Patient experience of early high grade symptomatic adverse events on early phase clinical trials using the PRO-CTCAE.
Authors: Watson Geoffrey Alan , Veitch Zachary William Neil , Shepshelovich Daniel , Liu Zhihui (Amy) , Spreafico Anna , Abdul Razak Albiruni Ryan , Bedard Philippe L. , Siu Lillian L. , Minasian Lori M. , Hansen Aaron Richard 
Published: June 2021

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Background: There are limited data describing the patients’ experience of symptomatic adverse events (syAEs) on early phase clinical trials. This information is critical to understand the tolerability of experimental agents. The patient reported outcome version of the CTCAE (PRO-CTCAE) evaluates syAE components such as severity and interference in daily life. The aim of this study was to correlate clinician reported early, high grade (grade 3-4) AEs with patients’ reported experience of these toxicities. Methods: Advanced solid tumor patients (pts) enrolled on early phase clinical trials at Princess Margaret Cancer Centre were surveyed electronically using the full library of 78 items for PRO-CTCAE v1.0, which was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE v4.0. Worst responses for severity items are ‘severe’ and ‘very severe’ and for interference items are ‘quite a bit’ and ‘very much’. A logistic regression model was used to assess the association between CTCAE grade and PRO-CTCAE severity and interference. Results: A total of 292 pts were approached in phase 1 clinics from May 2017 to January 2019, and 219 pts were included in the analysis: median age 60 years (range 18-82), 111 (51%) were male; all were ECOG ≤1. A total of 140 pts (64%) received combination therapy (immunotherapy and targeted therapy), and 73 pts (33%) had received ≥3 previous lines of treatment. In terms of patient reported syAEs, a total of 114 pts (52%) reported a symptomatic AE as either severe or very severe at any timepoint and 79 pts (36%) reported a syAE with an interference that was either ‘quite a bit’ or ‘very much’. With regards to clinician reported AEs, a total of 82 pts (37%) had a clinician reported grade 3 or 4 syAE, and of these 34 pts (41%) reported these as either severe or very severe; and 26 pts (32%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Additionally 137 pts (66%) had a clinician reported grade 1 or 2 syAE, and of these 39 pts (28%) reported these as either severe or very severe; and 19 (14%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Higher grade clinician reported syAEs (CTCAE grade 3-4 vs 1-2) was associated with higher patient reported severity levels (odds ratio, OR = 1.78, 95% CI 1-3.16, p = 0.049), and was associated with higher patient reported interference levels (OR = 2.88, 95% CI 1.47-5.64, p = 0.002). Conclusions: A majority of patients had a very negative experience of syAEs on a phase I trial. Higher grades of clinician reported AEs correlated with greater severity and interference with daily living. Future phase I studies could incorporate the PRO-CTCAE and other PRO tools which could inform the tolerability of experimental regimens and enhance the description of symptomatic AEs.