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Adverse events risk associated with regorafenib in the treatment of advanced solid tumors: meta-analysis of randomized controlled trials

Authors Yin X, Yin Y, Shen C, Chen H, Wang J, Cai Z, Chen Z, Zhang B

Received 11 November 2017

Accepted for publication 12 August 2018

Published 2 October 2018 Volume 2018:11 Pages 6405—6414


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

Xiaonan Yin,1,* Yuan Yin,1,* Chaoyong Shen,1 Huijiao Chen,2 Jiang Wang,1 Zhaolun Cai,1 Zhixin Chen,1 Bo Zhang1

1Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China

*These authors contributed equally to this work

Background: Regorafenib is a novel multikinase inhibitor (MKI) approved for use in the treatment of metastatic colorectal cancer (CRC), treatment-refractory gastrointestinal stromal tumors, and other solid tumor malignancies. However, the adverse events (AEs) associated with regorafenib have not been systematically investigated. Hence, we performed a meta-analysis to identify AEs associated with regorafenib in patients with advanced solid tumors.
Methods: The databases of PubMed, MEDLINE, and Embase and abstracts presented in American Society of Clinical Oncology annual meetings were searched for relevant publications from January 2004 to September 2017. Eligible studies were limited to prospective randomized controlled trials (RCTs) that evaluate the use of regorafenib in patients with advanced solid tumors. Incidence, relative risk (RR), and 95% CIs were calculated using a random or fixed effects model on the basis of the heterogeneity of the included studies.
Results: A total of 2,065 patients from six RCTs were included, and 1,340 of them received regorafenib and 725 received a placebo. Sixteen all-grade AEs and 15 high-grade AEs were investigated for their association with regorafenib. Results showed that hand–foot skin reaction (HFSR; 54%), diarrhea (33%), fatigue (32%), hypertension (31%), oral mucositis (28%), and anorexia (23%) were the most frequent clinical AEs. The most common high-grade (grade, $3) AEs were HFSR (16%), hypertension (13%), fatigue (6%), increased aspartate aminotransferase (AST; 6%), and hypophosphatemia (6%). Pooled RR showed that the use of regorafenib was associated with an increased risk of developing AEs. Subgroup analysis based on the prior MKI treatment showed that prior MKI treatment was associated with an increased incidence of all-grade anorexia (P=0.03) and a reduced incidence of high-grade increased AST (P=0.04). However, subgroup analysis based on the tumor type showed that no significant differences were found when comparing the RR of all-grade and high-grade AEs in patients with CRC or non-CRC.
Conclusion: The meta-analysis systematically investigated regorafenib-associated AEs. Knowledge of these AEs is essential for minimizing treatment-related toxicities and improving clinical outcomes.

Keywords: regorafenib, adverse event, AE, safety, multikinase inhibitor, meta-analysis

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