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- Title
Variation in the Assessment of Immune-Related Adverse Event Occurrence, Grade, and Timing in Patients Receiving Immune Checkpoint Inhibitors.
- Authors
Hsiehchen, David; Watters, Mary K.; Lu, Rong; Xie, Yang; Gerber, David E.
- Abstract
Key Points: Question: How accurate are clinicians in diagnosing and characterizing immune-related adverse events from cancer immunotherapy? Findings: In a cross-sectional study using an algorithm-driven approach to characterize immune-related adverse events, poor concordance of interrater agreement was found in the occurrence, severity, and timing of 8 common immune-related adverse events. Discordance was associated with longer durations of therapy and higher comorbidity burden in patients. Meaning: These findings suggest that the diagnosis and characterization of immune-related adverse events are challenging and have direct relevance to immunotherapy clinical trials and the care of patients receiving immune checkpoint inhibitors. This cross-sectional study assesses the concordance of algorithm-driven medical record review by medical oncologists for the characterization of 8 immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors. Importance: Toxic effects of conventional chemotherapy and molecularly targeted cancer therapies are generally well defined and occur at predictable points. By contrast, owing to their heterogeneous manifestations, unpredictable timing, and clinical overlap with other conditions, immune-related adverse events (irAE) may be more difficult to diagnose and characterize. Objective: To determine concordance of algorithm-driven medical record review by medical oncologists for the characterization of 8 irAE in patients treated with immune checkpoint inhibitors. Design, Setting, and Participants: Cross-sectional study of patients treated with immune checkpoint inhibitors at a National Cancer Institute–designated comprehensive cancer center from November 30, 2015, to March 7, 2018. A sample size of 52 patients provided 80% power to distinguish substantial agreement (κ = 0.85) from poor agreement (κ = 0.5) based on the Cohen κ. Main Outcomes and Measures: Interrater agreement of 2 observers in the occurrence and grade of irAE. Results: Of 52 patients (32 [61.5%] male; mean [SD] age, 69 [9] years) analyzed, 42 (80.8%) had non–small cell lung cancer and all received anti–programmed cell death 1 or anti–programmed cell death ligand 1 antibodies, with 3 patients (5.8%) receiving combinations with anti–cytotoxic T-lymphocyte antigen 4 antibodies. A median (interquartile range) of 82 (47-180) documents were reviewed per case. There was limited or poor interrater agreement on irAE occurrence (Cohen κ, 0.37-0.64), with the exception of hypothyroidism (κ = 0.8). Weighted κ similarly showed limited or poor agreement for irAE grade (κ = 0.31-0.75). Differences in assessed time of onset ranged from 5 to 188 days. As a control for data availability and access, observers had a high degree of agreement for the exact start date (98%) and end date (96%) of immunotherapy administration, suggesting that information interpretation rather than identification largely accounted for assessment differences. In multivariable analysis, therapy duration (adjusted odds ratio, 4.80; 95% CI, 1.34-17.17; P =.02) and Charlson Comorbidity Index (adjusted odds ratio, 4.09; 95% CI, 1.10-15.18; P =.03) were significantly associated with discordant irAE assessment. Conclusions and Relevance: These findings underscore critical challenges in assessing the occurrence, type, timing, and severity of irAE. Apart from hypothyroidism (a condition that has a discrete diagnostic laboratory test and few other likely etiologies during immunotherapy treatment), interobserver agreement was poor. Given the importance of accurate and timely assessment of toxic effects for clinical trials and real-world disease management, efforts to improve irAE diagnosis and characterization are needed.
- Subjects
APOPTOSIS; CONFIDENCE intervals; IMMUNOTHERAPY; LUNG cancer; MULTIVARIATE analysis; ONCOLOGISTS; RESEARCH funding; STATISTICAL hypothesis testing; LOGISTIC regression analysis; NATIONAL Cancer Institute (U.S.); INTER-observer reliability; CROSS-sectional method; DATA analysis software; ELECTRONIC health records; ADVERSE health care events; DESCRIPTIVE statistics; ODDS ratio; IMMUNOLOGIC receptors
- Publication
JAMA Network Open, 2019, Vol 2, Issue 9, pe1911519
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2019.11519