Abstract
Objective: The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors. Methods: We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as “clinicaltrials.gov”. We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the publication time. Chi-square tests and binary logistic regression were used to identify the factors associated with improved SAEs reports. This study was registered on PROSPERO. Results: Of 1560 articles identified, 160 were eligible, with an RP of SAEs of 25.5% (41/160). In forty-one publications reporting SAEs, only 14.6% (6/41) described the pattern of SAEs in detail. In clinical trials sponsored by pharmaceutical companies, the RP of SAEs was significantly higher than that in those sponsored by investigators (57.6 versus 20.7%, p < 0.001). From 1993 to 2018, the RP of SAEs gradually increased (none (0/6) before 2000, 17.1% (12/70) from 2000 to 2009, and 34.5% (29/84) after 2009). The average RP of SAEs published in the New England Journal of Medicine (N Engl J Med), the Lancet, the Journal of the American Medical Association (JAMA), the Lancet Oncology (Lancet Oncol), and the Journal of Clinical Oncology (J Clin Oncol) was significantly higher than that published in other journals (31.9 versus 16.7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting. Conclusion: Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world.
Highlights
Colorectal cancer is the third most commonly diagnosed malignancy worldwide (Fitzmaurice et al, 2017)
We systematically reviewed serious AEs (SAEs) reporting from publications of colorectal cancer clinical trials, to further draw researchers’ attention to SAEs reporting
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%)
Summary
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). 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. Guidelines indicate that clinical trials should report AEs and SAEs in a consistent manner (Wallace et al, 2016)
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