Some Thoughts on the Reporting of Adverse Events in Phase II Cancer Clinical Trials

In this issue, Scharf and Colevas discuss discrepancies in adverse event (AE) reporting for phase II oncology trials in peerreviewed publications and the National Cancer Institute (NCI) Clinical Data Update System (CDUS). Many published articles do not provide an appropriate lexicon for AE assessment, and published reports of AEs in phase II studies are problematic in the following three areas: underreporting of low-grade AEs, underreporting of recurrent AEs, and inconsistent and incomplete characterization and reporting of high-grade AEs. The authors conclude that there is a lack of consistency between the definition of AEs in published trial results compared with the original study protocols, and published AE data markedly differ from the data available in CDUS. The authors suggest that journals set a standard of quality assurance for AE information. The authors based their conclusions on an analysis of 22 published reports of single-agent CDUS-monitored phase II clinical trials, culled from a potential pool of 355 singleand multipleagent CDUS-monitored phase II studies active between March 1998 and October 2003. In that time, the NCI Common Toxicity Criteria version 2.0 was the mandated lexicon for reporting and grading AEs in NCI-sponsored trials. Nevertheless, Scharf and Colevas point out that only 16 (73%) of the 22 publications identified a specific AE criteria system, and only 13 publications (59%) cited the NCI Common Toxicity Criteria as the method of AE classification. However, the main focus of the analysis involves a comparison of the AEs reported in the publications versus the AEs reported in the CDUS database. When all grade 3 to 5 AEs were considered, regardless of whether or not they were attributable to an agent, there were 611 grades 3 to 5 AEs in the CDUS database compared with 413 reported in publications. The authors do not mention if these differences are distributed relatively evenly across the 22 studies or if a small proportion of the studies account for the bulk of the differences. Most of the rest of the analysis is focused on AEs that were agent attributable, as summarized in Figures 2A and 2B. Figure 2A shows that the reporting of AEs of grade 3 in articles differs somewhat from the information they found in the CDUS database. Because of the small number of grade 3 to 5 AEs in many studies, some of the seemingly large relative differences in the text represent small differences in terms of absolute numbers. Interestingly, in eight of the 22 publications, investigators reported more attributable grade 3 to 5 AEs than were present in the CDUS database, whereas 12 others reported less attributable grade 3 to 5 AEs than were present in the CDUS database; two studies had concordant information. In Figure 2B, when all AE grades more than 0 are considered, significant underreporting of AE information was provided in the peer-reviewed articles. When Figures 2A and 2B are viewed together, one concludes that much of the underreporting of the AE information is a result of either not reporting or vastly underreporting grades 1 and 2 AEs. These results from Scharf and Colevas raise questions about quality assurance in the peer-reviewed reporting of safety information in phase II clinical trials. However, their methods and conclusions warrant further comment. First, the methods do not address whether the 22 single-agent studies included in the analysis are representative of all published phase II trials. In fact, Mahoney et al have reported that single-agent phase II trials have higher percentages of AEs unrelated to the study agents than observed in multiagent phase II clinical trials. In their first conclusion regarding the underreporting of low grade AEs in phase II trials, Scharf and Colevas do not report the disease stage of the patients in phase II clinical trials and the nature of the agents being tested. In most phase II oncology studies, aggressive therapies are piloted in patients who may have metastatic cancer to demonstrate improved response rates, disease-free survival and survival. Length constraints of journal articles force authors to prioritize the reporting of information to the most clinically important information about treatment outcomes. Therefore, when reporting the results of phase II trials, most investigators emphasize end points which exclude non life-threatening AEs. Importantly, most therapies being tested in phase II studies cause low-grade AEs in a high proportion of patients. Consequently, some authors have proposed strategies which reduce the collection of some low-grade AEs in phase II settings because of the amount of resources required to collect this informaton. Furthermore, Mahoney et al assert that the stage of drug development associated with the stage of the disease of the patients being studied may influence the ability to recognize drug-induced reactions. A more thorough analysis of the relationship between lowand highgrade AEs and disease-free and overall survival could perhaps be better achieved in the phase III setting where patient populations are larger and more information about agent attribution is available before the beginning of the studies. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 24 AUGUST 2