Colorectal cancer is the third most commonly diagnosed malignancy worldwide (Fitzmaurice et al., 2017). Chemotherapy and targeted therapy play an important role in standard treatments for colorectal cancer. Fluorouracil-based adjuvant chemotherapy significantly improved the disease-free survival (DFS) and overall survival (OS) of stage II/III colorectal cancer (Group et al., 2007; André et al., 2009; Iveson et al., 2018). Combination chemotherapy with bevacizumab or cetuximab as the initial treatment significantly improved the median progression free survival (mPFS) and median overall survival (mOS) of metastatic colorectal cancer (Saltz et al., 2008; Van Cutsem et al., 2009; Qin et al., 2018). Fruquintinib and regorafenib in the 3 + line significantly prolonged the mOS and mPFS of advanced colorectal cancer (Grothey et al., 2013; Li et al., 2015; Li et al., 2018). Based on the results of clinical trials that have confirmed the efficacy of many chemotherapeutic and targeted drugs, experts have formed guidelines and consensuses to guide the diagnosis and treatment of colorectal cancer in the real world. Reporting the occurrence, development, and prognosis of adverse events (AEs), especially serious AEs (SAEs), is particularly crucial for reducing or avoiding the toxicity of regimens in real-world clinical practice, improving patients’ quality of life, and decreasing the psychological and economic burden of patients. During the past 20 years, SAEs have attracted increasing attention as the number of SAEs reported to the U.S. Food and Drug Administration (FDA) increased by 2.6 times from 1998 to 2005 (Moore et al., 2007) and by 2 times from 2006 to 2014 (Sonawane et al., 2018). Guidelines indicate that clinical trials should report AEs and SAEs in a consistent manner (Wallace et al., 2016).

AEs reporting is relatively higher in cancer clinical trial publications, but the reporting quality is low. A review showed that 96% of cancer clinical studies reported AEs, but oncology-specific reporting standards were lacking (Sivendran et al., 2014). Another article reviewed 325 randomized clinical trials, all of which reported the occurrence of AEs. Nevertheless, the AEs collection and analysis methods were highly heterogeneous, and the quality of AEs reporting did not improve significantly over time (Péron et al., 2013). In addition, there was a considerable discrepancy between the final published AEs data and the sponsors’ database (Scharf and Colevas, 2006). Although there have been some reviews of AEs reports, analysis of SAEs reports on colorectal cancer clinical trials is scarce, and the report proportion of SAEs in publications is unknown.

We systematically reviewed SAEs reporting from publications of colorectal cancer clinical trials, to further draw researchers’ attention to SAEs reporting. The SAEs reporting was influenced by many social factors, such as regional policy, preciseness and awareness of investigators, purpose of sponsor, so this article analyzed the possible influencing factors of SAEs reporting. Because the results of phase III randomized clinical trials were the most instructive in the real world, herein we just reviewed phase III randomized clinical trials.

This study included randomized phase III colorectal cancer clinical trials whose intervention measures contained anticancer pharmaceuticals and whose results were published in PubMed, Embase, Medline, and the New England Journal of Medicine from January 1, 1993, to December 31, 2018. We analyzed several possible factors that may affect SAEs reporting in the literature. These factors included the region where the clinical trial was conducted, the sponsor of the clinical trial, whether the trial researched new drugs, the publication date which may reflect the change of policy and awareness of investigators, factors related with the rigorous of the clinical trials such as sample size, the type of journal and whether the clinical guidelines referenced the results of the study, and factors owned by clinical trials themselves, such as treatment line, therapeutic schedule.

The registration rate of oncology clinical trials has significantly increased since 2005 (Song and Kim, 2020), and the number of clinical trials for anticancer drugs has also increased in the past decade in China (Li et al., 2019). The China Food and Drug Administration (CFDA) has issued a series of innovations to accelerate new agent approvals in oncology (Wang, 2017). Randomized phase III clinical trials are considered to be the gold standard in clinical practice. Therefore, clinical trials and SAEs reports lay the foundation for selecting anticancer treatments and managing AEs in real-world practice. Chemotherapy and targeted therapy are still mainstream treatments in colorectal cancer, one of the most common malignancies worldwide. Safety is one of the leading factors in clinical decision-making, affecting patient quality of life and the benefit-risk ratio.

This article retrospectively analyzed 160 publications that met the inclusion criteria and showed that the RP of SAEs in phase III colorectal cancer clinical trials was only 25.5%, significantly lower than that of AEs, which was reported to be 96% in cancer clinical trials in a retrospective study (Sivendran et al., 2014). One of the reasons for the low RP of SAEs was insufficient attention to SAEs reports. Some researchers believed that systematic and complete SAEs reporting increased the workload and costs when the purpose of a clinical trial was only to verify drug efficacy (Wallace et al., 2016). Therefore, inadequate research funding was the other reason (Wallace et al., 2016).

Most publications included in this article did not report the type or prognosis of SAEs in detail. This was similar to a study examining the quality of SAEs reporting to sponsors by investigators from all clinical trials performed at Limoges University Hospital in 2012 (Crépin et al., 2016). In this study, 3.6% of the reports did not describe the seriousness of the SAEs, 9.3% were missing a causality assessment, and the date of SAEs onset was not mentioned in 5.7% of the reports. This phenomenon may be due to the lack of standard guidelines for SAEs reporting in clinical trials. On the other hand, the journal’s word count requirements may limit the author’s ability to provide a detailed SAEs description. The severity and duration of SAEs directly affect the prognosis and quality of life of patients, and both are essential factors for SAEs reports (Sartor, 2017). Detailed descriptions of the manifestation, severity, duration, and outcome of SAEs in phase III clinical trials, whose results have important reference value for clinical guidelines, have crucial guiding significance for real-world clinical practice. Therefore, in the future, journals about SAEs and SAEs case reports should be established for reporting SAEs in detail to better guide clinical practice and drug research and development, thereby improving cancer treatments and maximizing the benefits of patients.

The manifestations of AEs in patients with colorectal cancer were related to the drugs. The skin reactions reported in this article were more common for anti-EGFR antibodies, such as cetuximab and panitumumab, which was similar to previous reports. Some reviews and phase II clinical trials showed that the incidence of AEs and grade 3/4 AEs were 66.7% (Lynch et al., 2007) and 8%-16% (Soeda et al., 2014; Soda et al., 2015), respectively, for patients treated with cetuximab and 74.7% (Bouché et al., 2019) and 9%-15% (Nishi et al., 2016; Munemoto et al., 2018), respectively, for panitumumab. HFS was more common for regorafenib and capecitabine in this study. It has been reported that the incidence of HFS and grade 3/4 HFS were 65–69% and 15–16%, respectively, for regorafenib (Bekaii-Saab et al., 2019), and the incidence of grade 3/4 HFS for capecitabine was 8% (Soda et al., 2015) in non-phase III clinical trials. This study showed that regorafenib was related to hypertension and dyspnea, whose previously reported incidences were 62%–70% and 19%–23%, respectively, and the incidences above grade 3 were 7%–15% and 4%–6%, respectively (Bekaii-Saab et al., 2019). The incidences of hypertension, proteinuria, gastrointestinal perforation, and thrombosis were more common for bevacizumab, which was consistent with the results of many phase II clinical trials (Chen et al., 2006; Horita et al., 2011; Hong et al., 2012; Nakayama et al., 2012).

The chi-square analysis in this study showed that the RP of SAEs in clinical trials conducted worldwide (52.4%) was higher than that in those conducted in local region (21.6%). The worldwide clinical research is supervised and reviewed by an international ethics committee and global regulatory agencies. The management system is stricter, so the reporting of SAEs is more stringent. In addition, clinical studies conducted in only one country had various reports of SAEs. The RP of SAEs was higher in China, Spain, Italy, and Greece, at 75, 50, 50, and 33.3%, respectively (Figure 5). This may be related to the differences in supervision and management of clinical research in different regions and the differences in policies and regulations.

The RP of SAEs in new drug clinical research (45.5%) was significantly higher than that in non-new drug clinical studies (15.2%) (p < 0.001). In addition to the effectiveness of new drugs, the safety of new drugs was of paramount concern, so the RP of SAEs was higher. Non-new drug research mainly compared the efficacy of different treatment regimens and paid less attention to SAEs, and the RP of SAEs was lower. The SAEs reporting rate of clinical studies initiated by pharmaceutical companies (57.6%) was higher than that of investigators (20.7%) (p < 0.001). Among 33 clinical studies initiated by pharmaceutical companies, 69.7% (23) were new drug-related clinical studies, while only 39% (32 of 82) of clinical studies undertaken by investigators were new drug studies. The RP of SAEs in new drug clinical research was higher, so the RP of SAEs in clinical research initiated by pharmaceutical companies was higher. This was also the reason why the RP of SAEs was higher in clinical trials about second line and above treatment, and higher in targeted therapy based clinical trials.

This study showed that the RP of SAEs increased in the past 26 years, which may be attributed to the following. First, the National Health and Medical Research Council has provided increasingly rigorous regulations about how SAEs should be reported (Wallace et al., 2016). Second, the increasing attention paid to drug research safety has promoted the monitoring and management of data for clinical trials (Bhattacharyya et al., 2018). Pharmaceutical companies and journal editors have made recommendations on AEs (including SAE) reporting after a thorough discussion on how policies and guidelines were followed, what challenges existed, and how challenges should be addressed to improve AEs and SAEs reporting in clinical research publications to enhance the degree of authenticity and accuracy of clinical trial data (Lineberry et al., 2016). Third, the training recommendations in the Good Clinical Practice (GCP) guidelines require investigators and study coordinators executing a clinical trial to undergo training on GCP principles every 3 years (Shanley et al., 2017), enhancing investigators’ compliance with GCP (Kuusisto et al., 2011). Finally, SAEs reports are processed by an automated computer system instead of personal reports with the development of information technology, saving workforce resources and time and facilitating the analysis of reporting performance and the nature of SAEs reports (London et al., 2009; Pecoraro and Luzi, 2011). AEs capture and management systems for cancer clinical trials were set up to administer and manage clinical trials, improving the efficiency, accuracy, and safety of AEs reports (Lencioni et al., 2015).

The top five journals for RPs of SAEs were N Engl J Med, Lancet, Lancet Oncol, JAMA, J Clin Oncol, with an average RP of SAEs 31.9%, which was significantly higher than that of other journals (16.7%, p = 0.030). This was affected by the journal’s requirements. For example, Lancet has provided readers with links to websites that published clinical trial protocols since 2009, and J Clin Oncol has disclosed agreements that were previously only open to journal editors and reviewers since 2011 (Song and Kim, 2020). The improvement of clinical trial transparency is beneficial to the authenticity of clinical research data.

Patients in some clinical trials completed electronic surveys regarding symptomatic AEs according to the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) (Hagelstein et al., 2016) of the National Cancer Institute (NCI) during cancer treatment, which was demonstrated to be both feasible and informative (Chung et al., 2019). A pooled analysis showed that in oncology clinical trials, PRO and AEs reports had a different focus and were complementary (Atherton et al., 2015). Other systematic reviews showed that reported agreement between CTCAE and PRO ratings was poor to moderate in most trials (Atkinson et al., 2016). They provided evidence that PROs provided unique, valuable information that can complement CTCAE ratings, avoiding loss of AEs information because of a long interval between visits (Atkinson et al., 2016). The PRO-CTCAE included a rigorous method for capturing patient self-reports of symptomatic AEs in cancer clinical trials (Hagelstein et al., 2016) but has not been used worldwide. The effective combination of the PRO-CTCAE and clinician-reported CTCAE may be better for the management of AEs, especially SAEs, in cancer patients.

SAEs reports need more improvement. For example, improving the construction of SAEs reporting systems in electronic information platforms, establishing precise process and data collection methods, strengthening the training of medical staff, enhancing the safety ability assessment of patients via patient education, and improving the awareness and attention of SAEs have been reported. The authors believe that co-report of AEs/SAEs via PRO and researchers in clinical trials should be adopted in the future (Figure 6).

There were some shortcomings in this study. First, this was a retrospective study, and there may be omissions in data collection and selection bias. Second, the identification criteria for SAEs may vary because of the diverse designs of clinical trials and different judgment criteria of investigators. Third, bias existed in the data collection because the descriptions of SAEs in the publications were inconsistently attributed to the journal-specific publication requirements. Finally, this study’s included publications were all published clinical trials, and unpublished clinical trials, such as clinical trials with negative research results, were excluded. The reporting methods for SAEs have gradually improved as people pay increasing attention to SAEs. Independent reporting of SAEs by patients and researchers may better guide clinical practice and drug development in the future.

In conclusion, our findings showed that the RP of SAEs increased and aroused more researchers’ attention over time. However, more efforts should be made to improve the RP of SAEs and the quality of SAEs reporting. The patterns and outcomes of SAEs should be reported in detail and given more attention to better guide drug application by clinicians in the real world. In addition, independent reporting of SAEs by patients and researchers should be encouraged.