Publication status of contemporary oncology randomised controlled trials worldwide

BackgroundLittle is known about the extent of selective publication in contemporary oncology randomised controlled trials (RCTs) worldwide. This study aimed to evaluate the rates of publication and timely publication (within 24 months) for contemporary oncology RCTs from all over the world. We also investigated the trial characteristics associated with publication and timely publication.Patients and methodsWe identified all phase III oncology RCTs registered on ClinicalTrials.gov with a primary completion date between January 2008 and December 2012. We searched PubMed and EMBASE to identify publications. The final search date was 31 December 2015. Our primary outcome measure was the time to publication from the primary completion date to the date of primary publication in a peer-reviewed journal.ResultsWe identified 598 completed oncology RCTs; overall, 398 (66.6%) had been published. For published trials, the median time to publication was 25 months (interquartile range, 16–37 months). Only 192 trials (32.1%) were published within 24 months. Timely publication was independently associated with trials completed late in 2012. Trials conducted in Asia and other regions were less likely to have timely publication, but trials conducted in different locations were all equally likely to be published. Industry- and NIH-funded trials were equally likely to be published timely or at any time after trial completion. Among 391 published trials with clear primary outcomes, there was a trend for timely publication of positive trials compared with negative trials.ConclusionsDespite the ethical obligations and societal expectations of disclosing findings promptly, oncology RCTs performed poorly.     

Enregistrement et publication du critère d’évaluation principal dans les essais contrôlés randomisés en oncologie

PurposeTo improve the quality of reporting of randomized clinical trials (RCTs), international registries for RCTs and guidelines for primary endpoint (PEP) analysis were established. The objectives of this systematic review were to evaluate concordance of PEP between publication and the corresponding registry and to assess the intrapublication consistency in PEP reporting.MethodsAll adult oncology RCTs in solid tumors published in 10 journals between 2005 and 2009 were reviewed. Registration information was extracted from international trial registries.ResultsA total 366 RCTs were identified. Trial registration was found for 215 trials and the rate increased from 43% in 2005 to 82% in 2009 (P < 0.001). There were 134 RCTs with clearly defined PEPs in registry, with the rate increasing from 15 to 67% (P < 0.001). PEP differs between registration and final publication in 14% trials with clearly defined PEPs. Reporting issues in methodology were found in 15% RCTs, mainly due to inadequate reporting of PEP or of sample size calculation. Problems with the interpretation of trial results were found in 22% publications, mostly due to negative superiority studies being interpreted as showing equivalence.ConclusionThe rates of trial registration and of trials with clearly defined PEP have improved over time, however 14% of these trials reported a different PEP in the final publication. Intrapublication inconsistencies in PEP reporting are frequent. Our findings highlight the need for investigators, peer reviewers and readers for increased awareness and scrutiny of reporting outcomes of oncology RCTs.     

Planning and reporting of quality-of-life outcomes in cancer trials

BackgroundInformation about the impact of cancer treatments on patients' quality of life (QoL) is of paramount importance to patients and treating oncologists. Cancer trials that do not specify QoL as an outcome or fail to report collected QoL data, omit crucial information for decision making. To estimate the magnitude of these problems, we investigated how frequently QoL outcomes were specified in protocols of cancer trials and subsequently reported.DesignRetrospective cohort study of RCT protocols approved by six research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We compared protocols to corresponding publications, which were identified through literature searches and investigator surveys.ResultsOf the 173 cancer trials, 90 (52%) specified QoL outcomes in their protocol, 2 (1%) as primary and 88 (51%) as secondary outcome. Of the 173 trials, 35 (20%) reported QoL outcomes in a corresponding publication (4 modified from the protocol), 18 (10%) were published but failed to report QoL outcomes in the primary or a secondary publication, and 37 (21%) were not published at all. Of the 83 (48%) trials that did not specify QoL outcomes in their protocol, none subsequently reported QoL outcomes. Failure to report pre-specified QoL outcomes was not associated with industry sponsorship (versus non-industry), sample size, and multicentre (versus single centre) status but possibly with trial discontinuation.ConclusionsAbout half of cancer trials specified QoL outcomes in their protocols. However, only 20% reported any QoL data in associated publications. Highly relevant information for decision making is often unavailable to patients, oncologists, and health policymakers.     

Decreasing incidence of upper age restriction enrollment criteria among cancer clinical trials

BackgroundAge disparities among cancer clinical trial participants are pervasive and worsening over time. Identification of factors associated with age disparities is critical to improve enrollment of older patients on trials. The incidence and impact of trial eligibility criteria that exclude patients on the basis of age remains opaque.MethodsClinicalTrials.gov was queried for completed oncologic randomized controlled trials (RCTs). Phase 3 RCTs assessing a therapeutic intervention among adult cancer patients were included. Trial eligibility criteria were assessed using the ClinicalTrials.gov website as well as trial publications and protocol documentation.ResultsSeven hundred and forty-two trials met inclusion criteria, with a total combined enrollment of 449,720 patients. Upper age restriction enrollment criteria were identified for 10.1% of RCTs; the median age cutoff for restricted trials was 72 years (interquartile range 70–80 years). Linear regression modeling revealed decreasing incidence of age restriction criteria over time, at a rate of −1.1% annually (p = .03); trials initiating enrollment in 2002–2005, for example, had a 16.1% rate of age-restrictive eligibility criteria, compared with 7.6% for trials initiating enrollment in 2010–2014.ConclusionUse of eligibility criteria that explicitly exclude patients on the basis of age appears to be decreasing with time. Future efforts should aim to better characterize the relationship between eligibility criteria (such as those that exclude patients on the basis of specific organ function) and their association with age disparities among enrolled patients.     

Bias in reporting of end points of efficacy and toxicity in randomized,clinical trials for women with breast cancer

BackgroundPhase III randomized, clinical trials (RCTs) assess clinically important differences in end points that reflect benefit to patients. Here, we evaluate the quality of reporting of the primary end point (PE) and of toxicity in RCTs for breast cancer.MethodsPUBMED was searched from 1995 to 2011 to identify RCTs for breast cancer. Bias in the reporting of the PE and of toxicity was assessed using pre-designed algorithms. Associations of bias with the Journal Impact Factor (JIF), changes in the PE compared with information in ClinicalTrials.gov and funding source were evaluated.ResultsOf 164 included trials, 33% showed bias in reporting of the PE and 67% in the reporting of toxicity. The PE was more likely to be reported in the concluding statement of the abstract when significant differences favoring the experimental arm were shown; 59% of 92 trials with a negative PE used secondary end points to suggest benefit of experimental therapy. Only 32% of articles indicated the frequency of grade 3 and 4 toxicities in the abstract. A positive PE was associated with under-reporting of toxicity.ConclusionBias in reporting of outcome is common for studies with negative PEs. Reporting of toxicity is poor, especially for studies with positive PEs.     

A comparison of matched interim analysis publications and final analysis publications in oncology clinical trials

BackgroundProgression-free survival is an increasingly popular surrogate end point for overall survival. The strength of correlation between the two end points varies, raising questions about the correlation between results of interim analyses that report mature progression-free survival data with the subsequent final publication that report overall survival.MethodsWe searched PubMed from 2005 to 2015 for randomized controlled trials that measured both progression-free survival and overall survival. We matched interim publications that reported mature progression-free survival data with their final analyses that reported overall survival. We included 25 matched pairs and 8 unmatched interim analyses whose final analyses are not published. Our primary objectives are to compare interim publications with matched final publications in terms of journal prominence and Altmetric score and to compare progression-free survival and overall survival effect sizes.ResultsAll interim analyses (n = 33) were prespecified and there was a statistically significant progression-free survival benefit in 31 (93.9%). Only eight matched final analyses had statistically significant overall survival data. Interim analyses were more often published in top-5 general medicine journals (P < 0.01) but not in top-5 oncology journals (P = 0.26). Altmetric scores were higher in interim analyses (P < 0.01). Progression-free survival effect sizes from interim analyses were a median of 31% larger than overall survival effect sizes from final analyses.ConclusionInterim analyses with progression-free survival data may generate hype in oncology, as evidenced by journal impact factors and Altmetric scores. The cause of this hype may be due, in part, to large progression-free survival effect sizes. Regardless, in trials that investigate progression-free and overall survival, publishing interim analyses with mature progression-free survival data apart from the final analyses with mature overall survival should be cautioned.     

Challenges to quality assurance of surgical interventions in clinical oncology trials: A systematic review

Where surgery forms the primary curative modality in surgical oncology trials the quality of this intervention has the potential to directly influence outcomes. Many trials however lack a robust framework to ensure surgical quality. We aim to report existing published challenges to quality assurance of surgical interventions within oncological trials. A systematic on-line literature search of Embase and Medline identified 34 relevant studies, including 19 RCTs, 11 further analyses of the primary RCTs, and 4 trial protocols. Inclusion criteria: oncological RCTs with a surgical intervention and/or associated publications relevant to the research question; ‘Challenges to quality assurance of surgery in clinical oncology trials’. Selected articles were assessed by two reviewers to identify reported challenges to quality assurance of surgical intervention within these trials. Reported challenges to surgical quality could be classified as those affecting credentialing, standardisation and monitoring of surgical interventions. Constraints of using case volume for credentialing surgeons; inter-centre variation in the definition and execution of interventions; insufficient training, and monitoring of surgical quality, were the most commonly encountered challenges within each of these three domains. Findings confirmed an inadequacy in the implementation and reporting of effective surgical quality assurance measures. The surgical community should enable implementation of agreed upon mitigating strategies to overcome challenges to surgical quality in oncology trials.     

Lymphoma Study Titles on ClinicalTrials.gov Lack Details Necessary for Study Identification

BackgroundClinicalTrials.gov is used by clinicians and patients to identify clinical trials. We assessed the ease with which users could identify relevant trials related to lymphoma using the short and official titles. We hypothesized that lymphoma titles frequently lack important information.Materials and MethodsWe performed 2 searches on ClinicalTrials.gov. The first search was performed before June 2017, when ClinicalTrials.gov underwent updates to improve usability. The second was performed after 2017. We assessed whether the short and official titles of each trial provided information on the study phase, eligible disease status, lymphoma histologic subtype, study intervention, primary objective, and the presence of randomization and placebo control.ResultsOf the pre-overhaul lymphoma trials, the official versus short titles included information regarding study intervention (99% vs. 96%), study phase (82% vs. 14%), lymphoma histologic subtype (78% vs. 72%), disease status (46% vs. 35%), randomization (13% vs. 2%), presence of placebo (6% vs. 2%), and primary objective (38% vs. 26%). Of the post-overhaul trials, the official versus short titles included information regarding study intervention (97% vs. 96%), lymphoma histologic subtype (83% vs. 78%), study phase (78% vs. 8%), disease status (64% vs. 50%), primary objective (38% vs. 23%), presence of placebo (11% vs. 0%), and randomization (18% vs. 0%).ConclusionThe official titles were more informative than were the short titles on ClinicalTrials.gov. However, the short and official titles both often lacked the basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of the format and content included in study titles.     

Clinical Trial Design in Small Cell Lung Cancer: Surrogate End Points and Statistical Evolution

BackgroundSmall-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored.Material and MethodsThrough examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS).ResultsThere was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%.ConclusionThere is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.     

Bias in reporting of randomised clinical trials in oncology

BackgroundBias in reporting efficacy and toxicity in clinical trials may impact treatment decisions. Here, we report quality of reporting of efficacy and of toxicity in articles describing randomised controlled trials (RCTs) of cancer therapy and the association between biased reporting and study results, funding and financial relationships of the authors with the sponsor.Materials and methodsWe reviewed articles published from July 2010 to December 2012 in six high-impact journals reporting RCTs of systemic treatment for cancer. Bias in reporting of the primary end-point and toxicity were assessed. Associations between biased reporting and study results, funding source and financial ties of the author with the funding source were evaluated using logistic regression.ResultsTwo hundred articles were identified. Among 107 RCTs where there was no statistically significant difference in the primary end-point between the two arms, 50 (47%) reports used biased reporting in the abstract of the paper to imply benefit of the experimental treatment. Toxicity was not reported in the abstract in 18.5% of the studies and this was associated with a positive primary end-point. Source of funding and financial ties were not associated with biased reporting.ConclusionsBias in reporting of efficacy outcomes is common for studies with a negative primary end-point and can lead to off-label misuse of experimental therapies, if they are approved for other indications. Toxicity is under-reported, especially for studies with a positive primary end-point, leading to a biased view of the safety of new treatments.     

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events—a meta-analysis

BackgroundPrevious meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA.Materials and methodsWe searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials.ResultsThe literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12–2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33–2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04–1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83–1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19–1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30–1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13–2.43) in open-label trials.ConclusionsOpen-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.     

MET Exon 14 Skipping in NSCLC: A Systematic Literature Review of Epidemiology,Clinical Characteristics,and Outcomes

IntroductionMET exon 14 (METex14) skipping is a rare oncogenic driver in non–small-cell lung cancer (NSCLC) for which targeted therapy with MET tyrosine kinase inhibitors (TKIs) was recently approved. Given the heterogeneity in published data of METex14 skipping NSCLC, we conducted a systematic literature review to evaluate its frequency, patient characteristics, and outcomes.MethodsOn June 13, 2022 we conducted a systematic literature review of publications and conference abstracts reporting frequency, patient characteristics, or outcomes of patients with METex14 skipping NSCLC.ResultsWe included 139 studies reporting frequency or patient characteristics (350,997 patients), and 39 studies reporting clinical outcomes (3989 patients). Median METex14 skipping frequency was 2.0% in unselected patients with NSCLC, with minimal geographic variation. Median frequency was 2.4% in adenocarcinoma or nonsquamous subgroups, 12.0% in sarcomatoid, and 1.3% in squamous histology. Patients with METex14 skipping NSCLC were more likely to be elderly, have adenocarcinoma histology; there was no marked sex or smoking status distribution. In first line of treatment, median objective response rate ranged from 50.7% to 68.8% with targeted therapies (both values correspond to MET TKIs), was 33.3% with immunotherapy, and ranged from 23.1% to 27.0% with chemotherapy.ConclusionsPatients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.     

The influence of industry sponsorship on the reporting of subgroup analyses within phase III randomised controlled trials in gastrointestinal oncology

PurposeCorrect interpretation of subgroup analyses (SGA) is important as it influences selection of therapeutic interventions for patient subsets. The primary aim of our study was to compare reporting of SGA between industry and non-industry sponsored trials.MethodsWe performed a systematic literature review and extracted data from journal articles (JA) and conference abstracts (CA) published over a decade reporting SGA results of phase III randomised controlled gastrointestinal (GI) oncology trials with patient participants of ≥150.ResultsIn JA, SGA was reported in 100/145 (69%) trials: 41/54 industry sponsored (76%; 95% confidence interval [CI]: 63–86%) and 59/91 non-industry sponsored (65%; 95% CI: 55–74%) trials (p = 0.16). In CA, SGA was reported in 86/204 (42%) trials: 43/83 industry sponsored (52%; 95% CI: 41–62%) and 43/121 non-industry sponsored (36%; 95% CI: 28–44%) trials (p = 0.02). Number of SGA performed per trial was significantly larger for industry compared to non-industry sponsored trials in both JA (median 6 versus 2, p = 0.003) and CA (median 1 versus 0, p = 0.023). Claims of subgroup effect were made in 52% of trials in JA and 50% in CA, with significant test of interaction evident in only 25% of JA and 16% of CA, with no difference between industry and non-industry trials. Industry sponsored trials with a significant primary end-point reported more SGA (p < 0.001 JA; p = 0.046 CA).ConclusionsIndustry sponsored trials reported more SGA. Claimed subgroup effects were often not accompanied by significant interaction test; thus circumspection should be adopted when using SGA to deviate from standard therapeutic decision-making in GI oncology.     

Manual Lymphatic Drainage for Breast Cancer-related Lymphedema: A Systematic Review and Meta-analysis of Randomized Controlled Trials

BackgroundThe purpose of this systematic review was to meta-analyze the effectiveness of manual lymphatic drainage (MLD) in breast cancer-related lymphedema (BCRL) patients.MethodsThe following databases: the Cochrane Library, the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Web of Science, ClinicalTrials.gov were systematically searched. All English publications before April 2021 have been retrieved without any restrictions of countries, time, or article type. We included randomized controlled trials (RCTs) examining the effectiveness of MLD versus control group without MLD of women with BCRL. The outcomes were (1) the incidence of lymphedema, (2) volumetric changes of lymphedema, (3) pain, (4) quality of life. Review Manager 5.3 was used to perform statistical analysis.ResultsIn total, 11 RCTs involving 1564 patients were included, in which 10 trials were deemed viable for inclusion in the meta-analysis. Due to the effects of MLD for BCRL, statistically significant improvements were found on the incidence of lymphedema (RR = 0.58, 95% CI [0.37, 0.93], P =.02) and pain intensity (SMD = -0.72, 95% CI [-1.34, -0.09], P = .02). Besides, the meta-analysis carried out implied that the effects that MLD had on volumetric changes of lymphedema and quality of life, were not statistically significant.ConclusionThe current evidence based on the RCTs shows that pain of BCRL patients undergoing MLD is significantly improved, while our findings do not support the use of MLD in improving volumetric of lymphedema and quality of life. Note that the effect of MLD for preventing BCRL is worthy of discussion.