Hansasuta ◽  
...  

Abstract INTRODUCTION Low grade glioma (LGG) is the most common central nervous system (CNS) tumor in children accounted for 30–50%. Regarding benign characteristic of disease, surgical management remains the mainstay of treatment. However, surgical approach is limited in some conditions such as location at brainstem or infiltrative tumor. Chemotherapy and radiation treatments have been included in order to control tumor progression. The 5-years survival rate is approach 90% especially in patients who receive complete resection. However, the outcome of children with LGG in low to middle income is limited. Therefore, the aim of the study was to determine long-term outcome of children with newly diagnosed LGG. METHODS A retrospective study enrolled children aged <18 years who were newly diagnosed LGG during January 2006- December 2019. Diagnosis of LGG was confirmed by histological findings of grade I and II according to WHO criteria. RESULTS A total of 40 patients, female to male ratio was 1:1.35 and mean (SD) for age was 6.7 (4.0) years. The most common location was optic chiasmatic pathway (42.5%), followed by suprasellar region (25.0%). Sixty percent of patients received at least partial tumor removal. Chemotherapy and radiation had been used in 70% and 10.0% respectively. The 10-year progression free survival was 74.1±11.4% and overall survival was 96.2±3.8%. SUMMARY: Treatment of Pediatric LGG mainly required surgical management, however, chemotherapy and radiation had been used in progressive disease. The outcome was excellent.


2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Shahab Hajibandeh ◽  
Shahin Hajibandeh

Abstract Aims to evaluate prognostic significance of metabolic syndrome (MetS) in patients undergoing carotid artery revascularisation. Methods A systematic review and meta-analysis was performed in compliance with PRISMA standards to evaluate prognostic significance of MetS in patients undergoing carotid endarterectomy or carotid stenting. Short-term (<30 days) postoperative outcomes (all-cause mortality, stroke or transient ischaemic attack (TIA), myocardial infarction, major adverse events) and long-term outcomes (restenosis, all-cause mortality, stroke or TIA, myocardial infarction, major adverse events) were considered as outcomes of interest. Random effects modelling was applied for the analyses. Results Analysis of 3721 patients from five cohort studies showed no difference between the MetS and no MetS groups in terms of the following short-term outcomes: all-cause mortality (OR: 1.67,P=0.32), stroke or TIA (OR: 2.44,P=0.06), myocardial infarction (OR: 1.01,P=0.96), major adverse events (OR: 1.23, P = 0.66). In terms of long-term outcomes, MetS was associated with higher risk of restenosis (OR: 1.75,P=0.02), myocardial infarction (OR: 2.12,P=0.04), and major adverse events (OR: 1.30, P = 0.009) but there was no difference between the two groups in terms of all-cause mortality (OR: 1.11, P = 0.25), and stroke or TIA (OR: 1.24, P = 0.33). The quality and certainty of the available evidence were judged to be moderate. Conclusions The best available evidence suggest that although MetS may not affect the short-term postoperative morbidity and mortality outcomes in patients undergoing carotid revascularisation, it may result in higher risks of restenosis, myocardial infarction and major adverse events in the long-term. Evidence from large prospective cohort studies are required for more robust conclusions.


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