Adverse event load, onset, and maximum grade: A novel method of reporting adverse events in cancer clinical trials

• Published in: Clinical trials (London, England) England), 2021-02, Vol.18 (1), p.51-60
• Main Authors: Lopes, Guilherme S, Tournigand, Christophe, Olswold, Curtis L, Cohen, Romain, Kempf, Emmanuelle, Saltz, Leonard, Goldberg, Richard M, Hurwitz, Herbert, Fuchs, Charles, de Gramont, Aimery, Shi, Qian
• Format: Article
• Language: English
• Subjects: Adverse Drug Reaction Reporting Systems; Adverse events; Antineoplastic Agents - adverse effects; Benchmarks; Cancer; Cancer therapies; Clinical trials; Clinical Trials as Topic; Data points; Datasets; Diarrhea; Female; Human health and pathology; Humans; Irinotecan; Irinotecan - adverse effects; Leukopenia; Life Sciences; Male; Medical research; Nausea; Neoplasms - drug therapy; Neutropenia; Oxaliplatin; Oxaliplatin - adverse effects; Patients; Side effects; Toxicity; Vomiting
• ISSN: 1740-7745; 1740-7753
• DOI: 10.1177/1740774520959313

Background Current adverse event reporting practices do not document longitudinal characteristics of adverse effects, and alternative methods are not easily interpretable and have not been employed by clinical trials. Introducing time parameters in the evaluation of safety that are comprehensive yet easily interpretable could allow for a better understanding of treatment quality. In this study, we developed and applied a novel adverse event reporting method based on longitudinal adverse event changes to aid describing, summarizing, and presenting adverse event profile. We termed it the “Adverse Event Load, Onset, and Maximum Grade” method. Methods We developed two adverse event summary metrics to complement the traditional maximum grade report. Onset time indicates the time period in which the maximum grade for a specific adverse event occurred and was defined as “early” (i.e. maximum grade happened for the first time before 6 weeks) or “late” (i.e. after the 6th week). Adverse event load indicates the overall severity of a specific adverse event over the entire treatment. Higher adverse event load indicates a worse overall experience. These metrics can be calculated for adverse events with different maximum grades, in treatments with planned changes (e.g. dosage changes), using data sets with different number of adverse event data points between treatments (e.g. treatments with longer cycle lengths may have less adverse event data points) and on data sets with different adverse event data availability (e.g. cycle basis and patient-outcome reports). We tested the utility of this method using individual patient data from two major backbone therapies (“Irinotecan” and “Oxaliplatin”) from the N9741 trial available in the Fondation ARCAD database (fondationarcad.org). We investigated profiles of diarrhea, neutropenia/leukopenia, and nausea/vomiting. Results Our method provided additional information compared to traditional adverse event reports. For example, for nausea/vomiting, while patients in Irinotecan had a higher risk of experiencing maximum grade 3–4 (15.6% vs 7.6%, respectively; p