EClinicalMedicine最新文献

[This corrects the article DOI: 10.1016/j.eclinm.2023.102419.][This corrects the article DOI: 10.1016/j.eclinm.2025.103117.].

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi).

Methods: We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165).

Findings: With a median follow-up of 7.1 years (interquartile range 5.6-8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%-80%) and OS was 78% (95% CI 61%-89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1).

Interpretation: Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients.

Funding: This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

Background: It is unclear whether weight loss interventions worsen disordered eating in people living with overweight/obesity. We aimed to systematically evaluate the association between weight loss interventions and disordered eating.

Methods: Six databases were searched from inception until September 2024. Trials of weight loss interventions in people with overweight/obesity were included if they reported a validated score for disordered eating on either the Eating Disorder Examination Interview or the Eating Disorder Examination Questionnaire pre- and post-intervention. Interventions included behavioural weight loss programmes (BWL) and pharmacotherapy licenced for weight loss, with or without concurrent psychological support, provided for at least 4 weeks. Pooled standardised mean differences (SMD) in scores of disordered eating were calculated using random effects meta-analyses. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool and the Newcastle-Ottawa scale for randomised and single-arm trials, respectively (PROSPERO ID: CRD42023404792).

Findings: Thirty-eight studies with 66 eligible arms (61 interventions: 29 BWL, 11 BWL + pharmacotherapy, 20 BWL + psychological intervention, 1 pharmacotherapy + psychological intervention) and 3364 participants in total were included. The mean weight change was -4.7 kg (95% CI: -5.7, -3.7). Compared with baseline, disordered eating scores improved by -1.47 SMD units (95% CI: -1.67, -1.27, p < 0.001, I² = 94%) at intervention completion (median of 4 months). Seven randomised trials that directly compared a weight loss intervention to no/minimal intervention reported an improvement of -0.49 SMD units (95% CI, -0.93, -0.04, p = 0.0035, I² = 73%). Sub-group analyses showed: (a) disordered eating scores improved more in people with an eating disorder at baseline compared with people without high scores, (b) no clear evidence that the association depended upon intervention type, and (c) disordered eating scores improved more in trials rated at low overall RoB.

Interpretation: Despite heterogeneity in effect size, weight loss interventions consistently improved disordered eating scores. These findings provide reassurance that weight loss interventions might not worsen disordered eating and may improve it.

Funding: Novo Nordisk UK Research Foundation Doctoral Fellowship in Clinical Diabetes.

Background: Diversity, equity, and inclusion pertaining to race, ethnicity, and related concepts have historically been underrepresented in clinical trials for pharmaceutical drug development, although this is an increasing topic for regulators, payers, and patient advocacy groups. We aimed to develop a summary statistical measure to assess such representativeness.

Methods: A statistical measure using population demographic parameters derived from performance metrics through verbal autopsy research was proposed for using population frameworks in the UK. The summary measure, R-index, was demonstrated using simulation data with population frameworks from the UK (116 Roche UK clinical trials 2013-2022) and then using published clinical trial results (NCT02366143 [March 1, 2015-September 15, 2017], NCT04368728 [July 27, 2020-October 9, 2020], and NCT04470427 [July 27, 2020-November 25, 2020]). R-index was further proposed for use with benchmarking performance in representative trial development for internal processes, external benchmarking, and performance tracking in clinical trial development.

Findings: R-index was derived from a standardized statistical measure called the L1 norm, or Manhattan distance, and then normalized to the maximum theoretical error observed in some populations using population framework or ontology for reporting concepts such as race, ethnicity, and other dimensions of diversity used to characterize patient cohorts. R-index demonstrated desirable qualities in demonstration simulations, including a range of 0-1, ease of calculation and use, and interpretability and flexibility, as data standards in the space of inclusive research continue to develop.

Interpretation: R-index is an interpretable, accessible summary statistic that may be useful for tracking and benchmarking representativeness in inclusive research and related domains. R-index is adaptable to different population frameworks and ontologies across different settings and considerations in terms of underlying population variables.

Funding: F. Hoffmann-La Roche Ltd/Genentech, Inc.

Background: While different lung cancer risk prediction models have been established as essential tools to identify high-risk participants for lung cancer screening programs, evaluations of their risk discriminatory performances have reported heterogenous findings in different research cohorts. We therefore aimed to summarise results of head-to-head comparisons of the predictive performance of various lung cancer risk models performed within the same study population.

Methods: In this systematic review and meta-analysis, we performed a systematic search of PubMed and Web of Science databases for primary studies published from inception to Oct 16, 2024. Articles comparing the performance of questionnaire-based lung cancer risk models in an independent, external validation cohort of participants with previous or current smoking exposure were included. The main reasons for exclusion of studies were if only one model was assessed in the external population or risk discrimination was not evaluated. Random-effects meta-analyses were conducted to synthesize differences in the area under the curve (AUC) of two models compared in multiple populations. To assess the risk of bias, PROBAST (the Prediction model Risk of Bias Assessment Tool) was used. The study was registered with PROSPERO, CRD42023427911.

Findings: The systematic search yielded 5568 records. In total, 15 eligible studies were included in the meta-analysis, comprising 4,134,648 individuals with previous or current smoking exposure, of whom 45,448 (1.10%) developed LC within 5-7 years. Among the nine models that were compared, AUC differences reached up to 0.050 between two models. The Lung Cancer Risk Assessment Tool (LCRAT), Bach model and PLCOm2012 model consistently had a higher AUC when compared to any other model, with AUC differences ranging between 0.018 (95% CI 0.011, 0.026) and 0.044 (95% CI 0.038, 0.049). The risk of bias and applicability concerns were deemed low in eight, and high in seven of the included studies. Results excluding studies with high risk of bias were mostly consistent. Among eight of the 24 model pairs that were compared, there was notable between-study heterogeneity (I² ≥50%).

Interpretation: Our systematic review and meta-analyses of head-to-head comparisons disclose major differences in predictive performance of widely used lung cancer risk models. Although our review is limited to the availability of head-to-head comparisons, evidence from current cohort-based model comparisons indicates that the LCRAT, Bach and PLCOm2012 consistently outperformed alternative questionnaire-based risk prediction tools.

Funding: Funded by the European Union.

[This corrects the article DOI: 10.1016/j.eclinm.2023.102178.].

Background: Monitoring and evaluation of prostate cancer (PCa) screening is key to ensure that the programme achieves the desired objectives. Utilizing a set of prioritized, feasible and harmonized key performance indicators (KPIs) is crucial for this purpose. We describe the methodology used to identify the PCa screening KPIs and the outcome of this process within the scope of the EU-funded PRostate cancer Awareness and Initiative for Screening in the EU (PRAISE-U) project. Feasibility of implementing these KPIs will be evaluated in the five pilots set up at multiple sites in the EU (Spain-2 sites, Poland, Ireland, Lithuania).

Methods: The indicators were developed following a structured methodology involving the following steps: (i) Development of a specific conceptual framework for PCa screening is adapted from the existing risk-based algorithms and modified to guide the selection and mapping of indicators (from identification of population eligible for screening to the decision for treatment or follow-up), (ii) Scoping review of literature (coverage from 1971 to June 2023) to identify existing performance indicators for PCa screening to adapt to the new framework with redefining the indicators, where necessary, (iii) Survey among experts (October-November 2023) to select the indicators fulfilling pre-determined criteria such as accuracy of definition and calculation, importance, and feasibility, and (iv) Deliberations among experts to list the finalized set of indicators, held in December 2023.

Findings: A total of 63 KPIs were selected for review using the step-wise methodology as described earlier. Following the review, survey, and deliberations, 21 KPIs were finalized to be piloted in the PRAISE-U project. The resulting 21 KPIs cover the different phases of the screening programme, including invitation, screening test, risk stratification, diagnosis, and also on treatment, harms, and impact. Each KPI has been defined with agreed numerator and denominator.

Interpretation: Continuous monitoring of PCa screening programmes using the KPIs will serve as a powerful tool for optimizing service delivery, programme improvement, comparison per screening site, and ultimately contributing to a better benefit to harm ratio. The KPIs will be implemented in five pilot sites identified to be included in the PRAISE-U project aiming to identify an evidence-based scalable model for risk adapted PCa screening for Europe.

Funding: This project has received funding from the EU4Health program under grant agreement 101101217, co-funded by the European Union.

Background: Recent studies in patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction (GEJ)-Neo-AEGIS and ESOPEC-have explored the comparison of neoadjuvant chemoradiotherapy (nCRT) with chemotherapy, with conflicting results. To contextualize the findings from these studies using nCRT as a comparator, we aimed to investigate contemporary real-world outcomes of nCRT in patients with adenocarcinoma of the esophagus or GEJ.

Methods: From the Netherlands Cancer Registry, patients were selected who were diagnosed between 1 January 2015 and 31 December 2022 with a resectable (cT1N+M0 or cT2-4aNanyM0) esophageal, GEJ or gastric cardia adenocarcinoma and started treatment with nCRT according to the CROSS regimen, that is 5 weekly cycles of carboplatin (AUC 2 mg/mL per minute) and paclitaxel (50 mg/m²) combined with concurrent radiotherapy (41.4 Gy in 23 fractions of 1.8 Gy). Pathologic complete response (pCR) according to Mandard was the primary outcome of this study and defined as complete tumor regression of the primary tumor (Mandard grade I) irrespective of residual nodal involvement.

Findings: Of the 4765 included patients, 4170 (87.5%) completed the full CROSS regimen of radiotherapy and chemotherapy. A pCR was observed in 704 (20.5%) of 3439 patients who underwent surgical resection within 16 weeks after completing the CROSS regimen. In the complete study population, the median overall survival (OS) was 33.7 months (95% CI 32.0-35.6), with a 3-year OS rate of 48.1%.

Interpretation: Although survival rates in real-world settings are often lower compared to clinical trials, in our real-world cohort the 3-year OS was only 2.6% lower compared to that reported for the group that underwent nCRT in ESOPEC. These real-world results underscore the potential of the CROSS regimen in daily clinical practice.

Funding: None.