A toolbox of different approaches to analyze and present PRO-CTCAE data in oncology studies

Abstract

Background: The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is used to assess symptomatic adverse events in oncology trials. Currently, no standard for PRO-CTCAE analysis exists.

Methods: Key methods of descriptive analysis and longitudinal modeling using PRO-CTCAE data from an oncology clinical trial, DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2), a phase II trial of belantamab mafodotin in multiple myeloma (NCT03525678), were explored. Descriptive methods included maximum postbaseline ratings, mean change over time, ratings above a predefined cutoff, line graphs, and stacked bar charts to illustrate patient-reported adverse events at one timepoint or dynamics over time. Analysis methods involving modeling over time included toxicity over time (ToxT) (repeated measurement model, time-to-event, area under the curve analyses), generalized estimating equations (GEE), and ordinal log-linear models (OLLMs).

Results: Visualizations of PRO-CTCAE data highlighted different aspects of the data. Selection of the appropriate visualization will depend on the audience and message to be conveyed. Consistent results were obtained by all modeling approaches; no difference was found between dose groups of the DREAMM-2 study in any PRO-CTCAE item by the ToxT approach or the more sophisticated GEE and OLLM methods. Interpretation of GEE results was the most challenging. OLLM supported the interval nature of the PRO-CTCAE response scale in the DREAMM-2 study. All modeling approaches account for multiple testing (driven by the number of items).

Conclusions: Descriptive analyses and longitudinal modeling approaches are complementary approaches to presenting PRO-CTCAE data. In modeling, the ToxT approach may be a good compromise compared with more sophisticated analyses.

Figure 1.

Maximum baseline-adjusted scores for Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) symptom items. Data from DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2) study PRO-CTCAE collection, full analysis set (N = 221). AE = adverse event; Inj = injection; IV = intravenous.

Figure 2.

Mean change from baseline in nausea over time. Data from DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2) study Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) collection, full analysis set (N = 221); 2.5 mg/kg, n = 97; 3.4 mg/kg, n = 124 (frozen, n = 99; lyophilized, n = 25); end of treatment 2.5 mg/kg, n = 63; 3.4 mg/kg, n = 73. Frequency questions are the first patients are asked on a specific symptom. If no symptoms are declared, the severity question is not asked, which can result in reduced sample sizes for severity measures. AE = adverse event; BL = baseline; EOT = end of treatment; PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; W = week.

Figure 3.

Percent of ratings for nausea at specific timepoints per dose arm by severity. Data from DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2) study Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) collection, full analysis set (N = 221). AE = adverse event; BL = baseline; EOT = end of treatment; FDA = US Food and Drug Administration; W = week.

Figure 4.

Cumulative frequencies of patients reaching scores of at least 2 and 3 per dose arm for nausea. Data from DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2) study Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) collection, full analysis set (N = 221). AE = adverse event; BL = baseline; EOT = end of treatment; FAS = full analysis set; W = week.

Figure 5.

Toxicity over time analysis for severity of constipation. A) Adjusted mean repeated measures analysis of variance (ANOVA) after Bonferroni correction; B) Kaplan-Meier (KM) estimates of time to first occurrence of maximum postbaseline rating for Patient-Reported Outcomes version of the Common Terminology for Adverse Events (PRO-CTCAE) and log-rank test; and C) Area under the curve (AUCs) of mean PRO-CTCAE ratings. Data from DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2) study PRO-CTCAE collection, full analysis set (N = 221). Results shown are for illustrative purposes only; modeling approaches were not compared with each other. CI = confidence interval; SE = standard error.