Time to deterioration in cancer randomized clinical trials for patient-reported outcomes data: a systematic review

Charton, Émilie; Cuer, Benjamin; Cottone, Francesco; Efficace, Fabio; Touraine, Célia; Hamidou, Zeinab; Fiteni, Frédéric; Bonnetain, Franck; Woronoff‐Lemsi, Marie‐Christine; Bascoul-Mollevi, Caroline; Anota, Amélie

doi:10.1007/s11136-019-02367-7

Cited by 22 publications

(13 citation statements)

References 56 publications

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“…Patient-reported outcomes (PROs) are incorporated as endpoints in clinical trials to assess the clinical benefit of new treatments for patients [ 1 , 2 ]. The most widely used instruments in phase 3 oncology trials are the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

et al. 2022

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Purpose The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored. Methods TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥ 10-point difference = clinically relevant). Results No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P = 0.034) when baseline was the reference, and for cough (HR 0.70; P = 0.009) and dyspnoea (HR 0.71; P = 0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P = 0.025) when baseline was the reference, and for cough (HR 0.70; P = 0.011), dyspnoea (HR 0.71; P = 0.003) and chest pain (HR 0.71; P = 0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms. Conclusion This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials. Clinical trial registration ClinicalTrials.gov NCT02296125.

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Section: Introductionmentioning

confidence: 99%

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

et al. 2022

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“…The chosen endpoint, TUDD, has recently been viewed as a more appropriate endpoint for metastatic settings than TTD. 15 , 16 By focusing on the time to which symptoms do not resolve, the analyses are able to account for dosing variability that allows for patients to continue modified treatment and experience resolution of treatment-related symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, while TTD is recommended for an adjuvant setting (where reversibility is important), recent research suggests that time until definitive deterioration (TUDD) in HRQOL, defined as the patient’s first clinically meaningful deterioration in HRQOL from baseline that does not subsequently resolve, may be more appropriate for studies in a metastatic setting. 15 , 16 Patients with late-stage disease may have an initial decline in HRQOL due to drug toxicity, which could be alleviated by using clinical interventions that allow patients to continue treatment. Therefore, it is important to understand the long-term impact of the treatment on patient QOL and symptoms in the context of the efficacy and safety profile.…”

Section: Introductionmentioning

confidence: 99%

Effect of Regorafenib in Delaying Definitive Deterioration in Health-Related Quality of Life in Patients with Advanced Cancer of Three Different Tumor Types

Hofheinz

Bruix

Demetri

et al. 2021

CMAR

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The efficacy and safety of regorafenib have been demonstrated in phase 3 trials for multiple tumor types, including metastatic colorectal cancer (mCRC) (CORRECT [NCT01103323]; CONCUR [NCT01584830]), advanced gastrointestinal stromal tumor (GIST) (GRID [NCT01271712]), and hepatocellular carcinoma (HCC) (RESORCE [NCT01774344]). The objective of this post hoc exploratory analysis was to explore the impact of regorafenib on delaying health-related quality of life (HRQOL) deterioration across these tumor types. Patients and Methods: HRQOL data (assessed with EORTC QLQ-C30 and EQ-5D questionnaires) were pooled for all trials to determine time until definitive deterioration (TUDD), defined as the patient's first minimal clinically important deterioration in HRQOL score from baseline that does not resolve, using stratified Kaplan-Meier estimators and Cox proportional hazards models adjusted for relevant trial, cancer type, and baseline covariates. Additional analyses based on cancer type were conducted by pooling mCRC trials (CORRECT and CONCUR) and pooling the two mCRC trials with the HCC trial (RESORCE). Results: A total of 1699 patients with HRQOL data were pooled across the four trials. The results showed that regorafenib significantly delayed TUDD compared with placebo across all three tumor types. Median time to deterioration across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and 8.6 to 12.1 weeks for placebo. The results from the individual studies, the pooled mCRC trials, and the pooled mCRC and HCC trials were similar to the overall pooled results. Conclusion:A pooled analysis of four phase 3 trials demonstrated that regorafenib delayed a clinically relevant exploratory endpoint, defined as TUDD, compared with placebo across three different tumor types (mCRC, GIST, and HCC), which supports a novel benefit of the impact of regorafenib with respect to patients with these three types of cancers by allowing initial declines in HRQOL to resolve and patients the opportunity to continue treatment.

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“…Curves showing time-to-deterioration of cognitive function can be useful to obtain a description of any clinically relevant worsening, either early or late. In fact, time-to-deterioration is an important modality of longitudinal analysis of PROs that, as well as for other functional scales, symptoms and global QoL, can be useful to describe the trajectory of cognitive function [ 25 ]. To be performed correctly, time-to-deterioration analysis should treat other events (including deaths or clinical progressions) as competing events, and not as events considered as cognitive worsening.…”

Section: Different Modalities Of Data Analysis and Presentation Ofmentioning

confidence: 99%

Evaluation of Cognitive Function in Trials Testing New-Generation Hormonal Therapy in Patients with Prostate Cancer: A Systematic Review

Marandino

Vignani

Buttigliero

et al. 2020

Cancers

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In patients with prostate cancer, earlier use and longer duration of new-generation hormonal therapy (NGHT), added to androgen deprivation therapy, requires careful evaluation of cognitive function. The aim of this systematic review is to describe the evidence about cognitive function in all the randomized trials (RCTs) testing NGHT (abiraterone, enzalutamide, apalutamide, darolutamide). We assessed the availability of both investigator-assessed cognitive impairment and disorders and patient-reported evaluation of cognitive function. Nineteen RCTs (17,617 patients) were included. The investigator-based evaluation of cognitive impairment was available in seven RCTs (36.8%). In total, 19/19 RCTs (100%) included patient-reported outcomes (PROs) collection, but PRO tools adopted allowed evaluation of cognitive function in two RCTs (10.5%). Among them, PRO-based cognitive function results were presented only in one RCT (5.3%): in ENZAMET, mean changes from baseline were worse with enzalutamide than with placebo, but deterioration-free survival favored enzalutamide. Despite cognitive deterioration could be relevant, clinical development of NGHT has not included a systematic evaluation of cognitive function. Assessment by investigators is at risk of underreporting, and commonly used PROs do not allow proper cognitive function analysis. Furthermore, the methodology of analysis can jeopardize the interpretation of results. Although direct comparisons are scanty, there could be differences between different NGHTs.

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Time to deterioration in cancer randomized clinical trials for patient-reported outcomes data: a systematic review

Cited by 22 publications

References 56 publications

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

Effect of Regorafenib in Delaying Definitive Deterioration in Health-Related Quality of Life in Patients with Advanced Cancer of Three Different Tumor Types

Evaluation of Cognitive Function in Trials Testing New-Generation Hormonal Therapy in Patients with Prostate Cancer: A Systematic Review

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