Cancer Randomized Controlled Trials Research Articles

Cost-utility of geriatric assessment (GA) in older adults with cancer: A model-based economic evaluation of four randomized controlled trials (RCTs).

1509 Background: Geriatric assessment (GA) is a guideline-recommended approach to optimize cancer management in older adults undergoing chemotherapy. Our recent cost-utility analysis of the published 5C (Clinical and Cost-effectiveness of a Comprehensive geriatric assessment and management for Canadian elders with Cancer) RCT comparing GA and management (GAM) with usual care in older adults with cancer did not demonstrate cost-effectiveness overall. However, the trial was limited by <5% of study participants receiving GA prior to starting treatment. Three other GAM RCTs (GAIN, GAP-70, and INTEGERATE) have recently been published with evidence of efficacy on clinically relevant endpoints. Whether these are more cost effective than 5C is unclear. We evaluated the cost-effectiveness of GAM versus usual care in older adults with cancer using a decision model under a range of plausible scenarios representing the 4 trials. Methods: We performed cost-effectiveness analyses using the healthcare payer perspective and a 12-month time horizon. We incorporated Canadian costs and utility data from 5C, and used intervention details and effectiveness data from the three RCTs. We reported healthcare costs per quality-adjusted life year (QALY) and the incremental net monetary benefit (INMB) using a $50,000 per QALY threshold. In scenario analyses we examined the main cost drivers. Results: Across trials, the average QALY per patient ranged 0.577–0.662 for GA and 0.606–0.665 for UC, and the average total costs $31,234–$39,432 for GA and $29,261–$41,756 for UC. Chemotherapy expenses accounted for 46%-66% of total costs across trials. The INTEGERATE trial had a positive INMB of $6,074. The GAIN and GAP-70 trials had negative INMB value of -$2,123 and -$1,172, respectively. In comparison, in 5C, the total costs were $39,812 and $37,450 for GAM and UC, respectively, and QALYs were 0.728 and 0.751, respectively; the INMB was $-2,713. Conclusions: Trial results and the associated model of care from INTEGERATE suggested a positive net monetary benefit, primarily driven by reduced hospitalization. Evaluation of cost-effectiveness under a range of plausible scenarios from RCTs can provide important insights about GAM. Our results add to the growing data supporting the need to implement GAM in older adults with cancer starting chemotherapy and argue for its cost effectiveness under specific scenarios. Future trials should include hospitalization outcomes. Future economic analyses need to accurately capture chemotherapy costs.

Statistical Analysis Methods and Reporting of Patient-Reported Outcomes in Randomized Controlled Trials for Cancer Conducted in Japan: A Systematic Review.

The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative was established in 2016 to assess the quality and standardization of patient-reported outcomes (PRO) data analysis in randomized controlled trials (RCTs) on advanced breast cancer. The initiative identified deficiencies in PRO data reporting, including nonstandardized methods for handling missing data. This study evaluated the reporting of health-related quality of life (HRQOL) in Japanese cancer RCTs to provide insights into the state of PRO reporting in Japan. The study reviewed PubMed articles published from 2010 to 2018. Eligible studies included Japanese cancer RCTs with ≥50 adult patients (≥50% were Japanese) with solid tumors receiving anticancer treatments. The evaluation criteria included clarity of the HRQOL hypotheses, multiplicity testing, primary analysis methods, and reporting of clinically meaningful differences. Twenty-seven HRQOL trials were identified. Only 15% provided a clear HRQOL hypothesis, and 63% examined multiple HRQOL domains without adjusting for multiplicity. Model-based methods were the most common statistical methods for the primary HRQOL analysis. Only 22% of the trials explicitly reported clinically meaningful differences in HRQOL. Baseline assessments were reported in most trials, but only 26% reported comparisons between the treatment groups. HRQOL analysis was based on the intention-to-treat population in 19% of the trials, and 74% reported compliance at follow-up; however, 41% did not specify how missing values were handled. Although the rates of reporting clinical hypotheses and clinically meaningful differences were relatively low, the current state of HRQOL evaluation in the Japanese cancer RCT appears comparable to that of previous studies.

Individual Patient Data Analysis of 17 Randomized Trials vs. Real-World Data for Men with Localized Prostate Cancer Receiving Radiotherapy.

Prior work has demonstrated poor correlation between the results of randomized controlled trials (RCTs) and real-world evidence (RWD). However, patients enrolled in RCTs are often considered to poorly represent the real-world population. Herein, we utilize multiple large data repositories to determine differences in baseline characteristics and long-term outcomes between patients enrolled in RCTs and RWD that received radiotherapy for localized prostate cancer. Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was leveraged, and 17 phase III randomized trials were included. RWD were accessed through the Staging Collaboration for Cancer of the Prostate (STAR-CAP) cohort, a cohort that is comprised of >60 centers across the United States and Europe. Additionally, RWD was assessed via the Surveillance, Epidemiology, and End Results (SEER) database. MARCAP and STAR-CAP both contain outcomes for distant metastasis (DM), metastasis-free survival (MFS), prostate cancer-specific mortality (PCSM), and overall survival (OS). SEER only contains PCSM and OS. Wilcoxon signed-rank test and chi-square test were used to compare continuous and categorical variables, respectively. Inverse probability of treatment weighting (IPTW) analysis was conducted, balancing for age, PSA, Gleason score, T stage, and treatment year in the three cohorts. Cox and Fine-Gray regression models were used to compare disease outcomes between RCTs vs. RWD. Data from 10,666 patients from RCTs, 6,530 patients in STAR-CAP, and 117,586 patients in SEER were included. SEER patients were slightly younger (p<0.001, median age 68 (IQR 62-73) than those in RCTs (70, IQR 65-74) and in STAR-CAP (70, IQR 64-74). 10-year OS in RCTs was 65.4%, STAR-CAP 70.2%, SEER 64.1%. OS was superior in STAR-CAP (RCTs as reference; HR 0.91, 95% CI 0.85-0.96, p<0.0001), but there was no significant difference between SEER and RCTs (HR 0.96, 95% CI 0.91-1.02, p = 0.22). 10-year PCSM cumulative incidence was 7.4% in RCTs, 8.1% in STAR-CAP, and 11.0% in SEER. There was no significant difference in PCSM between STAR-CAP RWD and RCTs (HR 0.88, 95% CI 0.78-1.01, p = 0.08), whereas PCSM was worse in SEER than RCTs (HR 1.37, 95% CI 1.21-1.55, p<0.0001). There was no significant difference in DM between STAR-CAP RWD and RCTs (HR 0.93, 95% CI 0.83-1.04, p = 0.2). While baseline differences exist in patients enrolled on localized prostate cancer RCTs and real-world datasets, there were small if any significant relative differences in oncologic outcomes. This provides reassurance that RCT results are generally applicable to patients in routine practice.

Randomised controlled trials evaluating anticancer therapies in haematological cancers: an overview of global research activity.

Design, results, and interpretation of oncology randomised controlled trials (RCTs) have changed substantially over the past decade. In this study, we describe all RCTs evaluating anticancer therapies in haematological cancers published globally during 2014-2017 with comparisons with solid tumours RCTs. A PubMed literature search identified all phase 3 RCTs of anticancer therapy for haematological cancers and solid tumours published globally during 2014-2017. Descriptive statistics, chi-square tests and the Kruskal-Wallis test were used to compare RCT design results, and output between haematological cancers and solid tumours as well as for different haematological cancer subtypes. 694 RCTs were identified; 124 in haematological cancers and 570 in solid tumours. Overall survival (OS) was the primary endpoint in only 12% (15/124) of haematological cancer trials compared to 35% (200/570) in solid tumours (p < 0.001). Haematological cancer RCTs evaluated the systemic novel therapy more often than the solid tumour RCT (98% versus 84%, p = 0.002). Use of surrogate endpoints like progression-free survival (PFS) and time to treatment failure (TTF) were more common in haematological cancers than solid tumours (47% versus 31%, p < 0.001). Within haematological cancers, the use of PFS and TTF was more prevalent in chronic lymphocytic leukaemia and multiple myeloma as compared to others (80%-81% versus 0%-41%, p < 0.001). Seventy-eight percent of haematologic trials were funded by industry as compared to 70% of solid tumour trials. Only 4% (5/124) of haematologicalcancer trials were led by investigators in upper-middle and lower-middle-income countries as compared to the 9% of solid tumour trials. The fact that only 12% of haematological cancer RCTs are designed to show improvements in OS is of grave concern for the field and the care of future patients. This is further compounded by the highly prevalent use of alternative primary endpoints that are rarely valid surrogates for OS in haematological cancers.

Exclusion of pregnant and lactating persons from breast cancer clinical trials: a review of active trials registered on ClinicalTrials.gov.

Treatment of pregnancy-associated breast cancer is complex, as providers try to balance risks to the pregnant person and the developing fetus. Given increased case fatality and increasing incidence, there is a pressing need understand the efficacy and safety of different treatment regimens in this population; however, pregnant and lactating people have traditionally been excluded from participating in randomized controlled trials (RCTs). Given recent efforts to expand the inclusion criteria for oncology RCTs, this study aimed to review the inclusion/exclusion criteria of current breast cancer RCTs to assess what proportion of trials permitted enrollment of pregnant and lactating persons. We conducted a comprehensive search of ClinicalTrials.gov in January 2022 to identify interventional studies of breast cancer in adults that were actively recruiting. The primary outcomes were the exclusion of pregnant and lactating people. The search identified 1706 studies, of which 1451 met eligibility criteria. Overall, 69.4% and 54.8% of studies excluded pregnant and lactating people, respectively. The exclusion of pregnant and lactating persons differed by study characteristics but extended across all trial designs, locations, phases and interventions. Exclusion of pregnant and lactating persons was most common in trials where the intervention was biological (86.3%), drug (83.5%) or radiation (81.5%). The exclusion of pregnant and lactating people from clinical trials contributes to evidence gaps in how to treat this population. A paradigm shift is needed that focuses on how research can be used to protect pregnant people from future harms, instead of protecting pregnant people from research-related risks.

Assessment of Successful Randomization Through a Machine Learning and Visualization Tool for Pre-Treatment Symptoms: Examples from CCTG/AGITG CO.17 and CO.20 Trials

Patients in randomized controlled trials (RCTs) must be successfully randomized to reduce or eliminate bias. Because pre-treatment symptoms have prognostic significance in cancer patients, qualitative and quantitative tools were developed to assess similarity of baseline pre-treatment symptoms across different treatment arms of RCTs as one measure of randomization success. Clinician-reported symptom data from two colorectal cancer RCTs, CO.20 and CO.17, were used to demonstrate the utility of a qualitative visualization tool and quantitative machine learning K-means tool, which grouped patients into clusters using baseline symptoms. Qualitatively, reflection bar graphs (RBGs) visualized potential imbalances in baseline symptoms (i) across treatment arms and (ii) by corresponding patient clusters identified within each treatment arm. RBGs found that the treatment arms for both RCTs had similar symptom profiles, while the lack of significant differences in the proportions of patients in each cluster across treatment arms further confirmed successful randomization. This paper details the creation of visualization, machine-learning, and statistical tools to compare baseline symptoms across RCT treatment arms, demonstrating that the CO.20 and CO.17 trials were successfully randomized by baseline symptoms and are comparable. These tools can therefore be implemented easily to ensure an extra layer of quality assurance of the randomization process for study assessment.

The Proportion of Prostate Cancer Randomized Control Trials Involving Radiation Therapy over Time

<h3>Purpose/Objective(s)</h3> As a cornerstone of oncologic treatment, radiation therapy (RT) is often incorporated in randomized controlled trials (RCTs). However, many trials may focus on systemic therapy rather than RT, despite numerous technological advances in RT. The primary purpose is to quantify the proportion of prostate cancer RCTs involving RT over time. <h3>Materials/Methods</h3> We conducted an analysis of all therapeutic prostate cancer RCTs from 2000 to 2021 in clinicaltrials.gov. We extracted all studies labeled condition or disease "Cancer," study type "Interventional." and other terms "prostate." We analyzed the percentage of trials with at least one RT arm. Study date was classified as 2000-2005, 2006-2010, 2011-2015, and 2016-2020. Covariates include study phase and patient enrollment. <h3>Results</h3> We extracted 1,104 prostate cancer RCTs of which 208 (19%) included at least one RT arm. Most prostate cancer RCTs were Phase 2 and Phase 3 trials (Table 1). The proportion of prostate cancer RT RCTs to all prostate cancer RCTs was 35/169 (21%), 28/242 (12%), 48/287 (17%), and 97/406 (24%) for 2000-2005, 2006-2010, 2011-2015, and 2016-2020, respectively. The median patient enrollment for RT prostate cancer RCTs decreased from 340 to 130 patients from 2000-2005 to 2016-2020. However, median patient enrollment for all prostate cancer RCTs remained stable at 141 to 120 patients from 2000–2005 to 2016-2020 (Table 1). <h3>Conclusion</h3> The proportion of RT prostate cancer RCTs remained stable over time, however, median patient enrollment decreased over time.

Generalizability of Randomized Controlled Trials in Rectal Cancer

BackgroundThe generalizability of outcomes from randomized controlled trials (RCTs) in oncology is a frequent concern. Given the prevalence and multidisciplinary management of rectal cancer, understanding the generalizability of rectal cancer RCTs is critical to surgical oncologists. MethodsAn exhaustive literature review identified 100 non-metastatic rectal cancer RCTs published in English over the past 10 years investigating surgery, chemotherapy, or radiotherapy. In order to evaluate the representativeness of these RCTs compared to the USA and each continent’s rectal cancer populations, demographic characteristics were stratified by surgical versus chemoradiotherapy (CRT) trial and by continent then compared with the National Cancer Database and CANCER TODAY using chi-squared and Welch’s t-tests. ResultsOf the 100 trials identified, 65% enrolled significantly younger patients, and 38% enrolled a significantly greater proportion of males than the US rectal cancer population. These demographic differences were more prominent among CRT trials than surgical trials. Half of all trials enrolled patients who were on average more than 7 years younger and enrolled a 5% greater proportion of males than their respective continental rectal cancer populations. Patients enrolled in trials had more advanced cancers than their corresponding continental populations. Sociodemographic data was rarely reported. ConclusionPatients enrolled in trials were younger, predominantly male, and had advanced stage cancer when compared to the rectal cancer population. Sociodemographic variables are underreported, further limiting equal participation in clinical trials. Future rectal cancer RCTs should strive to recruit representative samples. To enhance recruitment of women and underrepresented minorities, tailored recruitment strategies must be implemented.

Impact of Blinding on Patient-Reported Outcome Differences Between Treatment Arms in Cancer Randomized Controlled Trials.

Some concerns have been raised about potential bias in patient-reported outcome (PRO) results from open-label cancer randomized controlled trials (RCTs). We investigated if open-label trials favor the experimental treatment over the standard treatment more frequently than blinded trials. We also examined if the effect of blinding differs for distal vs more proximal PROs. We assessed 538 RCTs with a PRO endpoint conducted in the most prevalent cancers, of which 366 (68.0%) were open-label, 148 (27.5%) were blinded, and 24 (4.5%) were categorized as unclear. In our multivariable logistic regression model, we did not observe a statistically significant association of the independent variable treatment concealment (blinded vs open-label) on the dependent variable measuring the proportion of trials favoring the experimental treatment (adjusted odds ratio = 1.19, 95% confidence interval = 0.79 to 1.79; 2-sided P = .40). This was also the case when comparing distal and proximal PROs. Our findings provide novel evidence-based data that support the validity of PRO results from open-label cancer RCTs.

Investigating Trends in the Quality of Reporting of Patient-Reported Outcomes in Oncology Over Time: Analysis of 631 Randomized Controlled Trials Published Between 2004 and 2019

ObjectivesIncomplete reporting of key information on patient-reported outcomes (PROs) in randomized controlled trials (RCTs) in oncology has been highlighted repeatedly as a major barrier to the use of study findings in clinical practice. We investigated whether the quality of reporting of PRO data in cancer RCTs has improved over the last 15 years. MethodsWe identified all cancer RCTs with PRO endpoints conducted across the most prevalent solid tumor types worldwide published between 2004 and 2019. The quality of PRO reporting was assessed using the International Society for Quality of Life Research recommended standards, which include important aspects related to assessment methodology, statistical analyses, and interpretation of data. ResultsWe assessed a total of 631 cancer RCTs in breast (n = 187), lung (n = 131), prostate (n = 120), colorectal (n = 107), and gynecological (n = 86) cancer. We observed a higher adherence to the International Society for Quality of Life Research reporting criteria in the more recently published studies. In a multivariable linear regression analysis, we observed a statistically significant improvement in the quality of PRO reporting over time (P<.001), and this relationship was independent of other measured confounding factors, such as sample size and study sponsorship. Overall, the quality of PRO reporting was higher for studies published after the publication of the Consolidated Standards of Reporting Trials-PRO Extension. ConclusionsThe quality of PRO reporting in cancer RCTs published in the last 15 years has improved significantly. Our findings are encouraging because better reporting of PRO results may translate into a greater impact of study findings on real-world practice.

Censored patients in Kaplan-Meier plots of cancer drugs: An empirical analysis of data sharing.

Kaplan-Meier survival analysis, the cornerstone of evaluating efficacy of oncology drugs in randomised controlled trials (RCTs), assumes censored patients are neither healthier nor sicker than those followed. We sought to examine whether censoring patterns differ between the control and experimental arms in one oncology journal that mandates the reporting of the number of patients censored. In this retrospective review, proportion of censoring and study design data were gathered from RCTs published in The Lancet Oncology that reported Kaplan-Meier curves between May 2018 and August 2019. Differential censoring rates were analysed at the 1st, 3rd, 6th, and overall time points in each study. Analysis was stratified by curves reporting progression-free survival (PFS) or overall survival (OS) end-points. Of the 160 articles reviewed, 29 studies with 51 Kaplan-Meier curves were eligible. In both OS (N=25) and PFS curves (N=26), the absolute weighted difference in censoring between the control and experimental arms was initially positive, indicating more censoring in the control arm (first time point OS: 0.32%; PFS: 2.00%). The absolute difference then became negative, indicating more censoring in the experimental arm as time progressed (end-of-study OS: -7.54%; PFS: -9.09%). Differences in censoring between control and experimental arms of cancer RCTs suggest that there could be systematic bias present at various study time points that may influence key results. Further investigation is needed, as possible reasons include study assignment disappointment, inappropriate follow-up length, lack of efficacy, or intolerable toxicity, each predominant at specific time points after randomisation.

Examining the language demands of informed consent documents in patient recruitment to cancer trials using tools from corpus and computational linguistics

Obtaining informed consent (IC) is an ethical imperative, signifying participants’ understanding of the conditions and implications of research participation. One setting where the stakes for understanding are high is randomized controlled trials (RCTs), which test the effectiveness and safety of medical interventions. However, the use of legalese and medicalese in ethical forms coupled with the need to explain RCT-related concepts (e.g. randomization) can increase patients’ cognitive load when reading text. There is a need to systematically examine the language demands of IC documents, including whether the processes intended to safeguard patients by providing clear information might do the opposite through complex, inaccessible language. Therefore, the goal of this study is to build an open-access corpus of patient information sheets (PIS) and consent forms (CF) and analyze each genre using an interdisciplinary approach to capture multidimensional measures of language quality beyond traditional readability measures. A search of publicly-available online IC documents for UK-based cancer RCTs (2000-17) yielded corpora of 27 PIS and 23 CF. Textual analysis using the computational tool, Coh-Metrix, revealed different linguistic dimensions relating to the complexity of IC documents, particularly low word concreteness for PIS and low referential and deep cohesion for CF, although both had high narrativity. Key part-of-speech analyses using Wmatrix corpus software revealed a contrast between the overrepresentation of the pronoun ‘you’ plus modal verbs in PIS and ‘I’ in CF, exposing the contradiction inherent in conveying uncertainty to patients using tentative language in PIS while making them affirm certainty in their understanding in CF.

Investigating the impact of open label design on patient-reported outcome results in prostate cancer randomized controlled trials.

BackgroundWhile open‐label randomized controlled trials (RCT) are common in oncology, some concerns have been expressed with regard to Patient‐Reported Outcomes (PRO)‐based claims stemming from these studies. We aimed to investigate the impact of open‐label design in the context of prostate cancer (PCa) RCTs with PRO data.MethodsRandomized controlled trials of PCa with a PRO endpoint published between 2004 and 2018 were considered. RCTs were systematically evaluated on the basis of previously defined criteria, including international PRO reporting quality standards and the Cochrane Collaboration's tool for assessing Risk of Bias. The rate of concordance was estimated and compared between traditional clinical outcomes (eg, survival or tumor response) and PRO in open and blinded RCTs.ResultsWe identified 110 RCTs published between 2004 and 2018, of which 62% (n = 68) were open‐label. The general characteristics of PCa RCTs were not different according to their design (open‐label vs blinded). The proportion of PCa RCTs with high‐quality PRO reporting was not different between open‐label RCTs and blinded RCTs (41.2% vs 38.1%; P = .75). No statistically significant difference was found between PRO results and concordance with traditional clinical outcomes according to the study design.ConclusionOur findings suggest that there is no evidence of significant bias for PROs due to the absence of blinding in the context of PCa RCTs. Further analyses should be conducted in other cancer disease sites.

Bibliometric analysis of randomized controlled trials of colorectal cancer over the last decade.

BACKGROUNDColorectal cancer is one of the most common cancers globally. In China, its prevalence ranks fourth and fifth among females and males, respectively. Presently, treatment of rectal cancer follows a multidisciplinary comprehensive treatment approach involving surgery, radiotherapy, chemotherapy, and targeted therapy. With deepening theoretical and molecular research on colorectal cancer, randomized controlled trials (RCTs) on colorectal cancer have made significant progress. However, many RCTs have shortfalls.AIMTo investigate the RCTs of global colorectal cancer spanning from 2008 to 2018. To provide suggestions for conducting Chinese RCTs of colorectal cancer.METHODSPubMed and Web of Science databases were searched to obtain RCTs of colorectal cancer carried out between January 1, 2008, and January 1, 2018. The bibliometric method was used for statistical analysis of the publication years, countries/regions, authors, institutions, source journals, quoted times, key words, and authors.RESULTSColorectal cancer RCTs showed an upward trend between 2008 to 2018; the top 10 research institutions in the included literature were from the United States, the United Kingdom, and other countries with a high incidence of colorectal cancer. Most of the related research journals are sponsored by European and American countries. The 15 most cited studies involved international multicenter clinical research, having few participants from Chinese research institutions. Network visualization using key words showed that RCTs on colorectal cancer focus on screening, disease-free survival, drug treatment, surgical methods, clinical trials, quality of life, and prognosis. The result of the coauthorship network analysis showed that Chinese researchers are less involved in international exchanges compared to those from leading publication countries.CONCLUSIONHigh-quality RCTs are increasingly favored by leading international journals. However, there is still a large gap in clinical research between China and leading countries. Researchers should implement standardized and accurate clinical trials, strengthen international multicenter cooperation, and emphasize quality control.

Perspectives on the model-based approach to proton therapy trials: A retrospective study of a lung cancer randomized trial

PurposeThe goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. Methods and materialsA model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected ΔNTCP value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. ResultsOur analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. ConclusionsUncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium.

Patient-reported outcomes (PROs), such as symptoms, function, and other health-related quality-of-life aspects, are increasingly evaluated in cancer randomised controlled trials (RCTs) to provide information about treatment risks, benefits, and tolerability. However, expert opinion and critical review of the literature showed no consensus on optimal methods of PRO analysis in cancer RCTs, hindering interpretation of results. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium was formed to establish PRO analysis recommendations. Four issues were prioritised: developing a taxonomy of research objectives that can be matched with appropriate statistical methods, identifying appropriate statistical methods for PRO analysis, standardising statistical terminology related to missing data, and determining appropriate ways to manage missing data. This Policy Review presents recommendations for PRO analysis developed through critical literature reviews and a structured collaborative process with diverse international stakeholders, which provides a foundation for endorsement; ongoing developments of these recommendations are also discussed.

Reference values for the EORTC QLQ-C30 in early and metastatic breast cancer

BackgroundConsidering the worldwide incidence of breast cancer (BC) and the importance of health-related quality of life (HRQoL) assessment, there is a growing need to have accurate and up-to-date reference values (RVs). RVs are useful for the design of randomised controlled trials (RCTs) and as benchmarks for comparison of cancer RCTs and health care interventions. This study aimed to provide RVs for the QLQ-C30 in early BC (EBC) and metastatic BC (MBC). General patterns of main results from the EORTC dataset (main dataset) were compared with the PDS dataset (comparison dataset) to see whether they would be consistent across pre-defined covariates. MethodsEuropean Organization for Research and Treatment of Cancer (EORTC) (main dataset) and Project Data Sphere (PDS) (comparison dataset) were searched to identify BC RCTs where baseline HRQoL (before treatment) was assessed with the QLQ-C30. RVs were calculated and stratified by disease stage, age, and when available, performance status (PS), comorbidity and region. RVs were reported using descriptive statistics. ResultsData from three EORTC (n = 4115) and three PDS RCTs (n = 1406) were included in the analysis. While EBC patients presented better HRQoL with high baseline functioning scores and low prevalence of symptoms, MBC patients reported worse HRQoL with lower functioning scores and more prevalence of symptoms. In MBC, poor PS and presence of comorbidities reflected worse baseline HRQoL. No consistent differences were found for age and countries. ConclusionThese up-to-date RVs for the EORTC QLQ-C30 in BC show differences in HRQoL scores between stages, PS, and comorbidities. These findings, supported by an independent dataset, will help the clinical interpretation of scores for BCpatients.

Does the quality of patient-reported outcomes (PROs) assessment in randomized controlled trials (RCTs) differ across cancer types and over time? A pooled analysis of 610 RCTs published between 2004 and 2018.

e18218 Background: PRO endpoints are increasingly being used in cancer RCTs. However, the PRO assessment in such trials often suffers from serious methodological shortcomings, and the results seldom impact on clinical policy or practice. Methods: We performed a systematic review to identify RCTs with a PRO endpoint in breast, colorectal, lung, prostate, gynaecological and bladder cancer. A checklist score for quality of PRO reporting (ranging between 0-100), based on that of the International Society for Quality of Life Research (ISOQOL) and the CONSORT PRO extension, was computed for each RCT. Analyses were also conducted by type of PRO endpoint (primary versus secondary) and year of publication (i.e. before and after the publication of the CONSORT PRO extension). Results: We identified 610 RCTs with a total of 323,482 patients. PROs were most frequently used in RCTs of breast (N = 176), followed by lung (N = 123), prostate (N = 108), colorectal (N = 103), gynaecological (N = 83) and bladder (N = 17) cancer. Quality of PRO reporting (mean score: 56.4) was highest in RCTs conducted in prostate cancer (PCa) (Table). Regardless of cancer type, quality of reporting was typically higher in RCTs where PROs were primary endpoints. Quality of reporting was higher for RCTs published after the CONSORT PRO Extension (2013), with the exception of RCTs conducted in PCa, where quality was stable over time. Conclusions: PRO reporting of RCTs conducted in PCa has better quality than in the other cancer sites that were reviewed. Regardless of cancer site, quality of PRO reporting has improved after the publication of the CONSORT PRO Extension. [Table: see text]

Inclusion of patient-reported outcomes (PROs) in randomized controlled trials (RCTs) with elderly cancer patients: A systematic review.

e18217 Background: Inclusion of PROs in RCTs involving elderly cancer patients may be particularly important, as the elderly are often frail and vulnerable, and treatment decisions need to carefully balance potential burden against benefit. We aimed to determine how many RCTs involving elderly patients have included a PRO endpoint, and identified the most relevant PRO information available in this area. Methods: A systematic review in PubMed/Medline and Cochrane Library identified RCTs with PRO endpoint that enrolled a cancer sample (breast, colorectal, lung, prostate, gynaecological and bladder cancer) with a mean/ median age ≥70 years, published from January 2004 to June 2018. The quality of PRO reporting was evaluated using the ISOQOL-PRO recommended criteria. Two reviewers independently performed data extraction. RCTs meeting at least two-thirds of the recommended criteria were considered as “probably-robust” and therefore most likely to be able to inform patient care. Results: Out of the 610 RCTs with PRO endpoint identified, only 67 RCTs (11%) enrolled a sample that met the above criteria. In 19 RCTs (28.4%) PROs were the primary endpoint and 35 RCTs (52.2%) were conducted in a metastatic population. Less than one-third of these trials (n = 21) were considered as probably-robust. In 10 (47.6%) out of the 21 probably-robust RCTs, PROs favored the experimental arm and in 8 (38.1%) the arms did not differ. Overall survival (OS) was an endpoint in 13 of the probably-robust RCTs. In only 3 of these RCTs (23.1%) did OS improve in the experimental arm and in 10 (76.9%) there was no difference in OS between arms. In about half of the probably-robust trials evaluating OS (n = 7, 53.8%), PROs provided information that contrasted with survival findings. In two RCTs, OS improved in the experimental arm, while PROs either did not change between arms (n = 1) or favoured the control arm (n = 1). Conversely, in 5 RCTs (38.5%), OS did not differ between arms whereas PROs favoured the experimental arm. Conclusions: Among cancer RCTs including PROs, the proportion of those conducted in the elderly is low. However, PRO data may provide useful information for these type of patients and their clinicians.

Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment

BackgroundMultiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR.MethodsWe carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0–10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose.ResultsWe randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference −0.8, 95% confidence interval, −1.3 to −0.4, P < 0.01) and when compared with the HR+RMSTD group (difference −0.6, −1.1 to −0.1, P = 0.05). In all, 47.2% (42.7%−51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk.ConclusionMisinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.