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Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]). Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits. Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Background The aim of the study was to estimate the minimally important difference (MID) for interpreting group-level change over time, both within a group and between groups, for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scores in patients with prostate cancer. Methods We used data from two published EORTC trials. Clinical anchors were selected by strength of correlations with QLQ-C30 scales. In addition, clinicians’ input was obtained with regard to plausibility of the selected anchors. The mean change method was applied for interpreting change over time within a group of patients and linear regression models were fitted to estimate MIDs for between-group differences in change over time. Distribution-based estimates were also evaluated. Results Two clinical anchors were eligible for MID estimation; performance status and the CTCAE diarrhoea domain. MIDs were developed for 7 scales (physical functioning, role functioning, social functioning, pain, fatigue, global quality of life, diarrhoea) and varied by scale and direction (improvement vs deterioration). Within-group MIDs ranged from 4 to 14 points for improvement and − 13 to − 5 points for deterioration and MIDs for between-group differences in change scores ranged from 3 to 13 for improvement and − 10 to − 5 for deterioration. Conclusions Our findings aid the meaningful interpretation of changes on a set of EORTC QLQ-C30 scale scores over time, both within and between groups, and for performing more accurate sample size calculations for clinical trials in prostate cancer.

Purpose The inclusion of patient-reported outcome (PRO) instruments to record patient health-related quality of life (HRQOL) data has virtually become the norm in oncology randomised controlled trials (RCTs). Despite this fact, recent concerns have focused on the quality of reporting of HRQOL. The primary aim of this study was to evaluate the quality of reporting of HRQOL data from two common instruments in oncology RCTs. Design A meta-review was undertaken of systematic reviews reporting HRQOL data collected using PRO instruments in oncology randomised controlled trials (RCTs). English language articles published between 2000 and 2012 were included and evaluated against a methodology checklist. Results Four hundred and thirty-five potential articles were identified. Six systematic reviews were included in the analysis. A total of 70,403 patients had completed PROs. The European Organization for Research and Treatment of Cancer QLQ-C30 and Functional Assessment of Cancer Therapy-General questionnaire accounted for 55 % of RCTs. Eighty per cent of RCTs had used psychometrically validated instruments; 70 % reported culturally valid instruments and almost all reported the assessment timing (96 %). Thirty per cent of RCTS reported clinical significance and missing data. In terms of methodological design, only 25 % of RCTs could be categorised as probably robust. Conclusion The majority of oncology RCTs has shortcomings in terms of reporting HRQOL data when assessed against regulatory and methodology guidelines. These limitations will need to be addressed if HRQOL data are to be used to successfully support clinical decision-making, treatment options and labelling claims in oncology.

Purpose The recommended method for establishing a meaningful threshold for individual changes in patient-reported outcome (PRO) scores over time uses an anchor-based method. The patients assess their perceived level of change and this is used to define a threshold on the PRO score which may be considered meaningful to the patient. In practice, such an anchor may not be available. In the absence of alternative information often the meaningful change threshold for assessing between-group differences, the minimally important difference, is used to define meaningful change at the individual level too. This paper will highlight the issues with this, especially where the underlying measurement scale is not continuous. Methods Using the EORTC QLQ-C30 as an example, plausible score increments (“state changes”) are calculated for each subscale highlighting why commonly used thresholds may be misleading, including leading to sensitivity analyses that are inadvertently testing the same underlying threshold. Results The minimal possible individual score change varies across subscales; 6.7 for Physical Functioning, 8.3 for Global Health Scale and Emotional Functioning, 11.1 for fatigue, 16.7 for role functioning, cognitive functioning, social functioning, nausea and vomiting, pain and 33.3 for single items. Conclusions The determination of meaningful change for an individual patient requires input from the patients but being mindful of the underlying scale ensures that these thresholds are also guided by what is a plausible change for patients to achieve on the scale.

Bisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events. Patients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111. 1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001). The results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline. Medical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Background Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. Main We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, “What is the effect of treatment X on patient’s quality of life?”, we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. Conclusion The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

Background This study aims to evaluate the feasibility and acceptability of the PhunkyFoods Programme, a primary school-based intervention to promote healthy nutrition and physical activity knowledge and behaviours to assess outcomes to inform a phase 3 trial. Methods The cluster randomised feasibility trial recruited eight primary schools from the North of England. Elibility criteria included all primary schools in one town, excluding independent and special schools and schools that comprised of only key stage 2 pupils (years 3–6). Eight schools agreed to participate. Randomisation to intervention or control arms was in a 1:1 ratio. Intervention schools received PhunkyFoods over 17 months. Control schools continued with usual curriculum. Assessors were blinded to group assignment. Measures comprised of a Healthy Lifestyle Knowledge Questionnaire and Synchronised Nutrition and Activity Program to assess diet and physical activity, height, weight, and psychological wellbeing. Feasibility outcomes were recruitment, attrition rates, interviews with teaching staff, focus groups with pupils to explore the acceptability of outcome measures, implementation, intervention content, and programme fidelity. Results Three hundred fifty-eight pupils, aged 6–9 years from eight schools were recruited at baseline (control n = 170, intervention n = 188); 337 (94.1%) at 6 months (control n = 163, intervention n = 181); and 331 (92.5%) at 18 months (control n = 152, intervention n = 179), and 6 pupils opted out. Trends in increased knowledge of healthy lifestyle behaviours, healthier eating, and liking of fruit and vegetables were reported in the intervention compared to the control group. Year 4 intervention pupils had significantly higher healthy balanced diet knowledge scores compared to control pupils, mean difference 5.1 (95% CI 0.1 to 10.1, p=0.05). At 18 months, the mean percentage of vegetables liked was higher (intervention 53.9% vs. 43.0% control). Similarly, percentage of fruits liked was also higher (intervention 76.9% vs. 67.2% control). Qualitative data showed that delivery of the intervention was feasible and acceptable to teachers and pupils. Lessons were learned to inform the phase 3 trial around the dietary assessment measure and timing of recruitment. Conclusions Whilst the study was not powered to detect a definitive effect, results suggest a potential to increase knowledge of healthy lifestyle behaviours and dietary behaviours, suggesting that with minor changes, a phase 3 trial is likely to be deliverable. Trial registration ISRCTN, ISRCTN15641330. Registered 8 May 2015—retrospectively registered, https://doi.org/10.1186/ISRCTN15641330

Background Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30. Patients and methods The process followed a predefined and systematic stepwise iterative process as defined by the EORTC guidelines for questionnaire development. The process was divided into 3 phases: (1) generation of relevant HRQOL issues, (2) operationalization of the HRQOL issues into a set of items, and (3) pretesting the questionnaire for relevance and acceptability. Descriptive statistics and psychometric analyses were also performed. Results Overall, 655 CML patients were enrolled in 10 countries including the USA and countries in Europe and Asia. Interviews with health-care professionals experienced in CML (n = 59) were also conducted. Results from the interviews, clinical experiences, and statistical analyses were used to develop the EORTC QLQ-CML24. The final module consists of 24 items assessing the following aspects: symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.73 to 0.83 for the proposed scales. Conclusion The EORTC QLQ-CML24 is an internationally developed HRQOL questionnaire for CML patients, and its implementation in clinical research and practice can provide important information to facilitate clinical decision-making.

Background Time to deterioration (TTD) endpoints are often utilized in the analysis of patient-reported outcome (PRO) data in oncology clinical trials but different endpoint definitions and analysis frameworks exist that can impact result interpretation. This review examined the analysis, reporting and heterogeneity of TTD endpoints in the literature, the impact of analysis methods on results, and provides recommendations for future trials. Methods A targeted literature review of articles published between 2017 and 2022 was performed to collate TTD endpoints reported in oncology randomized controlled trials (RCTs). Details of endpoints and results were extracted including; deterioration definition, PRO assessment schedule, methods for handling intercurrent events, statistical analysis methods, main trial results (overall survival and/or progression-free survival) and TTD endpoint results. Results Seventy RCTs were included covering 849 individual TTD endpoints. There were 17 primary cancer types, with lung (26%), breast (11%), and prostate (7%) cancers the most common. Most trials (71%) were for people with advanced cancer. Full definitions of TTD endpoints were often missing. There were no clear trends for a specific TTD definition within cancer types or stages. However, statistical analysis methods were consistent among trials. Conclusion The TTD definition can vary and is ultimately driven by the research question. Points to consider for successfully implementing PRO TTD endpoints in oncology include consideration of the trial setting (e.g., early vs. advanced cancer), expected treatment effect (e.g., improvement vs. worsening), likely adverse event profile (including early vs. delayed) and PRO data collection frequency in order to improve utility of these endpoints.

We compared patient-reported outcomes (PROs) with once-weekly carfilzomib 70 mg/m2 (Kd70 mg/m2) vs. twice-weekly carfilzomib 27 mg/m2 (Kd27 mg/m2) plus dexamethasone in relapsed or refractory multiple myeloma (RRMM). Patient-reported convenience/satisfaction collected at Cycle 2, Day 1 was compared between groups using logistic regression. European Organization for Research and Treatment of Cancer QOL Questionnaire (QLQ-C30), MM-module (QLQ-MY20), and EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) questionnaires were administered at baseline, then every other cycle. PROs were compared between groups using mixed models for repeated measures. Times from randomization to first deterioration (TTD) in scores were analyzed using Cox regression. PRO analyses included 469 patients. Once-weekly Kd70 mg/m2 patients reported greater convenience (odds ratio [OR], 4.98; p < 0.001) and satisfaction (OR, 2.41; p = 0.059) vs. twice-weekly Kd27 mg/m2. The mixed models for repeated measures demonstrated no clinically meaningful differences in scores between treatment arms. Clinically meaningful deterioration in QLQ-C30 Global Health Status/QOL rates were 34.2% (once-weekly Kd70 mg/m2) vs. 40.3% (twice-weekly Kd27 mg/m2). TTD was longer for once-weekly Kd70 mg/m2 vs. twice-weekly Kd27 mg/m2 for QLQ-C30 fatigue (HR, 0.79; p = 0.035), QLQ-MY20 disease symptoms (HR, 0.67; p = 0.008), EQ-5D-5L index score (HR, 0.58; p = 0.002), and EQ-5D-5L Visual Analog Scale (HR, 0.75, p = 0.031). Once-weekly Kd70 mg/m2 improved convenience/satisfaction, and reduced HRQOL deterioration vs. twice-weekly Kd27 mg/m2, supporting convenient, once-weekly Kd70 mg/m2 dosing in RRMM.