Methods for Implementing and Reporting Patient-reported Outcome (PRO) Measures of Symptomatic Adverse Events in Cancer Clinical Trials

Abstract

Purpose: There is increasing interest to use patient-reported outcome (PRO) measures to evaluate symptomatic adverse events (AEs) in cancer treatment trials. However, there are currently no standard recommended approaches for integrating patient-reported AE measures into trials.

Methods: Approaches are identified from previous trials for selecting AEs for solicited patient reporting, administering patient-reported AE measures, and analyzing and reporting results.

Findings: Approaches for integrating patient-reported AE measures into cancer trials generally combine current standard methods for clinician-reported AEs and established best practices for using PRO measures. Specific AEs can be selected for a PRO questionnaire based on common and expected reactions in a given trial context, derived from literature review and qualitative/mixed-methods evaluations and should be the same set administered across all arms of a trial. A mechanism for collecting unsolicited patient-reported AEs will also ideally be included. Patients will preferably report at baseline and at the end of active treatment as well as on a frequent standardized schedule during active treatment, such as weekly from home, with a recall period corresponding to the frequency of reporting (eg, past 7 days). Less frequent reporting may be considered after an initial intensive monitoring period for trials of prolonged treatments and during long-term follow-up. Electronic PRO data collection is preferred. Backup data collection for missed PRO reports is advisable to boost response rates. Analysis can use a combination of approaches to AE and PRO data. If a high proportion of patients is experiencing baseline symptoms, systematic subtraction of these from on-study AEs should be considered to improve reporting of symptoms related to treatment. More granular longitudinal analyses of individual symptoms can also be useful.

Implications: Methods are evolving for integrating patient-reported symptomatic AEs into cancer trials. These methods are expected to further evolve as more data from trials become available.

Keywords: Adverse event; Cancer; Common Terminology Criteria for Adverse Events; Patient-reported outcome; Symptom; Toxicity.

Figure 1

Example graphical display showing the distribution of maximum post-baseline grades reported by patients during treatment in a phase 2 cancer clinical trial (Clin Trials. 2015 Nov 4. pii: 1740774515615540. PMID:26542025). Grades are based on items modified for patient use from the Common Terminology Criteria for Adverse Events (CTCAE).

Figure 2

Example longitudinal graphical displays showing the distribution of patient grade levels for four symptomatic adverse events at time points during treatment in a phase 2 cancer clinical trial (Clin Trials. 2015 Nov 4. pii: 1740774515615540. PMID:26542025). Grades are based on items modified for patient use from the Common Terminology Criteria for Adverse Events (CTCAE). Few patients experienced alopecia at baseline (Day 1) and this number markedly increased at Day 28. In contrast, about half of patients had dyspnea at baseline and this proportion did not change substantially, although the distribution of patient-reported grades improved during the trial, suggesting improvement. Mucositis and nausea both increased at Day 15 then improved, suggesting symptomatic control with supportive measures, and suggests the need for earlier preventive measures for mucositis and nausea with the study regimen.

Figure 2

Example longitudinal graphical displays showing the distribution of patient grade levels for four symptomatic adverse events at time points during treatment in a phase 2 cancer clinical trial (Clin Trials. 2015 Nov 4. pii: 1740774515615540. PMID:26542025). Grades are based on items modified for patient use from the Common Terminology Criteria for Adverse Events (CTCAE). Few patients experienced alopecia at baseline (Day 1) and this number markedly increased at Day 28. In contrast, about half of patients had dyspnea at baseline and this proportion did not change substantially, although the distribution of patient-reported grades improved during the trial, suggesting improvement. Mucositis and nausea both increased at Day 15 then improved, suggesting symptomatic control with supportive measures, and suggests the need for earlier preventive measures for mucositis and nausea with the study regimen.