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Radiotherapy and Oncology : Journal of... Sep 2022Up to 50% of radiotherapy courses are delivered in palliative intent for various indications. Despite the large number of treated patients, we know little about the... (Meta-Analysis)
Meta-Analysis
PURPOSE
Up to 50% of radiotherapy courses are delivered in palliative intent for various indications. Despite the large number of treated patients, we know little about the choice of endpoints in trials of palliative radiotherapy. Our primary aim was, therefore, to analyze primary endpoints in trials of palliative radiotherapy.
METHODS
We conducted a pre-registered (https://doi.org/10.17605/OSF.IO/GMCAF) meta-research analysis searching Pubmed/MEDLINE, EMBASE, CENTRAL, and "ClinicalTrials.gov" for clinical trials of palliative radiotherapy published 1990-2020. Endpoints were categorized in "patient-centered endpoints", including overall survival and patient-reported outcomes, and "tumor-centered endpoints" such as local control. The remainder were "other endpoints" including toxicity or observer-rated symptoms. We applied descriptive statistics to summarize data and logistic regression to assess if year of publication predicted the choice of primary endpoints.
RESULTS
Of 7379 records screened, 292 were eligible. Trials were characterized by small sample sizes and use of external beam radiotherapy for metastases or thoracic primaries. Median patient age was 64 and median ECOG was 1. Only 64.4%(145/225) of published trials clearly stated their primary endpoint. Published trials employed a "patient-centered primary endpoint" in 45.5%(66/145) and a "tumor-centered primary endpoint" in 17.3%(25/145) of the cases. There was no statistically significant trend in time for the use of "patient-centered primary endpoints". Registered ongoing trials used a "patient-centered primary endpoint" in 32.8%(22/67) and a "tumor-centered primary endpoint" in 26.9%(18/67) of the cases.
CONCLUSION
Although "patient-centered primary endpoints" appear relatively prevalent in published trials of palliative radiotherapy, their use is still suboptimal and appears to be lower in currently ongoing trials.
Topics: Humans; Neoplasms; Palliative Care; Radiation Oncology
PubMed: 35868602
DOI: 10.1016/j.radonc.2022.07.013 -
JACC. Cardiovascular Imaging Mar 2017Cardiovascular imaging is an integral component of many clinical trials beyond those for which the primary goal is to evaluate or validate imaging technologies. The... (Review)
Review
Cardiovascular imaging is an integral component of many clinical trials beyond those for which the primary goal is to evaluate or validate imaging technologies. The scope of such trials is broad, ranging from those in which a medical, surgical, or interventional cardiovascular device or drug is being evaluated to those in which there is concern about cardiovascular adverse events complicating treatment for noncardiac conditions. This paper discusses study design as it pertains to the incorporation of imaging elements, the important role played by imaging core laboratories, the rationale for and approaches to involvement of imagers in clinical trials, and guidance by the U.S. Food and Drug Administration on imaging endpoints in clinical trials.
Topics: Cardiac Imaging Techniques; Cardiovascular Diseases; Clinical Trials as Topic; Endpoint Determination; Humans; Observer Variation; Predictive Value of Tests; Reproducibility of Results; Research Design; United States; United States Food and Drug Administration
PubMed: 28279377
DOI: 10.1016/j.jcmg.2016.12.003 -
Bulletin Du Cancer Apr 2014The choice of the activity endpoint is crucial when designing phase II screening trials. This choice is usually guided by convention, but the level of evidence for... (Review)
Review
What is an active regimen in carcinoma of unknown primary sites? Analysis of correlation between activity endpoints reported in phase II trials. Correlation of activity endpoints in phase II trials.
BACKGROUND
The choice of the activity endpoint is crucial when designing phase II screening trials. This choice is usually guided by convention, but the level of evidence for picking-up one of them is limited.
METHODS
We have analysed the phase II trials in carcinoma of unknown primary patients (CUP; 48 strata). We calculated the Pearson correlation coefficient using weighted linear regression to measure the degree of association between the different available activity endpoints (Best objective response - BORR, best tumour control rate - BTCR, 3- and 6-month progression-free rates, 3- and 6-month PFR and median progression-free survival). We also explored the correlation between these endpoints and OS.
RESULTS
All activity endpoints were strongly correlated in CUP studies; all of these endpoints were strongly correlated with OS. The median BORR across the studies was 30%. Positive trials defined by BORR ≥ 30% were associated with statistically longer PFS (4.8 versus 3.7 months, P = 0.013) and OS (10.0 versus 8.0, P = 0.0007).
DISCUSSION
In phase II studies with CUP patients, BORR and the threshold of BORR > 30% for defining promising drug appears adequate.
Topics: Antineoplastic Agents; Carcinoma; Clinical Trials, Phase II as Topic; Disease-Free Survival; Humans; Neoplasms, Unknown Primary; Treatment Outcome
PubMed: 24793622
DOI: 10.1684/bdc.2014.1934 -
BMJ Open Oct 2022Using a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is,...
INTRODUCTION
Using a surrogate endpoint as a substitute for a primary patient-relevant outcome enables randomised controlled trials (RCTs) to be conducted more efficiently, that is, with shorter time, smaller sample size and lower cost. However, there is currently no consensus-driven guideline for the reporting of RCTs using a surrogate endpoint as a primary outcome; therefore, we seek to develop SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) extensions to improve the design and reporting of these trials. As an initial step, scoping and targeted reviews will identify potential items for inclusion in the extensions and participants to contribute to a Delphi consensus process.
METHODS AND ANALYSIS
The scoping review will search and include literature reporting on the current understanding, limitations and guidance on using surrogate endpoints in trials. Relevant literature will be identified through: (1) bibliographic databases; (2) grey literature; (3) handsearching of reference lists and (4) solicitation from experts. Data from eligible records will be thematically analysed into potential items for inclusion in extensions. The targeted review will search for RCT reports and protocols published from 2017 to 2021 in six high impact general medical journals. Trial corresponding author contacts will be listed as potential participants for the Delphi exercise.
ETHICS AND DISSEMINATION
Ethical approval is not required. The reviews will support the development of SPIRIT and CONSORT extensions for reporting surrogate primary endpoints (surrogate endpoint as the primary outcome). The findings will be published in open-access publications.This review has been prospectively registered in the OSF Registration DOI: 10.17605/OSF.IO/WP3QH.
Topics: Consensus; Humans; Publications; Randomized Controlled Trials as Topic; Reference Standards; Research Design; Review Literature as Topic; Treatment Outcome
PubMed: 36229145
DOI: 10.1136/bmjopen-2022-062798 -
Therapie Feb 2016In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional... (Review)
Review
In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.
Topics: Biomedical Research; Endpoint Determination; Humans; Research Design; Sample Size
PubMed: 27080628
DOI: 10.1016/j.therap.2016.01.002 -
Surrogate end-points or primary outcomes in clinical trials in women with polycystic ovary syndrome?Human Reproduction (Oxford, England) Aug 2004There are multiple surrogate variables in polycystic ovary syndrome (PCOS), including biometric and biochemical parameters. The number of surrogate variables and their... (Review)
Review
There are multiple surrogate variables in polycystic ovary syndrome (PCOS), including biometric and biochemical parameters. The number of surrogate variables and their poor validity in relationship to primary clinical end-points pose major problems to conducting a trial in women with PCOS. The aim of this review is to discuss the use of surrogate variables compared with primary clinical end-points in women with PCOS. Arguably the best documented correlation between a surrogate variable and a primary clinical end-point is that between ovulation and pregnancy in women with PCOS. Good correlation has been noted between the increase in ovulation frequency with clomiphene citrate and the chance of pregnancy in women with PCOS. However, ovulation cannot be equated with pregnancy, as a host of other factors may affect the true outcome of interest: a healthy liveborn child. Pregnancy and an improvement in hirsutism are clinical end-points that have been successfully studied in past and ongoing clinical trials in women with PCOS. Many other clinical end-points, such as endometrial cancer and cardiovascular disease, are rare in premenopausal women with PCOS, and may not be suitable as the primary outcome of clinical studies. Future multicentre trials in women with PCOS should focus on primary clinical end-points.
Topics: Female; Hormone Replacement Therapy; Humans; Polycystic Ovary Syndrome; Randomized Controlled Trials as Topic
PubMed: 15192061
DOI: 10.1093/humrep/deh322 -
Injury Jun 2008The selection of appropriate endpoints is the key to successful clinical studies. The chosen primary outcome measure ultimately determines the required sample size,... (Review)
Review
The selection of appropriate endpoints is the key to successful clinical studies. The chosen primary outcome measure ultimately determines the required sample size, significantly affects trial logistics, and establishes acceptance of results in the scientific community. Confirmatory statistics may only be conducted on the primary endpoint, while secondary endpoints are better analysed in an exploratory fashion. While investigators may prefer surrogates (e.g., radiographic results, laboratory markers) clinical trials should no longer be planned without addressing function or quality of life. Valid outcome tools (e.g., Short-Form 36) are needed to ensure comparability of findings to other studies.
Topics: Clinical Trials as Topic; Health Status Indicators; Humans; Quality of Life; Research Design; Treatment Outcome
PubMed: 18514657
DOI: 10.1016/j.injury.2008.02.014 -
Translational Lung Cancer Research Mar 2012In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become... (Review)
Review
Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer?
In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (≥30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven.
PubMed: 25806152
DOI: 10.3978/j.issn.2218-6751.2011.12.08 -
Journal of the National Cancer Institute Sep 2021Screening mammography was assessed in 9 randomized trials initiated between 1963 and 1990, with breast cancer-specific mortality as the primary endpoint. In contrast,...
Screening mammography was assessed in 9 randomized trials initiated between 1963 and 1990, with breast cancer-specific mortality as the primary endpoint. In contrast, breast cancer detection has been the primary endpoint in most screening trials initiated during the past decade. These trials have evaluated digital breast tomosynthesis, magnetic resonance imaging, and ultrasound, and novel screening strategies have been recommended solely on the basis of improvements in breast cancer detection rates. Yet, the assumption that increases in tumor detection produce reductions in cancer mortality has not been validated, and tumor-detection endpoints may exacerbate the problem of overdiagnosis. Indeed, the detection of greater numbers of early stage breast cancers in the absence of a subsequent decline in rates of metastatic cancers and cancer-related mortality is the hallmark of overdiagnosis. There is now evidence to suggest that both ductal carcinoma in situ and invasive cancers are overdiagnosed as a consequence of screening. For each patient who is overdiagnosed with breast cancer, the adverse consequences include unnecessary anxiety, financial hardships, and a small risk of morbidity and mortality from unnecessary treatments. Moreover, the overtreatment of breast cancer, as a consequence of overdiagnosis, is costly and contributes to waste in health-care spending. In this article, we argue that there is a need to establish better endpoints in breast cancer screening trials, including quality of life and composite endpoints. Tumor-detection endpoints should be abandoned, because they may lead to the implementation of screening strategies that increase the risk of overdiagnosis.
Topics: Breast Neoplasms; Early Detection of Cancer; Female; Humans; Mammography; Mass Screening; Overdiagnosis; Quality of Life
PubMed: 32898241
DOI: 10.1093/jnci/djaa140 -
Alzheimer's & Dementia : the Journal of... Nov 2011Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer's disease (AD). Currently, two co-primary endpoints must be...
BACKGROUND
Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer's disease (AD). Currently, two co-primary endpoints must be specified, which measure cognitive and functional impairments. Generally, the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is one of the co-primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co-primary approach.
METHODS
Internal consistency, structural and convergent validity, and 2-year internal and external responsiveness of the CDR-SB were assessed in 667 very mild to moderate (global Clinical Dementia Rating, 0.5-2) AD patients from the REAL.FR (Réseau sur la Maladie d'Alzheimer Français) study.
RESULTS
The CDR-SB showed good internal consistency (Cronbach's alpha = 0.88), and acceptable structural (separate "cognitive" and "functional" factors) and convergent validity. Variability in mean changes over time was low, leading to excellent internal responsiveness (effect size = 1.2; standardized response mean = 1.17 at 2 years) and smaller sample sizes as compared with the ADAS-Cog. External responsiveness was acceptable when compared with "clinically meaningful" changes on the Activities of Daily Living scale but only borderline acceptable when compared with the ADAS-Cog and Instrumental Activities of Daily Living. Levels of missing data and floor/ceiling effects were low.
CONCLUSIONS
The CDR-SB measures cognitive and functional impairment simultaneously, and has excellent 2-year internal responsiveness. This makes it a promising candidate as a sole primary endpoint for AD trials, although more work is required to determine the clinical relevance of CDR-SB changes, and its usefulness as an endpoint at other disease stages.
Topics: Activities of Daily Living; Aged; Alzheimer Disease; Cholinesterase Inhibitors; Female; Follow-Up Studies; Humans; Male; Multicenter Studies as Topic; Psychometrics; Research Design; Treatment Outcome
PubMed: 21745761
DOI: 10.1016/j.jalz.2011.01.005