Underreporting of symptomatic adverse events in phase I clinical trials

Menée au Canada à partir d'une enquête auprès de 292 patients atteints d'un cancer, cette étude met en évidence une sous-déclaration par les cliniciens des événements indésirables symptomatiques dans les essais cliniques de phase I

Résumé en anglais

Background : Clinician reporting of symptomatic adverse events (AEs) in phase I trials utilizes the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PRO) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic-AEs in phase I patients.

Methods : Phase I study eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full item library (78 symptomatic-AEs) at baseline (BL), mid-cycle 1 (C1) and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence/absence of patient- (PRO-CTCAE) or clinician-reported (CTCAEv4) symptomatic-AEs were compared (kappa) at defined timepoints and overall (BL+C1+C2).

Results : Of 292 patients approached from 05/2017–01/2019, 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic-AEs identified 50 PRO-CTCAE and 11 CTCAE items with ≥10% reporting frequency. 19 CTCAE items were reported at ≤ 1% despite matched PRO-CTCAE items with reporting ≥10%. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic-AEs with a ≥ 50-fold lower clinician reporting rate. Overall patient-clinician agreement for individual symptomatic-AEs ranged from poor (kappa = 0.00–0.19) to moderate (kappa = 0.40–0.59) with discordance driven by lack of clinician reporting. Dyspnea (kappa = 0.54) and peripheral neuropathy (kappa = 0.63) at BL, and limb edema (kappa = 0.55) at C2 demonstrated highest patient-clinician agreement.

Conclusion : Poor to moderate patient-clinician agreement for symptomatic-AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.