Background
Randomized phase III trials (RCTs) are the gold standard in assessing medical interventions. The findings from RCTs enable clinicians to make treatment recommendations, describe the risks and benefits of various treatments, and facilitate shared decision-making [
1]. Most cancer therapies have a narrow therapeutic index, and the high levels of toxicity generated by many of them require stringent and uniform standards of reporting to describe the scope and severity of adverse events (AEs). Reproducible and systematic reporting of toxicity allows studies to be more easily compared with one another [
2‐
4] and facilitates the generation of toxicity-related meta-analyses and other secondary analyses [
5‐
7].
The Common Terminology Criteria for Adverse Events (CTCAE) [
8] is a uniform system of nomenclature for classifying AEs and their associated severity in cancer clinical trials. It was designed to aid clinicians in the detection and documentation of an array of AEs commonly encountered in oncology. Although CTCAE was designed for use in clinical trials, it is often used in routine care to guide treatment decisions, including drug dosing and supportive care interventions [
3,
9]. In 2003, the NCI announced the third revision of the CTC, labeled CTCAE v3.0 [
10], which is a comprehensive standardized AE lexicon and grading system for multimodality interventions. The CTCAE v3.0 is the primary method for reporting AEs in medical journals and oncology meetings [
8].
The wide use of CTCAE v3.0 has been critical in understanding treatment-related harms and has facilitated comparisons of toxicity profiles among different anticancer reagents and multimodality therapeutics [
11,
12]. However, there has been no systematic evaluation of the extent to which reports of phase III RCTs adhere to guidelines associated with CTCAE v3.0 [
12] (
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/resp_AE_rpt.ppt). The primary aim of the present study was to assess the quality of reporting of AEs in publications describing the results of recent RCTs.
Discussion
A careful balance between efficacy and toxicity is of primary importance in medical interventions. Concerns have been raised previously that anticancer drugs have toxicities that might outweigh their benefits [
11]. AE reporting is a critical component in the conduct and evaluation of clinical trials [
13]. With approximately 1,000 standardized descriptive terms, CTCAE v3.0 has become the worldwide standard dictionary for reporting AEs in cancer clinical trials [
8]. To our knowledge, this is the first large-scale study evaluating the conformity of oncology RCTs publications using CTCAE v3.0 to the corresponding guideline.
Our study provides evidence of poor reporting of toxicity in clinical trials.
Overall, many articles included had some deficiencies or incorrect reporting of AE terms and grades with possible clinical relevance. Concerning that many publications only reported the “pooled,” “selected,” or “worst” AEs which cannot allow for detailed analysis and that we only evaluated the AEs in the tables, the actual number of misused AE terms and grades maybe even higher. In addition, without the access to individual toxicity data, our analysis was only based on the reported toxicity data in trials. This suggests that the undetectable and inaccurate grades of other AE terms may also exist.
It was reported that the subjective AE such as fatigue might be variable when they were assessed by different health practitioners [
14]. The objective AEs are generally more consistent and accurate when they are supported by laboratory or imaging results [
8]. However, it was demonstrated even for this kind of high-fidelity objective AEs, there are considerable inconsistencies between clinical trial adverse events entered into the Clinical Data Update System, the NCI’s electronic database, and in subsequent publications [
15]. Our results further extended these findings, specifically evaluating the quality of reporting toxicity in the context of CTCAE v3.0.
There is one potential reason for the observed problems in our analysis. A lack of authors’ awareness of the explanatory file/guideline for CTCAE 3.0 is a likely contributing factor. It is possible that some authors are not familiar with this document compromising the correct use of CTCAE v3.0.
There are some potential limitations in our study. We restricted our analysis to randomized phase III trial publications for solid tumor treatments in recent years, although adherence to CTCAE v3.0 in phase II trials, hematologic malignancy trials and trials testing multimodality treatment (for example, radiation therapy) should also be required. Moreover, CTCAE v4.0 was released in 2009 and it was gradually implemented recently. Because oncology studies usually take years to complete, only a few publications of RCTs report toxicity with this new version currently. However, the essential parts of CTCAE (AE terms and grades) remain similar. It is possible the problems identified in this analysis would carry over to 4.0 and to future versions, so they need to be recognized and corrected.
Abbreviations
CTCAE v3.0, common terminology criteria for adverse events; NCI, national cancer institute; RCT, randomized clinical trials
Acknowledgements
We gratefully thank the staff members in the Department of Medical Oncology at Fudan University Cancer Center for their suggestions.
This work was finished in Shanghai Cancer Center, Fudan University.
Grant support: None.
This study has not been presented elsewhere.
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