Composite grading algorithm for the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Abstract

Background: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested.

Methods: A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443).

Results: In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation.

Conclusion: A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting.

Keywords: Adverse event; Common Terminology Criteria for Adverse Events; Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; health-related quality of life; oncology; patient-reported outcome; symptom; toxicity.

Figure 1.

Contour plots of PRO-CTCAE composite grades by frequency, severity, and interference scores. Circles show score combinations that have composite grades that were directionally inconsistent with the composite grades of neighboring score combinations.

Figure 2.

Mean EORTC QLQ-C30 Health-Related Quality of Life (HRQL) Summary Scores with 95% confidence intervals by PRO-CTCAE composite grades for PRO-CTCAE symptomatic adverse events matching the recommended core symptoms of Reeve et al. Higher EORTC QLQ-C30 scores indicate better health-related quality of life.

Figure 3.

Distribution of PRO-CTCAE data (individual severity and interference scores and composite grades) for hand-foot syndrome in A091105 at each assessment time point.