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Clinical Studies

Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE

Abstract

Background

Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients’ reported experience of these toxicities using PRO-CTCAE.

Methods

Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses.

Results

Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either ‘quite a bit’ or ‘very much’, respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild–moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions.

Conclusion

This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

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Fig. 1: Clinician-reported symptomatic grade 2 AEs and associated patient-reported severity and interference scores.
Fig. 2: Clinician-reported symptomatic grade 3/4 AEs and associated patient-reported severity and interference scores.
Fig. 3: Consort diagram of clinician-reported AEs (blue) and associated PRO-CTCAE severity scores (green).
Fig. 4: Consort diagram of clinician-reported AEs (blue) and associated PRO-CTCAE interference scores (green).

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Acknowledgements

The study group would like to acknowledge the patients and their families who contributed to and made this research possible.

Funding

No funding was procured for this study.

Author information

Authors and Affiliations

Authors

Contributions

Study concepts and design: DS and ARH. Data acquisition—GW, ZWV and DS. Quality control of data and algorithms: GW, DS, ZWV and ZAL. Data analysis and interpretation—GW, ZWV, ZAL and ARH. Statistical analysis: ZAL, GW and ZWV. Manuscript preparation: GW and ARH. Manuscript editing: GW, ZWV, ARH, DS, ZAL, AAR, AS, PLB, LLS and LM.

Corresponding author

Correspondence to Aaron R. Hansen.

Ethics declarations

Ethics approval and consent to participate

This protocol was approved by the Princess Margaret Cancer Centre Research Ethics Board (REB) and conformed to the Helsinki Declaration. All participants provided written informed consent prior to study enrolment.

Competing interests

GW has received travels grants from BMS and Abbvie, and received honoraria from Pfizer. ZWV has received an honorarium from Pfizer and Genomic Health. He has also served on an advisory board for Genomic Health. PLB reports grants from Bristol-Myers-Squibb, Sanofi, Genentech/Roche Novartis, GlaxoSmithKline, Nektar Therapeutics, Merck, Lilly, Servier, PTC Therapeutics, Seattle Genetics, Mersana outside the submitted work; and Uncompensated advisory boards for Bristol-Myers-Squibb, Sanofi, Pfizer, Genentech/Roche. LLS reports compensated consultancy/advisory board participation for Merck, Pfizer, Celgene, AstraZeneca/Medimmune, Morphosys, Roche, GeneSeeq, Loxo, Oncorus, Symphogen, Seattle Genetics, Glaxo-Smith-Kline, Voronoi, Treadwell Therapeutics, Arvinas, Tessa and Navire; and reports institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks and Avid. Spouse hold stock in Agios and Treadwell Therapeutics. ARH reports institutional support for clinical trials to conduct by Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Astellas and Bayer; and compensated consulting/advisory boards for AstraZeneca, Merck and GlaxoSmithKline. ARAR has received research funding from Roche, Genentech, Eli Lilly, Merck, Boehringer-Ingelheim, Novartis, AbbVie, Deciphera, Karyopharm, AstraZeneca, Medimmune, Blueprint, Bristol-Myers Squibb, GSK, Entremed/Casi Pharmaceuticals, Adaptimmune and BetaCat. He also has also served the advisory board for Eli Lilly, Merck, Adaptimmune, Boehringer-Ingelheim. AS has served as an advisory board consultant for Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). She has also received research funding from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma, GSK. DS, ZAL, LM report no competing interests.

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Watson, G.A., Veitch, Z.W., Shepshelovich, D. et al. Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE. Br J Cancer 127, 1629–1635 (2022). https://doi.org/10.1038/s41416-022-01926-z

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