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

  • E. ChartonEmail author
  • B. Cuer
  • F. Cottone
  • F. Efficace
  • C. Touraine
  • Z. Hamidou
  • F. Fiteni
  • F. Bonnetain
  • M.-C. Woronoff-Lemsi
  • C. Bascoul-Mollevi
  • A. Anota



The time to deterioration (TTD) approach has been proposed as a modality of longitudinal analysis of patient-reported outcomes (PROs) in cancer randomized clinical trials (RCTs). The objective of this study was to perform a systematic review of how the TTD approach has been used in phase III RCTs to analyze longitudinal PRO data.


A systematic literature search was conducted in PubMed/MEDLINE, the Cochrane Library and through manual search to identify studies published between January 2014 and June 2018. All phase III cancer RCTs including a PRO endpoint using the TTD approach were considered. We collected general information about the study, PRO assessment and the TTD approach, such as the event definition, the choice of reference score and whether the deterioration was definitive or not.


A total of 1549 articles were screened, and 39 studies were finally identified as relevant according to predefined criteria. Among these 39 studies, 36 (92.3%) were in advanced and/or metastatic cancer. Several different deterioration definitions were used in RCTs, 10 studies (25.6%) defined the deterioration as “definitive”, corresponding to a deterioration maintained over time until the last PRO assessment available for each patient. The baseline score was explicitly stated as the reference score to qualify the deterioration for most studies (n = 31, 79.5%).


This review highlights the lack of standardization of the TTD approach for the analysis of PRO data in RCTs. Special attention should be paid to the definition of “deterioration”, and this should be based on the specific cancer setting.


Patient-reported outcomes Randomized clinical trials Time to deterioration Systematic review 



This work was supported by a grant from the “Institut National du Cancer (INCA 11862)”. The authors thank François Calais (University of Franche-Comté, Besançon, France) for developing and executing the search strategy. The authors thank Fiona Ecarnot (EA3920, University Hospital Besançon, University of Franche-Comté, Besançon, France) for editorial assistance.


This work was funded by the “Institut National du Cancer (Grant INCA 11862)”.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

11136_2019_2367_MOESM1_ESM.docx (36 kb)
Supplementary material 1 (DOCX 38 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • E. Charton
    • 1
    • 2
    Email author
  • B. Cuer
    • 3
    • 4
  • F. Cottone
    • 5
  • F. Efficace
    • 5
  • C. Touraine
    • 3
  • Z. Hamidou
    • 6
    • 7
  • F. Fiteni
    • 3
    • 8
  • F. Bonnetain
    • 1
    • 2
    • 7
  • M.-C. Woronoff-Lemsi
    • 2
    • 9
  • C. Bascoul-Mollevi
    • 3
    • 4
    • 7
  • A. Anota
    • 1
    • 2
    • 7
  1. 1.Methodology and Quality of Life Unit in Oncology (INSERM UMR 1098)University Hospital of BesançonBesançonFrance
  2. 2.University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et GéniqueBesançonFrance
  3. 3.Montpellier Cancer Institute (ICM)University of MontpellierMontpellierFrance
  4. 4.Institute of Cancer Research of Montpellier (IRCM), ICM, INSERMMontpellierFrance
  5. 5.Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA)RomeItaly
  6. 6.EA3279 Self-perceived Health Assessment Research UnitAix-Marseille UniversityMarseilleFrance
  7. 7.French National Platform Quality of Life and CancerBesançonFrance
  8. 8.Department of Medical OncologyUniversity Hospital of NîmesNîmesFrance
  9. 9.Department of Clinical Research and InnovationUniversity Hospital of BesançonBesançonFrance

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