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Clinical Cancer Research : An Official... Aug 2022Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival... (Meta-Analysis)
Meta-Analysis
PURPOSE
Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS.
PATIENTS AND METHODS
A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis.
RESULTS
Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses.
CONCLUSIONS
OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies.
Topics: Antineoplastic Agents; Biomarkers; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Randomized Controlled Trials as Topic; Response Evaluation Criteria in Solid Tumors; Survival Analysis
PubMed: 34907081
DOI: 10.1158/1078-0432.CCR-21-3135 -
Journal of Crohn's & Colitis Jun 2024Outcomes after ileocolonic resection in Crohn's disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our...
BACKGROUND
Outcomes after ileocolonic resection in Crohn's disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] aimed to standardise postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define those which could be used in trials or registries.
METHODS
Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after two rounds of voting, the statement was excluded.
RESULTS
In the systematic review, 3071 manuscripts were screened of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy, or as reflected by the presence of complications.
CONCLUSIONS
Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints.
Topics: Crohn Disease; Humans; Recurrence; Ileum
PubMed: 38112601
DOI: 10.1093/ecco-jcc/jjad205 -
Heart, Lung & Circulation Sep 2023Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We... (Review)
Review
BACKGROUND
Current pharmacological options for hypertrophic cardiomyopathy (HCM) are not disease-specific; while it treats symptoms, mavacamten targets the underlying pathology. We aim to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive HCM.
METHODS
This systematic review of the literature followed the PRISMA guidelines. Title/abstract and topics were searched using the following term: "mavacamten". The electronic research literature databases included the Cochrane Library, MedLine, and clinicaltrials.gov from July to August 2022. Primary efficacy endpoint was to assess clinical response at the end of treatment compared with baseline, defined as, at least one New York Heart Association (NYHA) class reduction. Two secondary endpoints from baseline were determined. The first was defined as improvement in mixed venous oxygen pressure (pVO). The second was defined as reduction of the post-exercise left ventricular outflow tract (LVOT) gradient.
RESULTS
We included in our analyses data from four studies that met our review eligibility criteria. There were three randomised placebo-controlled clinical trials and one non-randomised open-label clinical trial. All four studies showed a reduction in NYHA class from mavacamten use. Three out of four studies demonstrated >1 NYHA functional class improvement ranging from 34% to 80%, while only one study showed a smaller percentage of patients remaining at class 3. Three out of four studies measured pVO as an outcome, and all three studies noticed an increase in peak oxygen consumption after mavacamten treatment. Additionally, three out of four studies measured post-exercise LVOT gradient reduction as an outcome and all three found significant reduction in the post-exercise LVOT gradient after treatment. The most commonly observed adverse side effects were atrial fibrillation and decreased left ventricular ejection fraction, but all participants recovered without long-term sequelae and only one patient dropped out of the trial.
CONCLUSIONS
Mavacamten has a greater efficacy than placebo in the treatment of HCM. It also showed promising tolerability and efficacy profiles in the treatment of HCM in adults. The three endpoints used in the evaluation of studies were reduction in NYHA class, increase in pVO, and post-exercise LVOT gradient reduction. Mavacamten showed greater reduction in NYHA, larger effects on increase of pVO, and significant reduction of the LVOT gradient. Mavacamten was also found to be well tolerated, like the placebo. The side effect profile was limited for the majority of individuals taking mavacamten. In the future, authors recommended dose-optimisation studies, and studies that evaluate mavacamten both in comparison to, and in conjunction with other current treatments.
Topics: Adult; Humans; Cardiomyopathy, Hypertrophic; Heart; Stroke Volume; Ventricular Function, Left; Clinical Trials as Topic
PubMed: 37453852
DOI: 10.1016/j.hlc.2023.05.019 -
Survey of Ophthalmology 2022Pars plana vitrectomy (PPV) and scleral buckling (SB) are two of the most common surgical treatments for rhegmatogenous retinal detachment (RRD). This meta-analysis... (Meta-Analysis)
Meta-Analysis Review
Pars plana vitrectomy (PPV) and scleral buckling (SB) are two of the most common surgical treatments for rhegmatogenous retinal detachment (RRD). This meta-analysis compares the efficacy and safety of PPV and SB for RRD. A systematic literature review was performed using Ovid MEDLINE, EMBASE and Cochrane CENTRAL from 2000 to June, 2021. Comparative studies, randomized controlled trials and observational studies investigating PPV and SB for RRD repair were included. The primary endpoint was final best- corrected visual acuity (BCVA). Secondary endpoints were reattachment rates, total operation time, and incidence of adverse events. Subgroup analyses including phakic status, presence of PVR-C or greater at baseline, and macular attachment status were conducted. Across 41 studies (8 RCTs, 33 observational studies), 5,401 SB and 10,546 PPV eyes were included. SB achieved a statistically significant, but likely not clinically significant, better final BCVA than PPV (0.38 ± 0.53 vs. 0.33 ± 0.53 logMAR (20/48 vs. 20/43 Snellen); weighted mean difference [WMD]: 0.07; 95% confidence interval: [0.02-0.11]; P = 0.005). SB had a better final BCVA compared to PPV in observational studies (P = 0.007) but not in RCTs (P = 0.21). SB had a lower incidence of post-operative cataract formation (P < 0.00001) and iatrogenic breaks (P < 0.00001), but a higher incidence of choroidal/subretinal hemorrhage (P = 0.007), choroidal detachment (P = 0.004), and residual subretinal fluid (RSRF) (P < 0.00001). Primary (86.5% vs. 84.8%; P = 0.13) and final (96.7% vs. 97.7%; P = 0.12) reattachment rates were similar between PPV and SB. PPV had a significantly higher primary reattachment rate in RCTs (P = 0.02) but not in observational studies (P = 0.30). SB was associated with a better final BCVA than PPV; however, this result was primarily driven by observational studies and phakic patients who developed cataracts. Primary and final reattachment rates were similar between the comparators. SB was associated with a significantly lower incidence of iatrogenic breaks and cataracts, while PPV was associated with a reduced risk of choroidal detachment, subretinal hemorrhage, and RSRF.
Topics: Cataract; Choroidal Effusions; Hemorrhage; Humans; Iatrogenic Disease; Retinal Detachment; Retrospective Studies; Scleral Buckling; Treatment Outcome; Vitrectomy
PubMed: 34896191
DOI: 10.1016/j.survophthal.2021.12.005 -
Annals of Translational Medicine Jun 2019Few cancer drugs or their indications achieved survival benefit in subsequent trials during postmarket period after approval based on surrogate endpoints. This causes a... (Review)
Review
Few cancer drugs or their indications achieved survival benefit in subsequent trials during postmarket period after approval based on surrogate endpoints. This causes a concern of using surrogate endpoints instead of overall survival (OS) as the primary endpoint for trial design, implementation and regulation approval. We conducted a systematic review to summarize the findings from published meta-analyses which have evaluated endpoint surrogacy for OS in oncological randomized controlled trials (RCTs) with immunotherapies. After searching articles indexed in PubMed prior to 24 February 2019, we identified a total of 11 meta-analyses for advanced multiple tumors, non-small cell lung cancer (NSCLC), urothelial carcinoma, renal cell carcinoma, melanoma; most (91%; 10/11) focused on immune checkpoint inhibitors. Although the evaluation criteria adopted by these meta-analyses for validating endpoint surrogacy were not consistent (ranging from R ≥0.60 to R ≥0.80), the results were consistent. Few studies show an association between OS and progression-free survival (PFS)/objective response rate (ORR) that met the lowest evaluation criteria (R ≥0.60), based on treatment effects (8%; 2/26 indications) or absolute results from experimental arm (0%; 0/11 indications). However, the association between OS and 1-year survival rate met the lowest criteria based on both the trial-level results (4/4 indications) and the arm-level results (5/5 indications). In lieu of this finding, we are supportive of an alternative endpoint, e.g., 1-year survival rate, rather than the more conventional choices PFS and ORR, as promising surrogate endpoint for OS in immunotherapy RCTs. We encourage further investigation on endpoint surrogacy based on the same or different settings, especially an assessment on survival rate at milestone time (e.g., 1-year), which has been demonstrated valuable for predicting OS in meta-analyses.
PubMed: 31317014
DOI: 10.21037/atm.2019.04.72 -
Minerva Endocrinologica Mar 2017Long-term outcome of patients with adrenal incidentaloma (AI) is unknown. The aim of this study was to systematically summarize the follow-up and outcome of clinically... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Long-term outcome of patients with adrenal incidentaloma (AI) is unknown. The aim of this study was to systematically summarize the follow-up and outcome of clinically silent AI who do not undergo surgery.
EVIDENCE ACQUISITION
All major databases and medical literature in English-language, published from 1998 to May 2015, were systematically searched for publications on AI. Primary endpoint was hormonal hyper function; secondary endpoints were time from diagnosis to study endpoint and the outcome of adrenalectomy. Meta-analysis was performed using both qualitative and quantitative approach.
EVIDENCE SYNTHESIS
A total of 11 publications were included. Total sample size was 1298 patients. Mean follow-up duration was 44.2 months. There were 82 patients confirmed to have subclinical Cushing's syndrome at diagnosis, with 1.79% new cases at the end of follow up (95% CI, 0.002 to 0.045). Incidence of Cushing's syndrome was 0.7% (95% CI, 0.001 to 0.013) and pheochromocytoma 0.4% (95% CI, 0.001 to 0.008). The mean tumor size was 2.52cm, with mean increment of 0.03cm to 2.9cm at the end of follow up. About 3% of patients ended up with surgery (95% CI, 0.01 to 0.05) but none were due to primary adrenal malignancy. Time of greatest risk of developing Cushing's syndrome and pheochromocytoma was between months 36 and 42 (hazard rate 14%), and between months 48 and 54 (hazard rate 7%) respectively.
CONCLUSIONS
Malignant change in non-functioning AI is rare. The risk of developing overt disease over the follow-up period is low. A less stringent imaging and functional work-up interval can be considered.
Topics: Adrenal Gland Neoplasms; Disease Progression; Humans; Treatment Outcome
PubMed: 26698544
DOI: 10.23736/S0391-1977.16.02394-4 -
PloS One 2017Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct... (Meta-Analysis)
Meta-Analysis Review
Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09,-12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE's risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction.
Topics: Animals; In Vitro Techniques; Metformin; Mice; Myocardial Infarction; Rabbits; Rats; Swine
PubMed: 28832637
DOI: 10.1371/journal.pone.0183664 -
European Urology Oct 2023In the oncology setting, patient-reported outcome measures (PROMs) provide important data that help to ensure patient-relevant endpoints are captured and reported. Use... (Review)
Review
CONTEXT
In the oncology setting, patient-reported outcome measures (PROMs) provide important data that help to ensure patient-relevant endpoints are captured and reported. Use of this information for treatment decision-making by clinicians and patients in real-world settings is facilitated by consistent and transparent reporting of trial methods.
OBJECTIVE
To identify and compare PROMs used in advanced renal cell carcinoma (RCC) trials in terms of the rationale for the choice of measure, endpoint hierarchy (primary, secondary, exploratory), assessment time points, statistical methods, and statistical metrics for interpretation.
EVIDENCE ACQUISITION
A systematic literature review via searches of four online databases (2016-2021) and recent conference abstracts (2019-2021) identified 2616 articles, of which 33 were included in the review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
EVIDENCE SYNTHESIS
Among the 33 clinical studies included, 19 different PROMs were identified: three kidney cancer-specific scales, two cancer-specific scales, two generic scales, and 12 symptom-specific scales. The endpoint hierarchy for patient reported outcome (PRO) assessment was reported in 42% of the studies; one study included PROs as a primary endpoint. Reporting of time points, minimal important differences, and statistical analyses was highly heterogeneous.
CONCLUSIONS
A diverse range of PROMs have been included in clinical studies for patients with advanced/metastatic RCC. Prespecified analyses for PRO assessments were generally not stated, while analytical methods and reporting varied. An improvement in alignment across studies would better inform regulatory, market-access, reimbursement, and clinical decision-making to improve patient care.
PATIENT SUMMARY
We reviewed how the impact of cancer therapies on health outcomes from the patient's point of view is being measured in clinical trials for kidney cancer. The techniques and reporting varied across trials. Standardisation of how these data are captured and reported may improve care and decision-making for patients with kidney cancer.
Topics: Humans; Carcinoma, Renal Cell; Patient Reported Outcome Measures; Kidney Neoplasms; Patient Outcome Assessment; Research Design
PubMed: 37550153
DOI: 10.1016/j.eururo.2023.07.006 -
Frontiers in Cardiovascular Medicine 2023Hypertrophic cardiomyopathy (HCM) is recognized as the most prevalent form of genetic cardiomyopathy, and recent investigations have shed light on the existence of sex... (Review)
Review
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is recognized as the most prevalent form of genetic cardiomyopathy, and recent investigations have shed light on the existence of sex disparities in terms of clinical presentation, disease progression, and outcomes.
OBJECTIVES
This study aimed to systematically review the literature and perform a meta-analysis to comprehensively compare the clinical outcomes between female and male patients with HCM.
METHODS
A thorough search was conducted in databases including PubMed, Embase, Cochrane Library, and Web of Science, encompassing literature from inception until June 2023. The primary endpoints examined were: (1) all-cause mortality; (2) an arrhythmic endpoint comprising sudden cardiac death (SCD), sustained ventricular tachycardia, ventricular fibrillation, or aborted SCD; and (3) a composite endpoint incorporating either (1) or (2), in addition to hospitalization for heart failure or cardiac transplantation. Pooled estimates were derived using a random-effects meta-analysis model.
RESULTS
The analysis encompassed a total of 29 observational studies, involving 44,677 patients diagnosed with HCM, of which 16,807 were female. Baseline characteristics revealed that the female group exhibited an advanced age [55.66 ± 0.04 years vs. 50.38 ± 0.03 years, pooled mean difference (MD) = 0.31, 95% CI: 0.22-0.40, = 0.000, = 88.89%], a higher proportion of New York Heart Association class III/IV patients [pooled odds ratio (OR) = 1.94, 95% CI: 1.55-2.43, = 0.000, = 85.92%], and a greater prevalence of left ventricular outflow tract gradient greater than or equal to 30 mmHg (pooled OR = 1.48, 95% CI: 1.27-1.73, = 0.000, = 68.88%) compared to the male group. The female group were more likely to have a positive genetic test (pooled OR = 1.27, 95% CI: 1.08-1.48, = 0.000, = 42.74%) and to carry the myosin heavy chain beta 7 mutation (pooled OR = 1.26, 95% CI: 1.04-1.54, = 0.020, = 0.00%) compared to the male group. Female sex exhibited a significant association with increased risks of all-cause mortality (pooled OR = 1.62, 95% CI: 1.38-1.89, = 0.000, = 72.78%) and the composite endpoint (pooled OR = 1.47, 95% CI: 1.20-1.79, = 0.000, = 84.96%), while no substantial difference was observed in the arrhythmic endpoint (pooled OR = 1.08, 95% CI: 0.87-1.34, = 0.490, = 55.48%).
CONCLUSIONS
The present findings suggest that female patients with HCM tend to experience poorer clinical outcomes. It is imperative to critically reevaluate disease definitions and enhance awareness to mitigate delays in the diagnosis and treatment of HCM in women, thereby fostering equitable healthcare practices.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/, PROSPERO (CRD42023431881).
PubMed: 38116536
DOI: 10.3389/fcvm.2023.1252266 -
Breast Cancer Research and Treatment Dec 2021Docetaxel, carboplatin and trastuzumab, with or without pertuzumab (TCH(P)), has become the preferred (neo)adjuvant regimen for HER2-positive breast cancer. However, its... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Docetaxel, carboplatin and trastuzumab, with or without pertuzumab (TCH(P)), has become the preferred (neo)adjuvant regimen for HER2-positive breast cancer. However, its associated febrile neutropenia (FN) risk is unclear: pivotal studies reported FN risks < 10%, but in clinical practice, a high FN rate (> 20%) was observed. This systematic review and meta-analysis determine the FN risk associated with TCH(P) and the indication for primary prophylactic granulocyte colony-stimulating factor (PP G-CSF).
METHODS
The MEDLINE, Embase, Web of Science and Cochrane databases were searched for full-text English articles reporting the FN incidence in early breast cancer patients receiving (neo)adjuvant TCH(P). The primary endpoint was the pooled crude FN incidence in patients treated without PP G-CSF using the random effects method. Secondary endpoints were the FN risk with PP G-CSF support, age-related differences in FN and differences in risk with TCH versus TCHP.
RESULTS
Seventeen studies were included in the systematic review. The pooled estimates of FN incidences were 27.6% (95% CI 18.6 to 37.1) in patients who did not receive PP G-CSF (primary meta-analysis, 9 studies, n = 889) versus 5.0% (95% CI 2.6 to 8.0) in patients administered PP G-CSF (secondary meta-analysis, 7 studies, n = 445). Two studies reported non-significant age-related differences in FN. The risk comparison between TCH and TCHP was inconclusive.
CONCLUSIONS
The crude FN risk associated with (neo)adjuvant TCH(P) is over 20%, the upper limit above which the international guidelines unanimously advise PP G-CSF administration. G-CSF prophylaxis effectively reduces FN risk and should become the standard of care with (neo)adjuvant TCH(P).
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Febrile Neutropenia; Female; Granulocyte Colony-Stimulating Factor; Humans
PubMed: 34533681
DOI: 10.1007/s10549-021-06387-1