Improving completion rates of patient-reported outcome measures in cancer clinical trials: Scoping review investigating the implications for trial designs.

BACKGROUND: Patient-reported outcomes (PROs) play a crucial role in cancer clinical trials. Despite the availability of validated PRO measures (PROMs), challenges related to low completion rates and missing data remain, potentially affecting the trial results' validity. This review explored strategies to improve and maintain high PROM completion rates in cancer clinical trials. METHODOLOGY: A scoping review was performed across Medline, Embase and Scopus and regulatory guidelines. Key recommendations were synthesized into categories such as stakeholder involvement, study design, PRO assessment, mode of assessment, participant support, and monitoring. RESULTS: The review identified 114 recommendations from 18 papers (16 peer-reviewed articles and 2 policy documents). The recommendations included integrating comprehensive PRO information into the study protocol, enhancing patient involvement during the protocol development phase and in education, and collecting relevant PRO data at clinically meaningful time points. Electronic data collection, effective monitoring systems, and sufficient time, capacity, workforce and financial resources were highlighted. DISCUSSION: Further research needs to evaluate the effectiveness of these strategies in various context and to tailor these recommendations into practical and effective strategies. This will enhance PRO completion rates and patient-centred care. However, obstacles such as patient burden, low health literacy, and conflicting recommendations may present challenges in application.

Patient-reported outcomes and functional exercise capacity in a real-life setting in non-small cell lung cancer patients undergoing stereotactic body radiotherapy: the Lung PLUS study.

Introduction: To better understand the impact of stereotactic body radiotherapy (SBRT) and its treatment-related toxicity on early-stage non-small cell lung cancer (ES-NSCLC) patients, we conducted the Lung PLUS study in a real-world setting. Methods: This is a monocentric prospective longitudinal study up to 12 months post-treatment, evaluating clinician- and patient-reported toxicity (resp. CTCAE and PRO-CTCAE), health-related quality of life (HRQoL) (EORTC QLQ-C30 and LC-13), activities of daily living (HAQ-DI) and functional exercise capacity (6 Minute Walking Test (6MWT)). A mixed model approach was applied to analyze the data. Results: At baseline, clinicians and patients (n=51) reported mostly fatigue (63% vs 79%), cough (49% vs 75%) and dyspnea (65% vs 73%) of any grade. Dyspnea (p=.041) increased over time. Meaningful clinical improvements were particularly seen in pain, fatigue, and cough. Clinician reported clinically meaningful improvements and deteriorations over time in fatigue, cough, and dyspnea. Almost at every timepoint, more people reported deterioration to the clinician than improvement in aforementioned toxicities. Overall HRQoL (p=.014), physical (p=.011) and emotional (p<.001) functioning improved over time. At baseline, patients had a moderate daily functioning score and walked an average distance of 360 meters. No statistically significant differences were found in daily functioning and exercise capacity over time. Conclusion: Our study showed an increase in patient-reported toxicity and dyspnea, without impacting functional status, following SBRT. Overall HRQoL, physical and emotional functioning improved over time. Understanding the impact of treatment on patient-reported outcomes is crucial to identify the needs/problems of patients to enhance their HRQoL.

The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study.

BACKGROUND AND PURPOSE: To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS: Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS: Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION: Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.

Overview of health-related quality of life and toxicity of non-small cell lung cancer patients receiving curative-intent radiotherapy in a real-life setting (the REQUITE study).

OBJECTIVES: Radiotherapy-induced toxicity may negatively impact health-related quality of life (HRQoL). This report investigates the impact of curative-intent radiotherapy on HRQoL and toxicity in early stage and locally-advanced non-small cell lung cancer patients treated with radiotherapy or chemo-radiotherapy enrolled in the observational prospective REQUITE study. MATERIALS AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire up to 2 years post radiotherapy. Eleven toxicities were scored by clinicians using the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Toxicity scores were calculated by subtracting baseline values. Mixed model analyses were applied to determine statistical significance (p ≤ 0.01). Meaningful clinical important differences (MCID) were determined for changes in HRQoL. Analysis was performed on the overall data, different radiotherapy techniques, multimodality treatments and disease stages. RESULTS: Data of 510 patients were analysed. There was no significant change in HRQoL or its domains, except for deterioration in cognitive functioning (p = 0.01). Radiotherapy technique had no significant impact on HRQoL. The addition of chemotherapy was significantly associated with HRQoL over time (p <.001). Overall toxicity did not significantly change over time. Acute toxicities of radiation-dermatitis (p =.003), dysphagia (p =.002) and esophagitis (p <.001) peaked at 3 months and decreased thereafter. Pneumonitis initially deteriorated but improved significantly after 12 months (p =.011). A proportion of patients experienced meaningful clinically important improvements and deteriorations in overall HRQoL and its domains. In some patients, pre-treatment symptoms improved gradually. CONCLUSIONS: While overall HRQoL and toxicity did not change over time, some patients improved, whereas others experienced acute radiotherapy-induced toxicities and deteriorated HRQoL, especially physical and cognitive functioning. Patient characteristics, more so than radiotherapy technique and treatment modality, impact post-radiotherapy toxicity and HRQoL outcomes. This stresses the importance of considering the potential impact of radiotherapy on individuals' HRQoL, symptoms and toxicity in treatment decision-making.

Neurocognitive functioning following lung cancer treatment: The PRO-Long Study.

This observational cohort study investigates neurocognitive functioning (NCF) and its associations with overall survival (OS), disease-free survival (DFS) and patient-reported psychological toxicities in locally-advanced and metastatic non-small cell lung (NSCLC) cancer patients receiving loco-regional radiotherapy and/or systemic therapy. Objective NCF data was collected with six psychometrically validated neurocognitive tests. Subjective NCF was assessed with the cognitive domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items. Psychological toxicity data was collected with the patient-reported outcomes version of the common terminology criteria for adverse events. Meaningful clinical important differences were determined for changes in NCF. Univariate Cox proportional hazards models and generalized linear models were used to determine statistical significance (p < 0.01). In total, 50 patients were recruited. At baseline, 13 (26%) patients had an impaired objective NCF. Over time, deterioration was seen in 11% (n = 3), 5% (n = 1) and 6% (n = 1) of patients at 2-3, 6 and 12 months post-treatment. The OS of patients with a normal NCF at baseline was longer than those with an impaired baseline NCF (29.5 vs 17.1 months). No statistical significance has been reached between NCF and OS (p = .353) nor NCF and DFS (p = .251). Objective NCF was not correlated with subjective NCF (p = .193), nor anxiety (p = .504), depression (p = .513), memory problems (p = .813) and concentration problems (p = .813). Systemic treatment and loco-regional radiotherapy may have a temporarily negative impact on NCF in a small proportion of locally-advanced and metastatic NSCLC. Baseline NCF could be a predictor for OS.

Real Life Data on Patient-Reported Outcomes and Neuro-Cognitive Functioning of Lung Cancer Patients: The PRO-Long Study.

INTRODUCTION: This report investigates the impact of systemic treatments (chemotherapy or immunotherapy) with(out) loco-regional radiotherapy, on HRQoL, toxicity and neurocognitive functioning (NCF) in locally advanced and metastatic non-small cell lung cancer patients enrolled in the PRO-Long study. MATERIALS AND METHODS: Data on patient-reported HRQoL and fourteen toxicities was collected, while NCF was tested, up to one-year post-treatment. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30. Lung cancer, treatment and neuro-psychological related toxicities were scored with the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. NCF was evaluated with six neurocognitive tests. Mixed model analyses were conducted to determine statistical significance (p = .01). Meaningful clinical important differences (MCIDs) were applied for changes in HRQoL and NCF data, while toxicities were compared to baseline values. RESULTS: In total, 50 patients were enrolled. Overall HRQoL (p = .357) nor its domains (physical, p = .643; role, p = .069; emotional, p = .254; cognitive, p = 494; social, p = .735) changed significantly over time. Meaningful improvements in overall HRQoL were seen in 22, 38 and 39% and deteriorations in 22, 5 and 28% of patients at 2-3, 6 and 12 months respectively post-treatment. Overall toxicity (p = .007), lack of appetite (p = .001), nausea (p = .004) and dysphagia (p = .000) significantly decreased over time. Treatment caused acute toxicity, such as dyspnoea (45%) and memory problems (42%), but also alleviated pre-existing symptoms, including lack of appetite (32%), anxiety (29%) and depression (28%) at 2/3 months. The NCF domains of visual memory (p = .000) and cognitive processing speed (p = .000) showed significant improvements over time. In terms of MCIDs, at 2-3 months (18%) and 6 months (15%), verbal memory was particularly impacted; at 12 months, visual memory (18%) and executive function (18%) deteriorated primarily. CONCLUSION: The results suggest that therapy has no significant negative impact on overall HRQoL, its domains, and NCF. About one-third of patients reported a meaningful improved HRQoL at 1 year post-treatment. Treatment caused toxicity, but also alleviated pre-existing symptoms.

Psychometric properties of the updated EORTC module for assessing quality of life in patients with lung cancer (QLQ-LC29): an international, observational field study.

BACKGROUND: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) assesses quality of life (QOL) in patients with lung cancer and was the first EORTC module developed for use in international clinical trials. Since its publication in 1994, major treatment advances with possible effects on QOL have occurred. These changes called for an update of the module and its international psychometric validation. We aimed to investigate the scale structure and psychometric properties of the updated lung cancer module, QLQ-LC29, in patients with lung cancer. METHODS: This international, observational field study was done in 19 hospitals across 12 countries. Patients aged older than 18 years with a confirmed diagnosis of lung cancer and no other previous primary tumour, and who were mentally fit with sufficient language skills to understand and complete the questionnaire were included. Patients were asked during a hospital visit to fill in the paper versions of the core questionnaire EORTC QLQ-C30 plus QLQ-LC29, and investigators selected half of these patients to complete the questionnaire again 2-4 weeks later. Our primary aim was to assess the scale structure and psychometric properties of EORTC QLQ-LC29. We analysed scale structure using confirmatory factor analysis; reliability using Cronbach's α value (internal consistency) and intra-class coefficient (test-retest reliability); sensitivity using independent t tests stratified by Karnofsky performance status; and responsiveness to change over time by ANOVA. This study is registered with ClinicalTrials.gov, NCT02745691. FINDINGS: Between April 12, 2016, and Sept 26, 2018, 523 patients with a confirmed diagnosis of either non-small-cell lung cancer (n=442) or small-cell lung cancer (n=81) were recruited. Confirmatory factor analysis provided a solution composed of five multi-item scales (coughing, shortness of breath, fear of progression, hair problems, and surgery-related symptoms) plus 15 single symptom or side-effect items: χ2=370·233, root mean square error of approximation=0·075, and comparative-fit index=0·901. Cronbach's α for internal consistencies of all multi-item scales were above the threshold of 0·70. Intra-class coefficients for test-retest reliabilities ranged between 0·82 and 0·97. Three (shortness of breath, fear of progression, and hair problems) of the five multi-item scales showed responsiveness to change over time (p values <0·05), as did nine of 15 single symptom items. Four (coughing, shortness of breath, fear of progression, and surgery-related symptoms) of the five multi-item scales and ten of the 15 single symptom items were sensitive to known group differences (ie, lower vs higher Karnofsky performance status). INTERPRETATION: Results determined the psychometric properties of the updated lung cancer module, which is ready for use in international clinical studies. FUNDING: EORTC Quality of Life Group.

Health-Related Quality of Life in Advanced Non-small Cell Lung Cancer: A Methodological Appraisal Based on a Systematic Literature Review.

Background: The majority of lung cancer patients are diagnosed with advanced non-small cell lung cancer (NSCLC), the bulk of which receive palliative systemic treatment with the goal to provide effective symptom palliation and safeguard health-related quality of life (HRQoL). Advanced NSCLC trials with HRQoL endpoints face methodological constraints limiting interpretability. Objectives: We provide a comprehensive overview of recent clinical trials evaluating the impact of systemic therapies on HRQoL in advanced NSCLC, focusing on the methodological quality, with the ultimate goal to improve interpretation, comparison and reporting of HRQoL data. Methods: A systematic literature review was performed. Prospective studies published over the last decade evaluating the impact of systemic treatments on HRQoL in advanced NSCLC were included. Methodological quality of HRQoL reporting was assessed with the CONSORT-PRO extension. Results: Hundred-twelve manuscripts describing 85 trials met all criteria. No formal conclusion can be drawn regarding the impact on HRQoL of different treatments. We report an important variety in methodological quality in terms of definitions of HRQoL, missing data points, lack of standardization of analyzing and presenting HRQoL and no standard follow-up time. The quality of HRQoL data reporting varies substantially between studies but improves over time. Conclusion: This review shows that in the heterogeneous landscape of trials addressing HRQoL in advanced stage NSCLC. Methodology reporting remains generally poor. Adequate reporting of HRQoL outcome data is equally important to support clinical decision-making as to correctly inform health policy regarding direct approval and reimbursement of the new drugs and combinations that will come online.

Systematic literature review of health-related quality of life in locally-advanced non-small cell lung cancer: Has it yet become state-of-the-art?

Lung cancer and its treatment have an important impact on the patients' health-related quality-of-life (HRQoL). A systematic literature review of prospective clinical studies published since 2005 and measuring HRQoL in patients with locally-advanced non-small cell lung cancer (LA- NSCLC) was performed. Besides reviewing the HRQoL impact of LA-NSCLC treatment, it critically examined the frequency, methodology and quality of HRQoL data collection and analysis in LA-NSCLC clinical studies. Out of 814 potentially eligible publications, only 27 (representing 19 individual studies) met the inclusion criteria. Eight studies documented an impact on HRQoL. Large variability in use of HRQoL instruments, statistical analysis and methodological quality was observed. Reporting of HRQoL data lacks standardization, but recent initiatives establishing recommendations to standardize the analysis and reporting of HRQoL in cancer trials are expected to address these issues. Overall, more research is needed to evaluate the treatment impact on HRQoL in both clinical trials and daily care.